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Health Protocols

Atherosclerosis and Cardiovascular Disease

Targeting Vascular Disease Risk Factors with Nutritional Therapeutics

Scientific studies have revealed that several nutrients effectively protect against endothelial dysfunction caused by the atherogenic factors identified above. Unlike mainstream medicine’s approach to treating atherosclerosis, which involves addressing only very few proven cardiac risk factors, a comprehensive nutritional regimen can be designed to target all of the risk factors that contribute to atherosclerosis.

Omega-3 fatty acids. Studies have shown that omega-3 fatty acids combat the development and progression of vascular disease via multiple mechanisms including, lowering triglycerides, lowering blood pressure, improving endothelial function and raising HDL levels (Robinson, 2006).

A team of researchers examined the correlation between tissue omega-3 fatty acid levels and measures of circulating Lp-PLA2, a marker of inflammatory arterial plaque, in over 300 patients. They found a strong, independent and inverse association between tissue omega-3 levels and circulating Lp-PLA2. The researchers went on to conclude that intake of omega-3 fatty acids might reduce Lp-PLA2 levels and reduce the risk of vascular disease (Schmidt, 2008).

In another study involving 563 elderly men, 2.4 grams per day of omega-3 fatty acid supplementation was found to improve arterial elasticity (Hjerkinn, 2006).

In 16 patients with peripherial artery disease who were already being treated with conventional methods, the addition of 2 grams daily of omega-3 fatty acids was shown to significantly improve endothelial function, as measured by brachial artery flow-mediated dilation (from 6.7% to 10.0%) and plasma soluble thrombomodulin (from 33.0 ng/mL to 17.0 ng/mL) (Schiano, 2008). Similarly, another study found that when omega-3 fatty acids were combined with rosuvastatin, the combination improved endothelial dependent vasodilation (-1.42% to 11.36%) while rosuvastatin alone failed to improve endothelial function (Mindrescu, 2008).

Propionyl L-carnitine (PLC). PLC has received attention for its ability to directly improve endothelial function. PLC passes across the mitochondrial membrane to supply L-carnitine directly to the mitochondria, the energy-producing organelles of cells. Carnitines are essential for mitochondrial fatty acid transport and energy production, which is important because endothelial cells and heart muscle cells burn fatty acids for 70 percent of their energy. By contrast, most other cells generate 70 percent of their energy from glucose and only 30 percent from fatty acids (Kaiser KP, 1987).

In human studies, PLC produced significant improvement in maximum walking distance with claudication (sclerotic peripheral vascular disease) and had no major side effects (Wiseman LR et al 1998). Another study found that PLC significantly reduced homocysteine levels when administered intravenously to hemodialysis patients (Signorelli, 2006).

Animal studies suggest PLC may help prevent or decrease the severity of vascular disease. In rabbits fed a high-cholesterol diet, which normally induces endothelial dysfunction and subsequent atherosclerosis, supplementation with PLC resulted in reduced plaque thickness, markedly lower triglyceride levels and reduced proliferation of foam cells (Spagnoli, 1995).

PLC also improves endothelial function by increasing nitric oxide production in animals with normal blood pressure and in animal models of hypertension. Nitric oxide is important because it helps keep arteries open. The increased nitric oxide production induced by PLC is related to its antioxidant properties; PLC reduces reactive oxygen species and increases nitric oxide production in the endothelium in the presence of the antioxidative enzymes superoxide dismutase and catalase (Bueno R et al 2005).

L-arginine. This amino acid has attracted attention for its ability to improve endothelial function. L-arginine serves as the precursor of nitric oxide in the endothelium (Cockcraft JR 2005). To find out whether L-arginine improved arterial function in people with peripheral arterial disease, as well as determine an optimal oral dose, a group of researchers from the University of California, San Francisco, looked at L-arginine’s ability to improve walking distance and walking speed among people with peripheral arterial disease. The research group found in a pilot study of 80 patients that 3 g L-arginine daily improved both walking speed and distance (Oka RK et al 2005).

