The Heart of Natural Cardiovascular Risk Management

References

The key to keeping cardiovascular disease (CVD) at bay is maintaining healthy arteries. To this end, most early intervention involves controlling the blood lipid profile in an effort to limit formation of atherosclerotic plaques, which can impede blood flow to vital organs and ripen the scene for ischemic cardiac events such as heart attack and stroke. Dietary supplement ingredients have formed a long line of cardiovascular defense, helping to manage various blood componentsnamely cholesteroland reinforce vascular integrity.

Heart disease, Americas number one killer, can refer to any number of diseases affecting the heart, vascular system and vital organs dependent on sufficient blood flow. Coronary heart disease (CHD) is marked by the formation of plaques within arterial walls, which can rupture and reduce blood flow to the heart. At some point, this condition can become ischemic heart disease, which is characterized by lack of oxygen-rich blood flow to vital organs, including the heart and the brain, causing these organs to work excessively hard for little reward, even death.

The top risk factors for CHD and the formation of plaques from hardening arteriesa condition called atherosclerosisinclude hypercholesterolemia, hypertension, smoking and inflammation, as well as other maladies such as diabetes and obesity. Although dietary supplement ingredients have demonstrated benefits in addressing all of these factors, it is their prowess against cholesterol, related blood components and hypertension that are the focus of preventive measures against atherosclerosis and CHD development.

The fatty deposits defining atherosclerosis are comprised of lipids, complex carbohydrates, proteins, fibrous tissue and calcium. These compounds can accumulate into a plaque, called an atheroma, when fatty streaks deposit lipids in the sub-endothelium, between the interior intima lining and muscular portion of the artery wall. Initial damage to the blood vessel triggers an inflammatory response, calling white blood cells to the deposit site in the artery wall.

Monocytes entering the artery wall become macrophages that consume oxidized cholesterol, forming large foam cells that, in turn, cause increased inflammation and fat deposits. These deposits steadily build up, becoming a primary contributor to arterial blockage.

Low-density lipoprotein (LDL) transports cholesterol and triglycerides to the arteries, where they are released and vulnerable to oxidation. On the other hand, high-density lipoprotein (HDL) carries cholesterol away from atheromas and to the liver for removal. Based on these opposing actions, LDL is considered bad, and HDL is deemed good. However, increasing research suggests the progression of atherosclerosis is more dependent on the size and concentration of LDL, with small amounts of large particles better than large quantities of small particles.

Although LDL is larger (in terms of particle size) than HDL, the smaller, denser forms of LDL have been found to be the most dangerous. Both sizes may carry similar amounts of cholesterol, but the smaller LDL particles are more apt to accumulate.

A marker of small-particle LDL is its structural protein component, apolipoprotein B (apoB). Researchers from University of Texas Health Sciences Center, San Antonio, reported while tests for LDL have historically screened for cholesterol in LDL, screening for apoB might provide a better indication of LDL particle size, and thus atherosclerosis risk.¹

In addition to apolipoproteins (including apoB and apoE), LDL also contains triglycerides, which are in high concentration in very low-density lipoprotein (VLDL), the initial form of LDL from the liver. Triglycerides are broken down in the intestines and reformed in the blood as constituents of lipoproteins. Thus, high blood levels of triglycerides, a condition called hypertriglyceridemia, have been associated with increased risk of atherosclerosis.

Taming Lipid Levels, CVD Biomarkers

Scientists honed in on a few diets, especially vegetarian/vegan and Mediterranean variations, when looking at populations with low incidence of heart disease. Long regarded as heart healthy, the Mediterranean diet is rich in fruits, vegetables, fish and olive oil, but low in animal fats. In 2005, Greek scientists studying more than 3,000 men and women found those with the highest adherence to the Mediterranean diet had 19-percent lower oxidized LDL levels than those with the lowest adherence.² Then in 2006, Spanish researchers added to the coffers fresh results showing subjects on a Mediterranean diet with either supplemental virgin olive oil (1 L/wk) or nuts (30 g/d) had lower total cholesterol (TC) to HDL ratios than subjects on a low-fat diet.³ Those in either of the Mediterranean interventions also had reduced mean plasma glucose and lower systolic blood pressure, while those on the olive oil-rich diet had reduced levels of C-reactive protein (CRP), a marker of inflammation, which can contribute to atherosclerosis.

