Photo: Vegetables by Peter Gloviczki
ACCORDING TO recent estimates, the human body has 30 trillion cells. Cells are the elementary components of all tissues and organs, such as the heart, liver, blood vessels, etc. At the cellular level, the human body is composed of three components: cells, extracellular fluids and extracellular solids. Proteins make up 27% of the solid cell mass, while the other 70% of the cell mass is made up of intracellular water.
Extracellular fluid is composed of 98% water, one percent protein and one percent other materials.1 In young, healthy adults this composition maintains homeostasis with constant parameters despite the variable environment. A cell’s life consists of ongoing metabolic processes, including cell division, renewal of organelles and all structures, and finally, death. No one atom in our bodies has stayed in place since we were conceived. According to the Greek philosopher Heraclitus, our world is based on constant change, which he called “panta rhei” (everything flows), positing that “no man ever steps in the same river twice.” Our replacement material comes from our food/nutrition and water. We are what we eat.
How Do Foods and Nutrition Interact With Our Vascular Health?
Since 1990, cardiovascular diseases (CVD) have been ranked as the number one cause of mortality in the United States, ahead of cancer and neurological disorders. CVD global mortality is estimated to occur in 17.7 million individuals. Interestingly, a major part of cardiovascular morbidity and mortality is related to well-identified, modifiable risk factors.2 In the Prospective Urban Rural Epidemiology (PURE) study,2 the authors followed 155,722 participants, exempt of cardiovascular diseases, from 21 countries with high, middle and low incomes. The median follow-up was 9.5 years. An estimated 70% of the cardiovascular diseases and related deaths were preventable in high-income countries. Among the list of modifiable risk factors, poor diet played a considerable role, as well as air pollution.
In the limited frame of this article, I will focus on the existing scientific evidence of how fruits, vegetables and nutraceuticals affect our vascular health.
Fruit and CVD
Fruit is a known ally in the prevention of CVD. The three most prevalent cardiovascular risk factors are high blood pressure, smoking and a diet low in fruit.3,4 Several positive effects of a diet high in fruit have been proven, such as reduced blood pressure, regulation of blood lipids and platelets, inhibition of thrombosis and inflammation, improved endothelial function, alleviation of ischemia/reperfusion injury and reduction of oxidative stress. Oxidative stress is heavily involved in the pathophysiology of endothelial dysfunction and CVD. Mitochondria are the main producers of reactive oxygen species (ROS), using, among others, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases or the NOX family of enzymes. Natural compounds such as hesperidin are NOX inhibitors5 and they may be beneficial by decreasing oxidative stress and modulating NOX in hypertensive patients.5 Hesperidin is present in citrus fruit, and it is included in the nutritional supplement, micronized purified flavonoid fraction (MPFF, Vein Formula as manufactured by VitasupportMD in the United States).
The scope of positive effects and properties are variable between grapes, blueberries, apples, pomegranates and others, but all demonstrate a protective cardiovascular activity.
Photo: Fruits by Peter Gloviczki
Apples in particular were shown to improve endothelial function thanks to their high content of flavonoids, predominantly located under the apple skin.6 An overview of 27 prospective cohort studies, assessing the correlation between an intake of flavonoids and CVD risk, concluded that “consumption of flavonoid-rich foods or diets higher in flavonoids appear nutritionally beneficial in the prevention of CVD.”7
Phenolic blueberry metabolites were reported to improve vascular function,8 although their mechanism of action is still unclear.
Grapes contain bioactive phenolic compounds, or polyphenols, characterized by antioxidant, cardioprotective, anticancer, anti-inflammation, anti-ageing and antimicrobial properties.9 Although the effects of grapes and wine produced from grapes certainly differ, these effects are part of the explanation of the “French paradox,” the relationship between moderate wine consumption and CVD, and of the advantages of the Mediterranean diet.
Historical findings on Masquelier’s original grape seed-derived flavanol extract suggest “a vitamin-like action on capillary function.”10 Several studies using grape seed extracts or red grape cell powder showed a decrease in blood pressure, mostly in individuals with hypertension.
Polyphenols represent the largest diversified group of plant metabolites. They can be divided into two families: the flavonoids, with common C6-C3-C6 structure, and non-flavonoids. Cholesterol metabolism is affected by polyphenols decreasing cholesterol absorption and transport to the liver. Other effects include modifications of apolipoprotein A and B, very-low-density lipoproteins (VLDL), triglyceride, and low-density lipoproteins (LDL) plasma levels.