Another study looked at the effects of oral L-arginine in patients with stable coronary artery disease. The team found that L-arginine therapy of 10 g daily improved brachial artery dilation, a measure of endothelial function (Yin WH et al 2005).

CoQ10. CoQ10 is critically important for vascular health, as it is directly involved in the production of ATP, the “energy currency” of the human body. Because the heart is a muscle that never rests, it needs a substantial amount of CoQ10. CoQ10 levels in heart tissue decline disproportionately with age. At age 20, the heart has a higher CoQ10 level than other major organs. At age 80 this is no longer true, with heart levels cut by more than half (Kalen, 1989). CoQ10 pioneer Karl Folkers (1985), in agreement with other Japanese studies, found lower CoQ10 levels in patients with more severe heart disease and showed that CoQ10 supplements significantly raised blood and heart tissue levels of CoQ10 in these patients.

In addition to its involvement in energy production, CoQ10 is also a potent antioxidant. CoQ10 is the first line of defense against LDL oxidation; oxidized LDL is a major contributor to endothelial dysfunction (Thomas, 1995).

CoQ10, in combination with vitamins C, E and selenium, was shown in a randomized controlled trial to significantly improve arterial elasticity in patients with multiple cardiovascular risk factors. The authors found that the antioxidant-induced increases in arterial elasticity were associated with improved glucose and lipid metabolism, as well as decreased blood pressure (Shargorodsky, 2010).

In an animal study, CoQ10 supplementation was shown to improve endothelial function, as measured by thoracic aorta nitric oxide availability and blood pressure (Graham, 2009).

Pomegranate. For HDL to perform its vital functions, an enzyme called paraoxonase-1 (PON-1) is attached to its surface. PON-1 serves to protect HDL from oxidation, which impairs its ability to protect arteries. As humans age, PON-1 levels markedly decline, thereby reducing the ability of HDL to protect against heart attack and stroke. This phenomenon helps explain the onset of accelerated atherosclerosis; where within a period of only a few years, an aging person’s healthy arteries rapidly occlude with plaque. In addition to its ability to protect HDL against oxidation, PON-1 has also been shown to hydrolyze (break apart) homocysteine thiolactones, which are responsible for damage to blood vessels. So PON-1, on its own, is a blood vessel protector (Jakubowski, 2001).

Lipid peroxidation is a free radical reaction that severely damages cell membranes and is implicated in a host of degenerative diseases. PON-1 blocks destructive lipid peroxidation reactions, making it a crucial enzyme for aging humans to maintain (Rozenberg, 2003; Leus, 2000; Sapian-Paczkowska, 2010; Ikeda, 2007).

Research indicates that pomegranate and its extracts can significantly elevate levels of PON-1 activity in the body. Pomegranate does this through a number of distinct biomolecular pathways that include combating inflammation and LDL adhesion and favorably modulating gene expression. Pomegranate extracts reduce oxidation and inflammation largely through their effect on PON-1 activity, intervening at each step in the development of atherosclerosis (Aviram, 2000).

Researchers studied the effects of pomegranate on human subjects who consumed pomegranate juice for 2 weeks. The team found dramatic reductions in LDL “clumping” and retention in vessels, accompanied by a 20% increase in PON-1 activity (van Himbergen, 2006).

In atherosclerosis-prone mice supplemented with pomegranate, a 90% reduction in oxidation of LDL cholesterol was seen. Supplemented mice also developed atherosclerotic lesions 44% smaller than controls, an effect attributed to reduction in the number of inflammatory foam cells (van Himbergen, 2006).

Lipoic acid. This naturally occurring antioxidant serves as a coenzyme in energy metabolism of fats, carbohydrates, and proteins. It can regenerate thioredoxin (an antioxidant protein), vitamin C, and glutathione, which in turn can recycle vitamin E. Lipoic acid also helps manage proper serum glucose levels in diabetic patients (Packer, 2001). In animal studies, it has been shown to reduce endothelial dysfunction (Lee WJ et al 2005a). Human studies have found that lipoic acid improves endothelial function among people with metabolic syndrome (Sola, 2005). Lipoic acid works best in combination with antioxidants including vitamin E, coenzyme Q10, carnitine, and selenomethionine (Mosca, 2002).