The Mediterranean diet is soaked in olive oil, which contains various polyphenolsextra virgin olive oil has higher polyphenolic content. Researchers have often found olive oil interventions improve blood flow, but a Spanish team found such benefit was diminished if the phenols were removed from the oil.⁴ They noted high-phenolic, extra virgin olive oil improves arterial blood flow by mediating endothelial vasodilation (enlargening), including oxidative stress and nitric oxide (NO) metabolites. Most recently, another Spanish team confirmed the relationship between phenolic content and degree of lipid modulation, reporting administration of olive oils in any of three different phenolic levels (low, medium and high) increased HDL levels, but decreases in TC-to-HDL ratios were significantly more pronounced with the higher phenolic levels.⁵ They added the most phenolic-rich olive oil also reduced oxidative stress markers, including oxidized LDL. In addition to limiting lipid peroxidation and managing LDL-to-HDL ratios,⁶ olive oil also helps curb high blood pressure in hypertensive subjects.^7,8

Olive oil also contains monounsaturated fatty acids (omega-9 oleic acid), as do various nuts, which are also rich in polyunsaturated fats. One review reported consumption of 50 g/d to 100 g/d of various nutsincluding almonds, peanuts, pecans and walnuts (macadamias excluded)may significantly decrease TC and LDL in people with either normal or high cholesterol.⁹ Peanuts¹⁰ and walnuts^11,12 have been linked to lipid and vascular health benefits, and recent research has shown almonds can lower the risk of oxidative damage to proteins by decreasing the glycemic excursion and providing antioxidants.¹³

Scientists believe the heart benefits of nuts are likely due to the fatty acid profile, which includes oleic acid as well as linoleic acid (LA) and alpha-linolenic acid (ALA). Penn State University research found LA and ALA can reduce LDL, TC and triglycerides; ALA alone can limit vascular cell adhesion and improve endothelial integrity.¹⁴ ALA, an omega-3 fatty acid, has also been credited with curbing eicosanoids (inflammatory compounds) and inhibiting coagulation that can promote atheroma formation.¹⁵

Some LA isomers, collectively known as conjugated linoleic acid (CLA), have been widely investigated for weight control, but there is also some evidence of mechanisms impacting lipid metabolism and oxidative factors in atherosclerosis.

An Irish study found CLA isomers reduced plasma triglycerol and VLDL levels in 51 healthy subjects, but had no effect on LDL, HDL or cholesterol transport.¹⁶ The results are mixed from this point forward. Whereas one study on hypercholesterolemic rats given CLA-rich butter reported a decreased ratio of atherogenic lipoproteins (VLDL, LDL and intermediate density lipoprotein) to HDL,¹⁷ another animal study discovered dairy products fortified with CLA isomers had no significant effect on blood lipid profile.¹⁸ Revealing the complexity of each CLA isomers impact on lipids, a 2006 University of Massachusetts, Lowell, study on hypercholesterolemic hamsters reported there were no differences between various CLA isomers and changes in plasma lipids or lipoprotein cholesterol concentrations.¹⁹

However, the c9,t11 isomer did appear to lower triglyceride levels compared to the t10,c12 isomer. A Canadian study found equally somber results, with no positive benefits on lipid profile from the c9,t11 isomer, and negative impact on lipids by the t10,c12 isomer.²⁰ But other research has shown CLA increases oxidative stability in the plasma and liver membranes of vitamin E-deficient mice.²¹

Omega-3 fatty acids

from marine sources have also turned the cholesterol tide for the good of the cardiovascular system. A recent human study revealed an intervention diet rich in fish oil, omega-3s, EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) actually increased LDL and apoB concentration (a marker of increased levels of small atherogenic LDL), compared to an ALA-rich diet, but the EPA/DHA diet did influence factors that can limit coagulation.22 However, an animal trial reported in early 2006

revealed fish oil supplementation lowered levels of LDL and triglycerides, resulting in less atherosclerosis in the aortic root and in the entire aorta.²³ And supporting the theory that fats from fish are more beneficial than the hydrogenated oils rampant in modern processed foods, a pair of studies out of Denmark showed EFAs from fish oil decreased triglycerides and mean arterial blood pressure, while hydrogenated soy oil decreased HDL.^{24, 25} Likewise, Scottish researchers confirmed fish oils anti-atherosclerotic, anti-inflammatory and anti-thrombotic properties, including an ability to normalize blood pressure, lower triglyceride concentrations and improve endothelial function.²⁶ Finnish scientists reported increased DHA levels within plasma phospholipids and also in triglycerides are inversely associated with arterial dysfunction and lesion development.²⁷