One of the polyphenols, resveratrol, showed a significant improvement in endothelial function (flow-mediated vasodilation) and a decrease in LDL levels in a double-blind, placebo-controlled trial.11 In addition, resveratrol may target pathways involved in atrial fibrillation.9 Some studies with grapes and grape juice suggest related improvement of platelet function.9
Although there is no agreement on a recommended quantity and on the type of nutrient (grape juice, grape seed extract, compound like resveratrol, white or red wine), the scientific evidence supports the hypothesis that grapes and wine polyphenols have beneficial effects, including an inhibition of platelet aggregation and a decrease in LDL oxidation, oxidative stress, blood lipids, inflammation and possibly blood pressure.9 On a lighter note, port wine was a central part of the diet of French supercentenarian Jeanne Calment, who lived an amazing 122 years.
Healthy nutrition with an abundance of polyphenols such as flavonoids, flavones, and flavanols from fruit promotes the beneficial composition of microbiota and prevents CVD thanks to the stimulation of Bifidobacterium and Lactobacillus. Dietary flavonoids have a significant impact on human endothelial function in peripheral and cerebral vessels.12 Flavonoid effects, measured by flow-mediated dilation, could therefore not only improve on CVD, but also on cerebrovascular health. The citrus flavonoids hesperidin, diosmin, and apigenin demonstrated protective activity in a hypoperfusion-reperfusion injury animal model.13 Leukocyte adhesion, microvascular leakage, and edema were reduced. Moreover, some flavonoids are clearly synergistic, like diosmin-hesperidin.14 The role of natural flavonoids in thrombotic, cardiovascular and inflammatory diseases was the topic of a recent review15 that found that antioxidant flavonoids reduced oxidative stress, platelets’ hyper-activation, and the risk of thrombosis.
Vegetables and CVD
Vegetables are universally considered to be beneficial to cardiovascular health.16,17 Beets, lettuce, and spinach are particularly rich in nitrates. Strong evidence suggests that the derivatives of vegetable nitrates (80% of dietary nitrates) have an effect on the vasodilatory nitric oxide (NO) balance and L-arginine-NO synthase.18
A diet rich in vegetables, therefore, plays an important role in vascular and cardiac health. The L-arginine- NO synthase pathway is stimulated in response to biochemical and mechanical trigger factors such as thrombin and shear stress. Endothelial alteration constitutes of an initial stage of vascular diseases, a stage that includes proinflammatory and prothrombotic modifications and is related to risk factors of cardiovascular diseases. NO is essential for these vasodilatory, antithrombotic, antiatherogenic, and antiproliferative properties.18 In fact, NO plays a role in the chain of events suppressing platelet activity through effect on cGMP, resulting in a decrease in intracellular platelet Ca2+ levels and of platelets aggregation.18 Even more, NO suppresses leucocytes migration and adhesion and prevents smooth muscle cell proliferation. However, some concerns have also been raised about the carcinogenic potential of nitrate and nitrite.19
Potatoes, tomatoes, onions, lettuce, celery, broccoli, asparagus and others are sources of essential elements, including the vitamins, fibers and bioactive substances involved in vasculo- protective mechanisms such as antioxidation, anti-inflammation, and anti-platelet activities.20
Leafy greens (spinach, kale, and others), asparagus, cabbage, broccoli, Brussels sprouts, turnips, avocados, kiwis, and grapes are essential sources of Vitamin K1. Sauerkraut is rich in Vitamin K2 (VK2). Both isoforms of Vitamin K are co-factors of the enzyme gamma-glutamyl carboxylase involved in hemostasis and are indispensable for anti-hemorrhagic activity.21 Interestingly, VK2 also intervenes in osteoporosis regulation, atherosclerosis, cancer and inflammatory diseases. It protects against vascular calcifications and improves vascular elasticity.21 Its supplementation demonstrated beneficial effects in treatment of liver cirrhosis and in renal function improvement in patients with chronic kidney disease.21 Ex vivo studies showed the immunomodulatory role of VK2 through the expression of TNF-alpha, IL-1alpha and beta, as well as decreased activation and proliferation of T-cells. Cohort human studies with VK2 administration suggested overall optimization of glucose and fat metabolism (better diabetes control, decreased weight and waist circumference). Recent research also attributed VK2’s protective properties on neurons to the P38 Mitogen-Activated Protein kinase pathway,21 responsive to different stress stimuli.
Based on a systematic review and meta-analysis of 95 studies,22 an estimated 7.8 million premature deaths recorded by the World Health Organization in 2013 were attributable to a low intake of fruit and vegetables. Optimal intake, corresponding to the lowest risk, was defined by the authors as 800 g/day or 10 servings/day for cardiovascular protection.