Garlic. Aged garlic extract has been studied for its ability to reduce inflammation and the damaging effects of cholesterol in the endothelium (Orekhov,1995). In one study of 15 men with coronary artery disease who were also being treated with statin drugs and low-dose aspirin, two weeks of supplementation with aged garlic extract significantly improved blood flow by improving endothelial function (Williams, 2005).

Finally, high-dose garlic was studied in 152 individuals with clinically observable atherosclerotic plaque buildup. Over 48 months, the study participants experienced significantly less increase in plaque deposits than a control group, and a regression of plaque was seen in some participants, leading researchers to conclude that garlic had a “not only preventative but possibly also a curative role in arteriosclerosis therapy” (Koscielny,1999).

Ginkgo biloba. Several studies have shown that ginkgo favorable alters endothelial function and reduces levels of oxidized LDL (Kudolo GB et al 2003; Ou, 2009; Pierre, 2008). Ginkgo has also been shown to protect against the formation of foam cells (Tsai, 2010).

In a study involving eight patients who had recently undergone aortocoronary bypass surgery, supplementation with ginkgo biloba extract, 120 mg twice daily, was shown to reduce atherosclerotic plaque formation by 11.9% and reduce nanoplaque size by 24.4%. Furthermore, ginkgo increased levels of endogenous antioxidant enzymes and reduce levels of the dangerous oxidized-LDL (Rodriguez, 2007).

In an animal model, researchers found that ginkgo was effective in reducing high homocysteine-induced intimal thickening, indicating a reversal in the atherosclerotic process (Liu, 2008).

Resveratrol. Experiments have shown that the benefits of resveratrol include improvements in the health of the endothelial tissue lining blood vessels (Balestrieri, 2007; Ungvari, 2007; Wang, 2007; Ballard, 2007). One mechanism by which it does this is to facilitate the generation of endothelial progenitor stem cells, thereby providing the endothelium with fresh new cells.

Resveratrol benefits the circulatory system by eliciting a decrease in the oxidation of low-density lipoprotein (LDL); by fostering decreases in platelet aggregation; and by promoting relaxation of small blood vessels called arterioles (Nissen, 2006; Taylor, 2002; Crouse, 2007; Cloarec, 2007). Collectively, these mechanisms benefit the overall health of the cardiovascular system by decreasing factors that contribute to the development of atherosclerosis, and by decreasing the likelihood of undesirable clotting, which, in turn, decreases the risk of stroke (Opie, 2007). Furthermore, data indicate that resveratrol decreases the incidence of dangerous heart arrhythmias (Chen, 2007).

Quercetin. The so-called French paradox is the phenomenon of low rates of heart disease in a country known for its high intake of fatty foods. Recent research suggests that one of the reasons French people are protected from heart disease is a high intake of quercetin, a potent antioxidant and polyphenol found in red wine (Kuhlman, 2005) and certain vegetables. Numerous studies have examined quercetin and found it to be both a powerful antioxidant and a stimulator of nitric oxide, which inhibits endothelial proliferation, a hallmark of atherosclerosis (Kuhlman, 2005).

In spontaneously hypertensive rats, quercetin, along with other bioflavonoids, preserved endothelial function by increasing nitric oxide and reducing blood pressure (Machha, 2005).

A porcine study showed that quercetin has potent antioxidative properties and protects endothelial cells against induced dysfunction (Reiterer, 2004). Quercetin and resveratrol may work particularly well together.

Green tea extract. Green tea extracts, which are rich in natural antioxidants and antiplatelet agents, are routinely used in Asia to lower blood pressure and reduce elevated cholesterol. In studies of smokers, 600 mL green tea (not extract) was shown to decrease markers of inflammation and decrease oxidized cholesterol, both of which are intimately involved in the development of atherosclerosis (Lee W et al 2005b).