In addition to fish, omega-3 DHA and EPA are also components of krill, a marine crustacean similar to shrimp. In 2004, a clinical trial conducted at McGill University, Montreal, found krill oil effectively manages hyperlipidemia by reducing TC, LDL and triglycerides, while also increasing HDL levels.²⁸

A vegetarian source of omega-3 fatty acids is flaxseed oil, which is abundant in ALA that can be converted in the body to EPA (and possibly DHA); flax also contains LA and oleic acid. Animal research has suggested flaxseed oil supplementation is beneficial in reducing plasma cholesterol and plaque formation by reducing the fatty streak area and the incidence of lesions.²⁹ In human research, the same team from Oklahoma State University, Stillwater, showed administration of flaxseed oil in postmenopausal women not on hormone therapy (who are at greater risk of hypercholesterolemia) slightly reduced serum LDL, HDL and triglycerides but had a more pronounced effect in lowering apoA and apoB concentrations.³⁰ The researchers found no benefit for their primary endpoint, bone health, but noted phytoestrogen lignans in flaxseed might be the basis for its cardioprotective benefits.

Lignans

are found in many plants, including flax, pumpkin seeds, sesame seeds and soybeans. Most recently, scientists from Taiwan investigated the effects of the sesame seed lignan sesamin on blood lipid profile, LDL oxidation and other hormone-influenced parameters in postmenopausal women.³¹ They showed sesame seed powder significantly decreased TC, LDL, LDL-to-HDL ratio and oxidative stress markers.

Based on the benefits of estrogen therapy to CVD risk factors, including hypertension and hyperlipidemia, Dutch researchers looked at the intake of phytoestrogensisoflavones and lignansrelative to blood pressure and lipid profile.³² They found the highest intakes of isoflavones and lignans correlated to reduced triglycerides and cardiovascular metabolic risk factor score, although the results for lignans were slightly more pronounced.

Still, research on isoflavones has dominated the inquiry into the role of phytoestrogens in CVD development. Trials on isoflavones in red clover have shown decreased triglycerides and increased HDL, as well reduced total and LDL cholesterol in men and women.^33,34,35

Phytoestrogens in soy and kudzu were found to decrease TC and non-HDL levels, with no effect on HDL levels, demonstrating both sources favorably modify lipoprotein profiles in an estrogendeficient animal model.³⁶ However, soy receives most of the research attention in this area.

A pair of Canadian studies achieved opposite results on the importance of isoflavone content in soys heart healthy actions. One study found soy protein decreased TC and triglycerides in hyperlipidemic subjects more effectively than animal protein, but isolated isoflavones did not produce the same effect.³⁷ The other study determined high- and low-soy isoflavone diets lower TC and improve the LDL-to-HDL ratio in hyperlipidemic subjects.³⁸ And Japanese researchers reported a high-isoflavone soy diet more effectively lowered LDL compared to a low-isoflavone diet.³⁹

Yet another soy compound suggested as beneficial to heart health is a chromatin-binding peptide. In late 2006, scientists from University of California, Davis, presented research showing this soy peptide (as Lunastatin®, from SoyLabs) inhibited expression of HMGCoA reductase, which is crucial in liver production of endogenous cholesterol.⁴⁰ They noted the ingredient also restricted expression of the LDL-R receptor gene, thereby increasing the number of LDL receptors on cell membranes; this results in more LDL cholesterol removed from the blood, lowering circulating cholesterol levels.

Regardless of its exact mechanism, soy protein intake, in general, has made its mark on CVD research to an extent that the Food and Drug Administration (FDA) in 1999 authorized a health claim on the connection between 25 g/d soy protein intake and decreased risk of heart disease. Among the legion of evidence to this end, increased intake of soy foods has been linked to improved blood lipid profile, reduced LDL oxidation and enhanced vascular function.^41,42 A Japanese team studying both soy and rice protein in apoE-deficient mice (the deficiency can promote foam cell formation and atherosclerosis) discovered the plant proteins more effectively inhibited formation of atherosclerotic lesions.⁴³

A more recent study on adult monkeys revealed long-term consumption of soy protein containing a modest amount of isoflavones inhibits the early progression of coronary atheromas without affecting endothelium-dependent or -independent arterial function.⁴⁴ In another animal study, eight weeks of soy protein isolate (SPI) or casein supplementation led to reduced plasma triglyceride and cholesterol levels;⁴⁵ researchers reported the soy modulated genes involved in lipid and energy metabolism. Around the same time, a meta-analysis of 23 trials confirmed soy and its isoflavones daidzein and genisteinlower serum TC, LDL and triacylglycerol while significantly increasing HDL cholesterol.⁴⁶

