The Vitamin K Way
NO isn’t the only game in town for improving endothelial function, says Eric Anderson, global vice president, sales and marketing, NattoPharma USA Inc. (Metuchen, NJ). He notes that calcium regulation in the vessels is crucial, too.
“Calcium accumulation in the arteries is an actively regulated process, strongly influenced by matrix Gla-protein, or MGP-the most potent inhibitor of calcification presently known,” he explains. But for MGP to inhibit calcification effectively, vitamin K2 must activate it via a carboxylation reaction. If insufficient vitamin K2 is available to do so, MGP remains insufficiently carboxylated and unable to function. This hampers removal of calcium from the arteries and increases the risk of blood-vessel calcification. Even worse, Anderson says, “Since this process occurs in the vessel wall, it leads to thickening of the wall via calcified plaques-that is, typical atherosclerosis progression-which is associated with a higher risk of cardiovascular events.”
All of which argues for looking at vitamin K supplementation as a healthy hedge. A study3, published in Thrombosis and Haemostasis in May 2015, involved 244 healthy, postmenopausal women who supplemented with 180 mcg of vitamin K2 in the long-acting MK-7 form (NattoPharma’s MenaQ7) or placebo. Carotid artery distensibility-a sign of a vessel’s elasticity, or ability to stretch or dilate-improved significantly over a three-year period in the treatment group compared to the placebo. “Also,” Anderson says, “pulse-wave velocity significantly decreased in the vitamin K2 group, but not the placebo group, demonstrating an increase in elasticity.” At the study’s conclusion, the beta stiffness index, a measure of arterial stiffness, in the MK-7 group with high initial arterial stiffness had fallen significantly, whereas the same measure in the placebo group had risen slightly. “Results confirmed that a nutritional dose of 180 mcg MenaQ7 taken daily for three years not only inhibited age-related stiffening of the artery walls but also made a statistically significant improvement in vascular elasticity,” Anderson says.
Incidentally, a more recent study, a rat study4 published in the journal Nutrients, hints that MenaQ7 Pure, a synthetic form of vitamin K2 MK-7 that NattoPharma recently added to its MenaQ7 line, may inhibit cardiovascular muscle damage caused by chronic kidney disease. Kidney disease patients often suffer from cardiovascular complications such as calcification of the aorta and coronary arteries, so the researchers created an in vivo rat model system for kidney disease to study MenaQ7 Pure’s effect on cardiovascular health. The researchers found that MenaQ7 Pure supplementation “inhibited cardiovascular calcification and decreased aortic alkaline phosphatase tissue concentrations.” They hypothesized that “the protective effect of MK-7 may be related to the inhibition of secondary mineralization of damaged vascular structures.” The researchers concluded that, based on the study findings, the ingredient could be a “promising therapeutic agent” in protecting against cardiovascular calcification. “Being able to provide the researchers with our new nature-identical MenaQ7 Pure to add to our growing body of clinical validation marks a true milestone for us,” said Hogne Vik, CEO, NattoPharma, in a press release.
At this October’s SupplySide West trade show, Kate Quackenbush, director of communications, NattoPharma, added that, “Most of our studies utilize our natural material, MenaQ7, but this was the first legitimate, peer-reviewed publication using the PURE version. So it was good to see. We’ve done bioequivalency studies that have shown our PURE material is equivalent to our original source material, which has been utilized in most of the studies, so this was just another piece of that puzzle showing that we’re going to start doing clinical validation on the PURE now that it’s out to market.” She said the company plans to pursue further studies exploring how the benefits of the synthetic PURE form compare to the benefits of natural-form MenaQ7.
Long Odds for Long Chains?
What about the role of the long-chain polyunsaturated fatty acids (PUFAs) docosahexaenoic acid (DHA) plus eicosapentaenoic acid (EPA)? These omega-3 fatty acids have received praise for delivering all sorts of health benefits, including cardiovascular ones. What aid, if any, can they bring to endothelial function?