A Japanese study of 203 patients found that the more green tea patients drink, the less likely they are to suffer from coronary artery disease (Sano J et al 2004). This study supported an earlier study that found that greater green tea consumption was related to a reduced presence of coronary artery disease in Japanese men (Sasazuki S et al 2000).

Vitamin C (ascorbic acid). Vitamin C inhibits damage caused by oxidative stress. In cigarette smokers, daily supplementation with 500 mg vitamin C significantly decreased the appearance of oxidative stress markers (Dietrich M et al 2002). Another study showed that supplementation with 500 mg vitamin C and 400 IU vitamin E daily reduced the development of accelerated coronary arteriosclerosis following cardiac transplantation (Fang JC et al 2002).

Vitamin C’s benefits seem especially profound in people who suffer from both diabetes and coronary artery disease. One study demonstrated that, in this group, vitamin C significantly improved vasodilation (Antoniades C et al 2004).

Vitamin K. Vitamin K is steadily gaining attention for its ability to reduce vascular calcification and help prevent vascular disease (Jie KSG et al 1996). Evidence for the ability of vitamin K to prevent calcification can also be found in an animal study in which researchers administered the anticoagulant warfarin to rats. Warfarin is known to deplete vitamin K. At the end of the study, all the animals had extensive calcification, suggesting they had lost the protective effect of vitamin K (Howe AM 2000).

A large study of more than 4,800 subjects followed for 7-10 years in the Netherlands demonstrated that people in the highest one-third of vitamin K2 intake had a 57% reduction in risk of dying from vascular disease, compared to those with the lowest intake. Furthermore, their risk of having severe aortic calcification plummeted by 52%—a clear demonstration of the vitamin’s protective effects (Geleijnse, 2004).

Another study by the same group showed that higher vitamin K2 intake was associated with a 20% decreased risk of coronary artery calcification (Beulens, 2009).

Vitamin E. Vitamin E is often studied in conjunction with vitamin C for its potent antioxidant powers. It has been shown to decrease lipid peroxidation and inhibit smooth muscle cell proliferation, platelet aggregation, monocyte adhesion, oxidized LDL uptake, and cytokine production—all of which occur during sclerotic vascular disease (Munteanu A et al 2004; Harris A et al 2002).

In cultured arterial endothelial cells, vitamin E increased the production of prostacyclin, a potent vasodilator and inhibitor of platelet aggregation (Wu D et al 2004). Most vitamin E supplements come in the form of alpha tocopherol, but it is also important to supplement with around 200 mg of gamma tocopherol to gain vitamin E’s comprehensive benefits.

Several studies show that patients with advanced cardiovascular disease exhibit normal plasma levels of alpha tocopherol but have substantially lower levels of gamma tocopherol (Ohrvall, 1996; Kontush, 1999; Ohrvall, 1994). In a seven-year follow-up study of more than 334,000 postmenopausal women with no previous heart disease, greater intake of dietary vitamin E—consisting predominantly of gamma tocopherol—was strongly associated with a lower risk of death from cardiovascular disease. The data did not appear to demonstrate a similarly protective role for supplemental alpha tocopherol (Kushi, 1996).

Numerous animal studies likewise suggest that gamma tocopherol may provide powerful protection for the heart. In laboratory rats, supplementation with gamma tocopherol reduced platelet aggregation and clot formation even more effectively than alpha tocopherol (Saldeen, 1999). In addition, gamma tocopherol at physiological doses was more effective than alpha tocopherol in enhancing the activity of superoxide dismutase (SOD), an antioxidant enzyme that may help reduce the risk of cardiac events (Li, 1999).

Niacin. Niacin reduces VLDL particles. Less VLDL leads to less small-dense LDL (prone to oxidation and atherogenesis) and higher HDL (Carlson, 2005). Niacin also improves endothelial function and nitric oxide synthase activity.