Soy and seeds are not the only staple plants containing phytoestrogens; recent scientific work has located new lignans in various grains, including wheat, triticale, barley, corn, amaranth, millet and oat bran.⁴⁷ In early 2006, Korean research results showed supplementation with either amaranth oil or grain reduced TC, LDL and VLDL levels in addition to improving serum glucose levels.⁴⁸ A Polish trial on amaranth and oatmeal showed supplementation with either type of grain positively affects plasma lipid profile in rats fed cholesterol-containing diets. They concluded amaranth could be a valuable substitute for hypercholesterolemic patients allergic to other grains such as oats.⁴⁹

However, oats are well-known for lowering cholesterol and blood pressure.⁵⁰ Much of oats heart benefits have been attributed to its fiber content. In a Tulane University, New Orleans, study, watersoluble fiber from oat bran moderately affected systolic and diastolic blood pressure in hypertensive subjects.⁵¹ Other research suggested an oat-rich diet might help patients reduce dosages of hypertensive drugs.⁵² Also, researchers from the Jean Mayer USDA (U.S. Department of Agriculture) Human Nutrition Research Center on Aging (HNRCA) at Tufts University, Boston, showed oat fiber could inhibit blood cells from sticking to artery walls, helping to prevent clogged arteries and atherosclerosis.⁵³

On lipid factors of atherosclerosis, oat beta-glucan fiber has shown its ability to lower cholesterol by speeding movement of intestinal contents. Researchers from the University of Minnesota showed increased viscosity of intestinal contents in rats administered oat beta-glucans (as Oat Vantage, from Nurture Inc.) led to a reduction in liver TC concentration.⁵⁴ In another trial, their colleagues demonstrated 6 g/d of oat beta-glucan concentrate administered to men and women with dangerous cholesterol levels (greater than 200 mg/L) lowered LDL cholesterol.⁵⁵ Oat beta-glucans effect on lipid factors was upheld by a Lund University, Sweden, trial, but researchers noted barley beta-glucans did not exhibit similar benefits.⁵⁶ However, scientists from the USDA Beltsville Human Nutrition Research Center reported barley beta-glucan supplementation reduced TC, LDL and various LDL particle sizes in hypercholesterolemic men and women.⁵⁷

A pair of recently presented trials validated the benefit of purified barley beta-glucans on CVD biomarkers, including LDL and CRP. In one trial, hypercholesterolemic patients taking either high or low molecular weight barley beta-glucans (as Barliv, from Cargill) had improved CVD biomarkers, although HDL and apoA were unchanged.⁵⁸ In the other trial, Barliv given to healthy adults (LDL between 130 and 190 mg/dL) improved fasting and postprandial CVD biomarkers, as well metabolic control.⁵⁹

Another form of fiber, this one from the Opuntia ficus indica plant (as Neopuntia®, from BioSerae), decreased LDL by 10 percent, compared to placebo, while elevating HDL levels.⁶⁰ In another trial, rats administered with Opuntia ficus indica powder had significantly increased HDL levels, as well as decreased blood glucose concentration.⁶¹

Plantsincluding grains, seeds and legumes (such as rapeseed, soybean and sunflower seed)also contain phytosterols, which are chemically similar in structure to cholesterol. Because of this structural similarity, plant sterols can compete with cholesterol for absorption. Research shows plant sterols, such as sitosterol, can lower serum LDL and other non-HDL cholesterol in diabetic and nondiabetic subjects.⁶² Although one Australian study contended plant sterols reach the bloodstream at the cost of decreased plasma carotenoid levels,⁶³ another Australian study found 2.4 g of sterol esters (as Vegapure®, from Cognis Nutrition & Health) lowered LDL without affecting plasma carotenoid or tocopherol levels.⁶⁴ A Mayo Clinic review also concluded increased consumption of foods rich in sterols and stanols reduces LDL by 20 percent without alphcarotene, lycopene and vitamin E levels.⁶⁵ Meanwhile, in an Iowa State University trial, 2.7 g of sterols (as Vegapure) lowered TC and LDL.⁶⁶ In addition, researchers from the University of California, Davis, upheld the concept of cholesterol-lowering via fortification of foods with plant sterols, which have been added to products such as margarine, butter and juice. In one trial, they showed orange juice containing 2 g/d of plant sterols (as CoroWise, from Cargill Health & Food Technologies) reduced TC, LDL, HDL and apoB in hypercholesterolemic individuals.⁶⁷ They performed a similar trial, this time in healthy volunteers who experienced reduced CRP and LDL, as well as increased HDL.⁶⁸