Nutraceuticals or Nutritional Supplements
One of the most well-known nutritional supplements is garlic (Allium sativum L). Evidence supports its beneficial effect on the cardiovascular system and in particular on atherosclerosis, hypertension and hyperlipidemia.23 In several recent studies, Curcumin, a component of turmeric, has also shown cardiovascular protective properties related to inflammation and oxidative stress pathways.24
Data has been inconsistent as to the advantageous effects of the most frequently used supplements such as multivitamins, vitamin C and D, coenzyme Q, calcium and selenium.25,26 Of course, confirmed iron deficiency should be treated, but the use of iron supplements by healthy individuals has not demonstrated any beneficial effects. Vitamins B6 and B12 with folic acid seem to contribute to decrease stroke prevalence.25 On the contrary, Niacin or vitamin B3 may even increase all-cause mortality.
Magnesium is involved in normal cellular metabolism, heart rhythm control, vascular tone regulation, atherogenesis, thrombosis, vascular calcification, and proliferation and migration of endothelial and vascular smooth muscle cells.27 Its use for constipation and dyspepsia is considered a part of standard care.28 However, no recommendation for CVD prevention or treatment could be drawn based on existing evidence with magnesium supplementation, with the exception of cases of documented hypomagnesemia.
Meta-analyses of observational studies with vitamin D inversely correlated cardiovascular risk with vitamin D levels.29 This could not be confirmed with the available results of randomized controlled trials, despite known cardiovascular manifestations of vitamin D deficiency: vascular dysfunction, arterial stiffening, left ventricular hypertrophy and hypertension.30
“Nutraceutical” is a term derived from “nutrition” and “pharmaceutical.” It is defined as “food or part of a food that provides medical or health benefits, including the prevention and/or treatment of a disease.”31,32 This principle was expressed by Hippocrates in Ancient Greece, who said “let food be your medicine.” Nutraceuticals or dietary supplements can contain vitamins, minerals, herbal extracts, metabolites of natural compounds or a combination of listed ingredients. They avoid the side effects of synthetic drugs, are often easily available and affordable, and may improve medical conditions.
There are seven categories of nutraceuticals: dietary fiber, probiotics, prebiotics, polyunsaturated fatty acids, antioxidant vitamins, polyphenols and spices.
The polyphenol family is important for the treatment and prevention of vascular and particularly venous and lymphatic disorders. Several nutraceuticals are qualified as venoactive or phlebotropic drugs. Among them, probably the most studied and prescribed is micronized purified flavonoid fraction (MPFF, Vein Formula as manufactured by VitasupportMD in the United States), a semi-synthetic preparation composed of 90% diosmin and 10% bioflavonoids expressed as hesperidin.33 A recent review and meta-analysis of randomized, double-blind, placebo-controlled trials concluded that “based on high quality evidence, MPFF is highly effective in improving leg symptoms, edema and quality of life in patients with chronic venous disease.”34 MPFF beneficial effects are related to its mechanism of action:35 enhancement of sympathetic-mediated venous contractility and calcium sensitivity; reduction of leukocyte adhesion; inhibition of production of leukocyte adhesion molecules; mitigation of venous valve deterioration and reflux; inhibition of the production of proinflammatory factors; increase of antioxidant enzyme ratios; reduction of endothelial cell activation; decrease of the serum concentrations of ICAM-1, VCAM, VEGF; increase in capillary resistance and reduction of capillary leakage.
Clinical observations included improved venous tone, reduced leg edema, improved skin trophic disorders, ulcer healing, reduction in chronic venous disease symptoms and higher quality of life.
Different venoactive supplements are known, such as rutosides, calcium dobesilate and sulodexide.35
The therapeutic potential of flavonoids in chronic venous insufficiency were shown for MPFF (as found in Vein Formula), natural pine bark extract (Pycnogenol), triterpene saponins, Ruscus aculeatus extract, centella asiatica, Ginkgo biloba extract and coumarin derivatives.36
Beside their antioxidant, anti-inflammatory and anticancer properties, Hesperidin and its aglycone hesperetin also protect against microbes and toxins.37 The proposed involved mechanism is the interaction with microbial enzymes. Hesperidin was investigated as the only compound potentially blocking the COVID-19 virus’ entry into lung cells.38 Other effects, such as the antidepressant effect of flavonoids, could be related to the protection of the neuroendocrine and immune systems.39
Fruits, vegetables and nutraceuticals have a significant effect on vascular health. Food choice is frequently the reflection of personal taste, budget and cultural tradition. Most healthy dietary patterns, however, like the Mediterranean diet, recommend a high intake of vegetables and fruits, as well as whole grains, nuts, healthy oils, fish and white meat. A moderate consumption of red wine is a part of this diet.