Niacin’s benefits are not limited to its influence on blood markers of vascular disease risk. It also reduces heart attack risk dramatically. The Coronary Drug Project was the first to establish that niacin is a powerful agent in lowering heart attack risk. When more than 1,000 heart attack survivors were given 3000 mg of (immediate-release/crystalline) niacin daily for six years, the incidence of recurrent non-fatal heart attacks was reduced by 27%, and the number of strokes was reduced by 26% (Canner, 1986).

Gynostemma pentaphyllum. Gynostemma pentaphyllum (G. pentaphyllum) has long been used in traditional Asian medicine to promote health (Liu 2015). It activates a critical enzyme called adenosine monophosphate-activated protein kinase (AMPK) (Park 2014; Gauhar 2012; Nguyen 2011).

AMPK is found inside every cell (Shirwany 2014). It serves as a master regulating switch, affecting metabolism and longevity (Ulgherait 2014). Levels of activated AMPK decrease with age (Hardman 2014; Yang 2010; Mortensen 2009; Liu 2012; Salminen 2012; Rojas 2011).

Results of G. pentaphyllum-induced AMPK activation include increased fat burning, as well as an increase in cellular glucose uptake (Gauhar 2012; Nguyen 2011). Studies of G. pentaphyllum demonstrate considerable cardiovascular benefits (Circosta 2005; Gou 2016; Tanner 1999; Yu 2016).

A study in people with type II diabetes who were not taking any medications showed daily supplementation with G. pentaphyllum tea for 12 weeks reduced fasting blood sugar, hemoglobin A1C levels, and insulin resistance significantly more than placebo (Huyen 2010). A similar study in people with type II diabetes who were already taking the antidiabetic drug gliclazide showed adding G. pentaphyllum significantly reduced fasting blood sugar more than two-fold, and significantly lowered hemoglobin A1C as well (Huyen 2012). A study in obese individuals showed daily supplementation with G. pentaphyllum extract for 12 weeks significantly reduced body weight, total abdominal fat area, body fat mass, percentage body fat, and body mass index compared with placebo (Park 2014).

Hesperidin. Hesperidin and related flavonoids are found in a variety of plants, but especially in citrus fruits, particularly their peels (Umeno 2016; Devi 2015). Digestion of hesperidin produces a compound called hesperetin along with other metabolites. These compounds are powerful free radical scavengers and have demonstrated anti-inflammatory, insulin-sensitizing, and lipid-lowering activity (Li 2017; Roohbakhsh 2014). Findings from animal and in vitro research suggest hesperidin’s positive effects on blood glucose and lipid levels may be related in part to activation of the AMP-activated protein kinase (AMPK) pathway (Jia 2015; Rizza 2011; Zhang 2012). Accumulating evidence suggest hesperidin may help prevent and treat a number of chronic diseases associated with aging (Li 2017).

Hesperidin may protect against diabetes and its complications, partly through activation of the AMPK signaling pathway. Coincidentally, metformin, a leading diabetes medication, also activates the AMPK pathway. In a six-week randomized controlled trial on 24 diabetic participants, supplementation with 500 mg of hesperidin per day improved glycemic control, increased total antioxidant capacity, and reduced oxidative stress and DNA injury (Homayouni 2017). Using urinary hesperetin as a marker of dietary hesperidin, another group of researchers found those with the highest level of hesperidin intake had 32% lower risk of developing diabetes over 4.6 years compared to those with the lowest intake level (Sun 2015).