From a different angle, a study conducted at McGill University found a proprietary combination of DHA and plant sterols (as cardiaBeat, from Enzymotec) decreased TC, LDL and triglycerides in overweight patients with elevated lipid levels.⁶⁹ At the same time, a USDA-sponsored study investigating the efficacy of various combinations of plant sterols and fish oil fatty acidsfree plant sterols; plant sterols esterified to fatty acids from sunflower oil; plant sterols esterified to very long-chain fatty acids from fish oil; or plant sterols combined with the same amount of very long-chain fatty acids from fish oildetermined each intervention raised HDL slightly, compared to control, but none of the sterol treatments had a significant positive effect on LDL, apoA, apoB or CRP.⁷⁰

A group of scientists from the University of Nebraska, Lincoln, studied sorghum components in a rat model, finding sterols from the grain reduced cholesterol in the blood, while policosanol content worked against cholesterol synthesis in the liver.⁷¹

A mixture of cyclic alcohols from plant waxes, including sugar cane wax and beeswax, policosanol has been investigated for its cholesterol-lowering properties. Review results from McGill University noted policosanols may reduce platelet aggregation, endothelial damage, foam cell formation as well as decrease TC and LDL.⁷² Likewise, studies conducted at the National Center for Scientific Research, Cuba, have shown short- and long-term supplementation of 5 mg/d and 10 mg/d of policosanol can significantly lower TC and LDL, and increase HDL in hypercholesterolemic patients.^73,74,75

However, 2006 was riddled with clinical trials reporting policosanol was ineffective in lowering cholesterol levels in various human and animal models of hyperlipidemia, including follow-up research from McGill University and studies on Cuban sugar cane-derived policosanols.^76,77 A German clinical trial reported in JAMA involved various doses of policosanol (10, 20, 40 or 80 mg/d) in hypercholesterolemic or hyperlipidemic patients, who were measured for LDL and other lipid levels.⁷⁸ According to published results, none of the policosanol dosages reduced LDL more than 10 percent from baseline, and there were no significant benefits to TC, HDL, triglycerides, apoA or various lipoprotein ratios. Despite such disparaging results, 2006 also produced some positive publications, including a University of Kentucky study on policosanol in an in vitro animal model that suggested policosanols hypocholesterolemic effect results from a decrease in cholesterol synthesis by suppression of HMG-CoA reductase activity.⁷⁹

Plant substances continue to draw more research attention. Polyphenols in red wineanother Mediterranean dietary staplecan increase antioxidant activity, reduce endothelial cell adhesion, and target LDL oxidation.^80,81

Research has provided evidence red wine and its phenolsincluding hydroxytyrosol, oleuropein and resveratrolcan also reduce plasma oxidative stress following a fatty meal,⁸² in addition to inhibiting lipid deposits in the aorta of apoE-deficient animal models.⁸³ According to a pair of 2004 reports, red wine polyphenols can increase NO synthase expression, leading to vasorelaxation,⁸⁴ and can help dilate the brachial artery for improved blood flow.⁸⁵ And in 2006, Australian researchers reported regular consumption of red wine reduced CVD risk in hypercholesterolemic postmenopausal women by decreasing fasting LDL and increasing HDL.⁸⁶

Grapes, the basis for red wine, contain powerful antioxidant compounds beneficial for heart health. In a joint study from Columbia University, New York, and University of Connecticut, Storrs, freeze-dried grape powder containing flavans, anthocyanins, quercetin, myricetin, kaempferol and resveratrol, reduced plasma LDL, apoB and apoE levels, and limited both oxidative stress and inflammation response, although it did not modify LDL oxidation.⁸⁷

Grape seed extract

(GSE) has also sweetened the heart health research cluster by exhibiting antioxidant actions useful in lowering LDL and curtailing LDL oxidation.^88,89 Adding to the knowledge base, a handful of proprietary studies (funded by Polyphenolics Inc., a division of Constellation Wines) conducted at University of California, Davis, elucidated GSEs benefits to atherosclerosis. Presented at the 2005 Experimental Biology Conference in San Diego, the three studies showed GSE can reduce arterial cholesterol accumulation triggered by a high-fat diet and preempt aortic endothelial dysfunction caused by saturated fatty acids. Most recently, additional research from UC Davis presented at 2006 SupplySide West reported two doses (150 g/d and 300 mg/d) grape seed extract (MegaNatural® BP, from Polyphenolics) reduced blood pressure, while the higher dosage also led to a significant decrease in the concentration of oxidized LDL in plasma.