According to Harry B. Rice, PhD, vice president of regulatory and scientific affairs, the Global Organization for EPA and DHA (GOED: Salt Lake City), the jury’s still kinda out. “Although current evidence suggests a possible role for EPA+DHA in improving endothelial function,” he says, “larger-scale, high-quality clinical trials are needed to evaluate these effects before we can come to a more definitive conclusion about their role in endothelial health and function.”
Until then, scientists are learning more about cellular markers of endothelial damage and repair, including the damage indicators known as endothelial microparticles (EMPs) and the repair compounds known as endothelial progenitor cells (EPCs). A 2014 study5 in the American Journal of Clinical Nutrition showed that, compared to a placebo, supplementation with 1.5 g/day of EPA+DHA fish oil increased the number of repair-associated EPCs while reducing the number of EMP (endothelial matrix component) damage markers. “The overall result potentially favors the maintenance of endothelial integrity,” Rice says. “Assuming the results can be replicated, then it’ll be time to determine clinical relevance.”
Further, by crunching data from a prospective population study6, authors reported in a 2014 article on the relationship between baseline plasma phospholipid PUFAs-including long-chain omega-3s-and arterial stiffness over five years. The findings: higher concentrations of long-chain omega-3s were associated with lower carotid-femoral pulse-wave velocity (cf-PWV). “This suggests that EPA and DHA have a positive effect on endothelial function,” Rice says.
And in another study7 published the same year in Biomedicine & Pharmacotherapy, 10 subjects received either 4 g/day of EPA+DHA or a placebo in a four-week, crossover-design trial. Among other measurements, researchers assessed the participants’ endothelial function using flow-mediated dilation and found that the omega-3 combination reduced endothelial dysfunction compared to the placebo. “While the short-term results look good,” Rice says, “the long-term implications have yet to be determined.”
So at least as far as EPA+DHA is concerned, caution is in order. But still: hope springs eternal. And on the topic of endothelial improvement, Salas Rushford is hopeful. “Our cardiovascular health is maintained by a very complex and tightly regulated system in which endothelial cells play a crucial role,” he says. “The study of how these cells behave and react to injury will bring to light options for prevention and treatment of many diseases. It’s becoming apparent that nutritional therapies will play a synergistic role with medication and lifestyle modifications in the treatment of chronic diseases.”
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2. Hu S et al., “Effects of Pycnogenol® on endothelial dysfunction in borderline hypertensive, hyperlipidemic, and hyperglycemic individuals: the borderline study,” International Angiology, vol. 34, no. 1 (February 2015):43-52
3. Knapen MHJ et al., “Menaquinone-7 supplementation improves arterial stiffness in healthy postmenopausal women. A double-blind randomised clinical trial,” Thrombosis and Haemostasis, vol. 113, no. 5 (May 2015): 1135–1144
4. Scheiber et al., “High-dose menaquionone-7 supplementation reduces cardiovascular calcification in a murine model of extraosseous calcification,” Nutrients, vol. 7, no. 8 (August 2015): 6991-7011
5. Wu SY et al., “Fish-oil supplementation alters numbers of circulating endothelial progenitor cells and microparticles independently of eNOS genotype,” American Journal of Clinical Nutrition, vol. 100, no. 5 (November 2014): 1232-1243
6. Reinders I et al., “Phospholipid n-3 PUFAs, but lower n-6 PUFAs, are associated with lower pulse wave velocity among older adults,” The Journal of Nutrition. Published online August 26, 2015
7. Miyoshi T et al., “Omega-3 fatty acids improve postprandial lipemia and associated endothelial dysfunction in healthy individuals-a randomized cross-over trial,” Biomedicine & Pharmacotherapy, vol. 68, no. 8 (October 2014): 1071-1077
8. A Jennings et al., “Amino acid intake is inversely associated with arterial stiffness and central blood pressure in women,” Journal of Nutrition, vol. 145, no. 9 (September 2015): 2130-2138