In a randomized controlled trial, 24 adults with metabolic syndrome were treated with 500 mg of hesperidin per day or placebo for three weeks. After a washout period, the trial was repeated with hesperidin and placebo assignments reversed. Hesperidin treatment improved endothelial function, suggesting this may be one important mechanism behind its benefit to the cardiovascular system. Hesperidin supplementation also led to a 33% reduction in median levels of the inflammatory marker high-sensitivity C-reactive protein (hs-CRP), as well as significant decreases in levels of total cholesterol, apolipoprotein B (apoB), and markers of vascular inflammation, relative to placebo (Rizza 2011). In another randomized controlled trial in overweight adults with evidence of pre-existing vascular dysfunction, 450 mg per day of a hesperidin supplement for six weeks resulted in lower blood pressure and a decrease in markers of vascular inflammation (Salden 2016). Another controlled clinical trial included 75 heart attack patients who were randomly assigned to receive 600 mg hesperidin per day or placebo for four weeks. Those taking hesperidin had significant improvements in levels of high-density lipoprotein (HDL) cholesterol and markers of vascular inflammation and fatty acid and glucose metabolism (Haidari 2015).

Lactobacillus reuteri. Various Lactobacillus species have demonstrated positive effects on risk factors for cardiovascular disease such as cholesterol levels, blood pressure, and markers of inflammation (Upadrasta 2016). A research review found that, of the probiotic strains studied, Lactobacillus reuteri (L. reuteri) NCIMB 30242 had the best evidence for reducing cardiac risk by safely lowering total and LDL cholesterol and levels of inflammatory markers (DiRienzo 2014).

In a randomized controlled trial, 114 participants with high cholesterol levels who were otherwise healthy consumed either a probiotic yogurt providing 2.8 billion colony forming units of microencapsulated L. reuteri NCIMB 30242 or a control yogurt daily for six weeks. The L. reuteri group had reductions in total cholesterol (9%) and LDL-cholesterol (5%), levels relative to the placebo yogurt group. ApoB100 (a structural component of atherogenic LDL and VLDL cholesterol), which at high levels is associated with vascular disease, was significantly reduced in the L. reuteri group (Jones, Martoni, Parent 2012; Semekovich 2016). In another controlled clinical trial on 127 healthy adults with high cholesterol levels, subjects received either capsules of L. reuteri NCIMB 30242 or placebo for nine weeks. Those taking the L. reuteri probiotic had a greater than 9% drop in total cholesterol and a drop in LDL cholesterol levels of over 11.5% compared with placebo. The ratio of apoB-100 to apoA-1 fell by 9% in the L. reuteri-supplemented group compared with placebo. The apoB-100:apoA-1 ratio is a strong predictor of cardiovascular risk, particularly in overweight and obese individuals (Lu 2011; Walldius 2012). High-sensitivity C-reactive protein and fibrinogen, additional markers of cardiovascular risk and inflammation, were also significantly reduced relative to placebo (Jones, Martoni, Prakash 2012). A later analysis of the same study showed vitamin D levels increased more in the L. reuteri group than the placebo group (Jones, Martoni, Prakash 2013). Since low vitamin D levels have been associated with high cardiovascular disease risk (Liu 2016), raising vitamin D levels is another way this probiotic may prevent cardiovascular disease. Interestingly, another post-trial analysis of the data from this study found subjects taking the probiotic also experienced general improvement in functional gastrointestinal symptoms (Jones, Martoni, Ganopolsky 2013).

Centella asiatica. Centella asiatica (C. asiatica) is a perennial herbaceous plant used in traditional Ayurvedic and Chinese medicine for thousands of years (Gohil 2010). The most important bioactive components in C. asiatica are triterpenes, which have been studied extensively for their healing properties, including to the endothelium (Bylka 2014; Incandela, Cesarone 2001; Alqahtani 2015; Zheng 2007; Fong 2015). Centella’s benefit to the vascular endothelium appears to be related, at least in part, to anti-inflammatory activity, modulation of collagen formation, and oxidative stress reduction (Belcaro 2011).

C. asiatica has been demonstrated to stabilize atherosclerotic plaques. In two randomized controlled trials in patients with atherosclerosis, supplementation with 60 mg of a triterpenoid extract of C. asiatica, three times daily for 12 months, stabilized atherosclerotic plaques in femoral and carotid arteries (Incandela, Belcaro 2001; Cesarone 2001). A series of studies lasting from 2.5 to 4 years examined the effect of a novel combination of C. asiatica triterpenoid extract and the pine bark extract known as Pycnogenol on progression of mild atherosclerosis. Researchers found the combination reduced and limited the progression of atherosclerotic plaque; they also observed an association between these benefits and a significant reduction in oxidative stress (Belcaro, Dugall 2015; Belcaro 2014; Belcaro, Ippolito 2015).