Flavonoids

are a hot category of antioxidant phenols, conferring various benefits to the cardiovascular system. Flavonoids are abundant in many plants, namely richly-colored red, blue and purple fruits and vegetables, including raspberries, strawberries, blackberries, blueberries, bilberries, plums, eggplant, red cabbage, red onion and red grapes.

Overall, flavonoids address LDL oxidation and thrombosis, as well as vascular endothelial function and inflammation. On specific flavonoid subgroups, anthocyanins have proven especially effective against atherosclerosis by strengthening the transport of excess cholesterol from peripheral tissues to the liver for biliary excretion.⁹⁰ Flavanols in cocoa and tea, including proanthocyanidins and catechins, have produced similar results. According to findings from human clinical trials and research reviews, cocoa flavanols can reduce LDL oxidation, inhibit thrombosis formation, enhance endothelial function, lower blood pressure, and modulate platelet activation and function.^91,92,93

The main flavanol in tea is EGCG (epigallocatechin gallate), which is a catechin found in green, black and oolong teas in varying amounts. EGCG (and its relative ECG) may decrease atherosclerosis development by as much as 63 percent and may lower hypertension risk by as much as 65 percent.^94,95

One theory on tea catechins reduction of atherosclerosis focuses on teas antioxidant mechanisms, which help lipoproteins resist oxidation. In support of this theory, University of California, Los Angeles, (UCLA) researchers showed EGCG treatment for 21 and 42 days increased antioxidant capacity in vascular tissue and blood, reducing progressive atherosclerotic plaque size by 55 percent and 73 percent, respectively.⁹⁶

Flavonols in tea are also heart protective. Quercetin has anti-hyperlipidemic and antiatherogenic properties, as demonstrated in Polish research that found supplementation with the flavonol effectively reduced serum triglycerides and cholesterol in hyperlipidemic and atherogenic rabbits;⁹⁷ researchers noted after four weeks of quercetin supplementation plaque size was decreased in rabbits with injured carotid arteries. Chilean researchers reported quercetin conveyed more potent in vitro antioxidant protection of LDL than did various phytoestrogensincluding the isoflavones daidzein and genistein.⁹⁸

In a study conducted at Hebrew University Medical School, Jerusalem, flavonoid-rich red grapefruit juice positively influenced serum antioxidant activity and serum lipid profile, especially serum triglyceride and antioxidant activity.⁹⁹ The scientists suggested the fruit would be a beneficial intervention for hyperlipidemia, especially hypertriglyceridemia, in patients with atherosclerosis. Grapefruit contains pectin fiber and a host of vitamins and minerals in addition to citrus bioflavonoids such as naringin. Based on results from animal research, some scientists have concluded naringin can increase serum antioxidant activity similar to that of statin drugs (which lower LDL, TC and curb oxidation).^100,101 This bioflavonoid may also minimize aortic fatty acid streaks common in high-cholesterol diets.¹⁰²

As a group, citrus bioflavonoids (polymethoxylated flavones), which also include hesperidin, nobiletin and tangeretin, have produced evidence for TC, LDL and triglyceride reduction.¹⁰³ Hesperidin from lemons and oranges normalized blood pressure and heart rate in an animal model of hypertension.¹⁰⁴ For its part, the tangerine bioflavonoid nobiletin reduced plasma concentrations of LDL and thwarted macrophage foam-cell formation.¹⁰⁵ Additional blood lipid management from tangerine comes from tangeretin, which delivers hypertriglyceridemic actions on apoB-containing lipoprotein metabolism by reducing apoB secretion, according to a study led by KGK Synergize.106

KGK developed a proprietary formula harnessing the antioxidant properties of citrus bioflavonoids (nobiletin and tangretin) and palm fruit in support of healthy LDL and triglyceride levels. This formula (as Sytrinol®, available from SourceOne Global) was featured in research presented at the 2006 Canadian Federation of Biological Sciences 48th Annual Meeting, Ontario. Results from the initial double blind, placebo-controlled clinical trial showed three months of Sytrinol supplementation in hypercholesterolemic subjects significantly reduced TC and LDL levels. The second stage of the study linked Sytrinol administration to improved blood glucose- and obesity-related parameters also relevant to CVD risk. A proprietary phase III clinical trial on Sytrinol confirmed its ability to reduce LD, TC and triglycerides by as much as a fourth, while slightly raising HDL.