The key recommendations of the Dietary Guidelines for Americans 2020-202540 are that a healthy diet should include vegetables of all types (dark green; red and orange; beans, peas and lentils; starchy; and other vegetables), fruits, but also grains, dairy (fat-free or low-fat milk, yogurt and cheese, and/ or lactose-free versions and fortified soy beverages and yogurt as alternatives), protein (lean meats, poultry and eggs; seafood; beans, peas and lentils; nuts, seeds and soy products), oils from vegetables, seafood and nuts.
A diet poor in fruits and vegetables is one of the leading modifiable risk factors for vascular health. The optimal intake of fruits and vegetables is defined as 800 g/day or 10 servings/day for cardiovascular protection.
Nutraceutical products available in the United States can also help in the prevention and treatment of cardiovascular diseases.
The author was employed for 15 years by the French pharmaceutical company Servier, a manufacturer of MPFF, and worked as the Project Leader of the Therapeutic Angiology Division. She is currently Chief Scientific and Clinical Advisor to VitasupportMD, a nutraceutical company in the United States, producing MPFF as the dietary supplements Vein Formula, Lymphatic Formula and Hemorrhoid Formula.
- Wang Z, Heymsfield SB, Pi-Sunyer FX, Gallagher D, Pierson RN, Jr. Body composition analysis: Cellular level modeling of body component Int J Body Compos Res 2008;6:173-84.
- Yusuf S, Joseph P, Rangarajan S, et al. Modifiable risk factors, cardiovascular disease, and mortality in 155 722 individuals from 21 high-income, middle-income, and low-income countries (PURE): a prospective cohort study. Lancet 2020;395:795-808
- Zhao CN, Meng X, Li Y, et Fruits for Prevention and Treatment of Cardiovascular Diseases. Nutrients 2017;9.
- Ezzati M, Riboli E. Behavioral and dietary risk factors for noncommunicable N Engl J Med 2013;369:954-64.
- Yousefian M, Shakour N, Hosseinzadeh H, Hayes AW, Hadizadeh F, Karimi The natural phenolic compounds as modulators of NADPH oxidases in hypertension. Phytomedicine 2019;55:200-13.
- Bondonno NP, Bondonno CP, Blekkenhorst LC, et Flavonoid-Rich Apple Improves Endothelial Function in Individuals at Risk for Cardiovascular Disease: A Randomized Controlled Clinical Trial. Mol Nutr Food Res 2018;62.
- Parmenter BH, Croft KD, Hodgson JM, et An overview and update on the epidemiology of flavonoid intake and cardiovascular disease risk. Food Funct 2020;11:6777-806.
- Wood E, Hein S, Heiss C, Williams C, Rodriguez-Mateos A. Blueberries and cardiovascular disease prevention. Food Funct 2019;10:7621-33.
- Rasines-Perea Z, Teissedre Grape Polyphenols’ Effects in Human Cardiovascular Diseases and Diabetes. Molecules 2017;22.
- Weseler AR, Bast Masquelier’s grape seed extract: from basic flavonoid research to a well-characterized food supplement with health benefits. Nutr J 2017;16:5.
- Magyar K, Halmosi R, Palfi A, et Cardioprotection by resveratrol: A human clinical trial in patients with stable coronary artery disease. Clin Hemorheol Microcirc 2012;50:179-87.
- Rees A, Dodd GF, Spencer The Effects of Flavonoids on Cardiovascular Health: A Review of Human Intervention Trials and Implications for Cerebrovascular Function. Nutrients 2018;10.
- Mastantuono T, Battiloro L, Sabatino L, et Effects of Citrus Flavonoids Against Microvascular Damage Induced by Hypoperfusion and Reperfusion in Rat Pial Circulation. Microcirculation 2015;22:378-90.
- Paysant J, Sansilvestri-Morel P, Bouskela E, Verbeuren Different flavonoids present in the micronized purified flavonoid fraction (Daflon 500 mg) contribute to its anti-hyperpermeability effect in the hamster cheek pouch microcirculation. Int Angiol 2008;27:81-5.
- Vazhappilly CG, Ansari SA, Al-Jaleeli R, et Role of flavonoids in thrombotic, cardiovascular, and inflammatory diseases. Inflammopharmacology 2019;27:863-9.
- Bazzano LA, Serdula MK, Liu Dietary intake of fruits and vegetables and risk of cardiovascular disease. Curr Atheroscler Rep 2003;5:492-9.