Pycnogenol. Pycnogenol® is a standardized bark extract of the French maritime pine tree (Pinus pinaster). Between two thirds and three quarters of Pycnogenol is made up of procyanidin compounds, specifically catechins and epicatechins (D'Andrea 2010; Rohdewald 2002). Pycnogenol benefits cardiovascular health through a variety of important mechanisms. It has been demonstrated to inhibit inflammation and clotting and to improve endothelial function (Gu 2008).

In a randomized, placebo-controlled, crossover trial, individuals with coronary artery disease received 200 mg Pycnogenol daily for eight weeks followed by placebo or vice versa. Treatment with Pycnogenol resulted in a significant reduction in oxidative stress and a 32% increase in a standardized measure of blood flow and vasodilation, a powerful indicator of endothelial function (Enseleit 2012). In a double-blind placebo-controlled trial in 58 hypertensive adults, those who took 100 mg Pycnogenol daily for 12 weeks reduced their dosage of a calcium-channel blocker and experienced a significant decrease in levels of the powerful vasoconstrictor endothelin-1 (Liu 2004).

In a preclinical study, Pycnogenol suppressed expression of inflammatory and tissue factors involved in the formation of atherosclerotic plaques, including nuclear factor-kappa B, interleukin-6, and interferon-beta (Gu 2008). In a mouse model of induced atherosclerosis, Pycnogenol reduced the size of atherosclerotic plaques; reduced total cholesterol, LDL cholesterol, and triglyceride levels; and raised HDL cholesterol levels (Luo 2015). A clinical trial in smokers found 200 mg Pycnogenol per day for two months, taken before the first cigarette of the day, inhibited smoking-induced platelet aggregation to the level of non-smokers (Araghi-Niknam 2000).

Pycnogenol has been shown, in a preclinical as well as in a randomized clinical trial, to enhance nitric oxide production via increased endothelial nitric oxide synthase activity, which can ameliorate endothelial dysfunction (Fitzpatrick 1998; Nishioka 2007). Enhanced nitric oxide function may also inhibit LDL cholesterol oxidation and platelet aggregation, which are critical steps in atherosclerotic plaque formation (Fitzpatrick 1998).

Citrus flavonoid glycoside. Citrus fruits have long been associated with good health, and research has found flavonoid molecules in citrus have powerful cardioprotective and anticancer activity (Turati 2015; Mulvihill 2012; Roohbakhsh 2015; Farooqi 2015; Peterson 2006). Flavonoids are highly concentrated in the peel of citrus fruit (Manthey 1996; Londoño-Londoño 2010; Rawson 2014).

Of particular interest is a unique flavonoid known chemically as hesperetin-7-O-rutinoside 2S. In a clinical absorption trial, hesperetin-7-O-rutinoside 2S was found to be 108% more bioavailable than standard hesperidin (BioActor 2013). Hesperetin-7-O-rutinoside 2S belongs to a special form of flavonoids known as flavonoid glycosides. Laboratory and animal experiments have demonstrated hesperetin-7-O-rutinoside 2S has a beneficial effect on endothelial function and inflammation. In a placebo-controlled crossover trial, 24 participants with metabolic syndrome received 500 mg per day of hesperetin-7-O-rutinoside 2S or placebo for three weeks. A significant improvement in endothelial function was apparent for those in the hesperetin-7-O-rutinoside 2S arm of the trial, and this effect was found even after the supplement had been discontinued. Inflammatory markers were significantly decreased in those taking hesperetin-7-O-rutinoside 2S. This beneficial effect appears to occur as a result of increased expression of endothelial nitric oxide synthase (Possemiers 2015).