Palm fruit is rich in both the vitamin E isomers tocopherols and tocotrienols; but, researchers from the Malaysian Palm Oil Board credit tocotrienols with palm fruit oils atherosclerotic benefits, including cholesterol reduction.¹⁰⁷ A Swiss trial clarified tocotrienols ability to inhibit enzyme activity to the benefit of reduced TC and LDL, with gamma-tocotrienol more effective than mixed tocotrienols.¹⁰⁸ A 2001 review tracked tocotrienol research on protecting against LDL oxidation, confirming the mechanism involving enzyme activity.¹⁰⁹

Similar protection against LDL oxidation has been attributed to alpha-tocopherols, which have enjoyed the most research attention among vitamin E isomers. A pair of studies showed tocopherol supplementation curbed LDL oxidation and increased vitamin E concentrations in atheromas but failed to affect plaque size.^110,111 Offering a sliver of fruitful affect on atheromas, a Linkoping University, Sweden, study concluded combined supplementation with vitamin E (as alpha-tocopherol) and astaxanthin (as AstaREAL®, from Fuji Health Science) improved plaque stability by decreasing macrophage infiltration and apoptosis in atherosclerotic rabbits.¹¹²

Astaxanthin, a carotenoid, has curtailed LDL oxidation in both cell cultures and human subjects.¹¹³ In fact,14 days of oral astaxanthin supplementation (as AstaREAL) decreased arterial blood pressure in hypertensive rats by inducing vasorelaxation via NO-mediation.¹¹⁴ Another study showed 6 mg/d of AstaREAL improved blood rheology (transit time) after only 10 days of supplementation.¹¹⁵

Carotenoidsincluding lycopene, beta-carotene, astaxanthin, beta-cryptoxanthin, lutein and zeaxanthinas a group are potent scavengers of singlet oxygen and peroxyl radicals, two byproducts of lipid peroxidation.¹¹⁶ Individual carotenoids have also colored the heart health research landscape.

The tomato-borne compound lycopene can protect against LDL oxidation^117,118 and has shown some potential to affect LDL degradation and particle size, as well as improved endothelial health.¹¹⁹ In fact, lycopene can lower CVD risk by as much as 33 percent,¹²⁰ and tomato juice can increase lycopene concentrations in HDL and LDL cholesterol, providing protection against lipid peroxidation.¹²¹ In new research results presented at the 2006 American Society of Hypertensions 20th Annual Scientific Meeting and Exposition, San Francisco, increased lycopene intake (as Lyc-O-Mato, from LycoRed) summarily increased serum levels of the carotenoid, which were linked to reduced systolic and diastolic blood pressure in subject who had previously found no benefit from conventional hypertension drugs. In results published in early 2006, the study authors reported lycopene also reduced thiobarbituric acid, a marker of lipid oxidation.¹²²

For its part, lute in helps disrupt atherosclerosis development by slowing progression of IMT (intima-media thickness), obstructing LDL migration to the artery wall and reducing atheroma size by 43 percent, according to research on apoE-deficient mice.¹²³ In a similar vein, a UCLA cohort study found higher plasma levels of lutein, alphacarotene, beta-cryptoxanthin and zeaxanthin reduced atherosclerotic progression by retarding IMT.¹²⁴

Carotenoids, flavonoids and micronutrients paint a healthy picture with various fruits, including some exotic varieties. Hot on the scene, pomegranate has blossomed in the heart health field due to its potent combination of ellagic acid and various polyphenolic tannins such as delphinidin, cyanidin, pelargonidin and punicalagin. These phenols have been shown to lower TC and LDL¹²⁵ in addition to lowering CVD risk via slowing of IMT.¹²⁶ Additional antia the roma action from pomegranate supplementation may include protection against LDL oxidation by accumulating polyphenols in arterial macrophages and interacting with the lipoprotein.¹²⁷ In one compound study, pomegranate juice consumption decreased LDL aggregation in men and reduced foam cells and atheroma size by 45 percent in mice.¹²⁸

Juice from bitter melon, the edible fruit of the plant Momordicacharantia , has generated similar results on lipid parameters. University of Hawaii, Honolulu, scientists clarified bitter melons mechanism of action in this area, explaining administration of the juice substantially inhibits apoB secretion and triglyceride synthesis that may be involved in the plasma lipid- and VLDL-lowering effects observed in animal studies.¹²⁹

Many juicy fruits, including melons and tropical fruits, contain vitamin C, which has addressed various aspects of atherosclerosis. Studies have linked vitamin C supplementation with improved endothelial function and improved blood flow.^130,131

However, other researchers failed to find a connection between vitamin C supplementation and hypertension. 