- Ness AR, Powles JW. Fruit and vegetables, and cardiovascular disease: a review. Int J Epidemiol 1997;26:1-13.
- Bondonno CP, Croft KD, Hodgson JM. Dietary Nitrate, Nitric Oxide, and Cardiovascular Health. Crit Rev Food Sci Nutr 2016;56:2036-52.
- Hord NG, Tang Y, Bryan NS. Food sources of nitrates and nitrites: the physiologic context for potential health benefits. Am J Clin Nutr 2009;90:1-10.
- Tang GY, Meng X, Li Y, Zhao CN, Liu Q, Li HB. Effects of Vegetables on Cardiovascular Diseases and Related Mechanisms. Nutrients 2017;9.
- Halder M, Petsophonsakul P, Akbulut AC, et al. Vitamin K: Double Bonds beyond Coagulation Insights into Differences between Vitamin K1 and K2 in Health and Disease. Int J Mol Sci 2019;20.
- Aune D, Giovannucci E, Boffetta P, et al. Fruit and vegetable intake and the risk of cardiovascular disease, total cancer and all-cause mortality-a systematic review and dose-response meta-analysis of prospective studies. Int J Epidemiol 2017;46:1029-56.
- Alali FQ, El-Elimat T, Khalid L, Hudaib R, Al-Shehabi TS, Eid AH. Garlic for Cardiovascular Disease: Prevention or Treatment? Curr Pharm Des 2017;23:1028-41.
- Li H, Sureda A, Devkota HP, et al. Curcumin, the golden spice in treating cardiovascular diseases. Biotechnol Adv 2020;38:107343.
- Ingles DP, Cruz Rodriguez JB, Garcia H. Supplemental Vitamins and Minerals for Cardiovascular Disease Prevention and Treatment. Curr Cardiol Rep 2020;22:22.
- Sunkara A, Raizner A. Supplemental Vitamins and Minerals for Cardiovascular Disease Prevention and Treatment. Methodist Debakey Cardiovasc J 2019;15:179-84.
- Tangvoraphonkchai K, Davenport A. Magnesium and Cardiovascular Disease. Adv Chronic Kidney Dis 2018;25:251-60.
- Guerrera MP, Volpe SL, Mao JJ. Therapeutic uses of magnesium. Am Fam Physician 2009;80:157-62.
- Skaaby T, Thuesen BH, Linneberg A. Vitamin D, Cardiovascular Disease and Risk Factors. Adv Exp Med Biol 2017;996:221-30.
- Al Mheid I, Quyyumi AA. Vitamin D and Cardiovascular Disease: Controversy Unresolved. J Am Coll Cardiol 2017;70:89-100.
- Chauhan B, Kumar G, Kalam N, Ansari SH. Current concepts and prospects of herbal nutraceutical: A review. J Adv Pharm Technol Res 2013;4:4-8.
- Das L, Bhaumik E, Raychaudhuri U, Chakraborty R. Role of nutraceuticals in human health. J Food Sci Technol 2012;49:173-83.
- Gloviczki ML. Micronized Purified Flavonoid Fraction (MPFF) for Chronic Venous and Lymphatic Disorders. Vein Therapy News 2021;14:1, 10, 20, 2.
- Kakkos SK, Nicolaides AN. Efficacy of micronized purified flavonoid fraction (Daflon(R)) on improving individual symptoms, signs and quality of life in patients with chronic venous disease: a systematic review and meta-analysis of randomized double-blind placebo-controlled
trials. Int Angiol 2018;37:143-54.
- Mansilha A, Sousa J. Pathophysiological Mechanisms of Chronic Venous Disease and Implications for Venoactive Drug Therapy. Int J Mol Sci 2018;19.
- Lichota A, Gwozdzinski L, Gwozdzinski K. Therapeutic potential of natural compounds in inflammation and chronic venous insufficiency. Eur J Med Chem 2019;176:68-91.
- Iranshahi M, Rezaee R, Parhiz H, Roohbakhsh A, Soltani F. Protective effects of flavonoids against microbes and toxins: The cases
of hesperidin and hesperetin. Life Sci 2015;137:125-32.
- Haggag YA, El-Ashmawy NE, Okasha KM. Is hesperidin essential for prophylaxis and treatment of COVID-19 Infection?
Med Hypotheses 2020;144:109957.
- Khan H, Perviz S, Sureda A, Nabavi SM, Tejada S. Current standing of plant-derived flavonoids as an antidepressant. Food
Chem Toxicol 2018;119:176-88.
- USDA. UDoHaHSa. Dietary Guidelines for Americans, 2020-2025. 2020.