Highlighting the merits of the dietary supergroup of plant-based foods, vitamin C (rich in fruits and vegetables) and vitamin E (found more abundantly in vegetables and nuts) have combined for positive results in heart research. In one trial, six years of combined supplementation with vitamins E and C in hypercholesterolemic men and women resulted in decreased carotid IMT.¹³² A combination of vitamins E and C, as well as the antioxidants beta-carotene and selenium, also decreased lipid peroxidation via antioxidant actions.¹³³

Antioxidants are in high demand for atherosclerosis intervention. Reviews of research on coenzyme Q10 (CoQ10) suggest the vitamin-like compound can lower systolic and diastolic blood-pressure in hypertension.^134,135 Indian researchers noted administration of 3 mg/d of CoQ10 (Q-Gel®, from Tishcon) in rabbits with high trans fat levels helped limit oxidative damage and atherosclerosis development.¹³⁶ CoQ10 might also be a useful adjunct to statin drugs, which may decrease CoQ10 levels in the body, especially in CVD patients.¹³⁷

CoQ10 and vitamin E have combined for important anti oxidant effect sin the cardiovascular system. This combination not only increases plasma levels of vitamin E and HDL cholesterol, but it also reduces atherosclerosis at the aortic root and descending thoracic aorta.^138,139

Another guardian of cardiovascular lipids from oxidation is fellow mitochondrial coenzyme alpha-lipoic acid. On its list of antioxidant actions in heart health, lipoic acid scavenges free radicals such as reactive oxygen species (ROS), in addition to reactivating with other oxidized antioxidants such as vitamin C, glutathione and CoQ10 which can then regenerate oxidized vitamin E.¹⁴⁰ This joint antioxidant action helps lipoic acid lessen lipid peroxidation and improve endothelial function, which in turn helps control blood pressure and lipid metabolism.

Research has shown alpha-lipoic acid can improve endothelium-related blood vessel relaxation in diabetic subjects and mitigate hypertension resulting frome it herhyperglycemia and high salt intake.^141,142 A McGill University research review backed these conclusions, noting the literature shows lipoicacid can protect against both hypertension and lipid peroxidation.¹⁴³

Blood lipid optimization accompanied by anti-hypertensive actions is a one-two punch against heart disease. Exemplifying the link between diabetes and CVD risk factors, glucose management hero chromium may provide the dual benefit of improved lipid profile and reduced blood pressure. In a 2005 trial, 12 weeks of supplementation with chromium picolinate and biotin ( a s Diachrome®, from Nutrition 21) lowered non- HDL cholesterol and triglycerides in type 2 diabetes patients.¹⁴⁴ Corroborating these findings, a 2006 Yale University pilot study concluded chromium picolinate and biotin (as Diachrome) administered to patients with diabetes not only improved glucose management but also significantly improved triglycerides and the ratio of triglycerides-to-HDL.¹⁴⁵ On the other hand, a Creighton University, Omaha, Neb., study credited decreased systolic blood pressure in healthy and hypertensive animals to chromium polynicotinate (as ChromeMate®, from InterHealth Nutraceuticals), both individually and combined with GSE (as Activin®, from San Joaquin Valley).¹⁴⁶

Hypertension might involve a disruption to magnesium metabolism.¹⁴⁷ A combination of magnesium and the heart herb hawthorn lowered systolic and diastolic blood pressure in hypertensive patients in a University of Reading, England, trial, in which hawthorn alone showed a greater reduction in resting diastolic blood pressure.¹⁴⁸ In another study, rabbits fed a high-cholesterol diet and administered hawthorn fruit powder had significantly reduced TC and triacylglycerols.¹⁴⁹

One method of subduing hyperlipidemia is via NO-related endothelial improvement, a mechanism used by garlic.¹⁵⁰ According to various research reports, garlic can decrease TC levels, LDL-to-HDL ratio, homocysteine, platelet aggregation, LDL oxidation and glycation (cause of tissue stiffening).^151,152,153 The B vitamin folic acid also acts via the NO pathway,¹⁵⁴ but research has not definitively found a link between supplemental folate and reduced atherosclerosis.¹⁵⁵ However, fellow B vitamins pantothenic acid (B5) and niacin (B3) have produced positive results on cholesterol and related blood factors of atherosclerosis. In mice taking B5 and its derivative pantethine, TC and triglycerides dropped significantly, while hypertriglyceridemic men and women taking 600 mg/d of pantethine had severely reduced fatty liver.^156,157 Similarly, a University of Minnesota study reported 600 mg/d to 900 mg/d of pantethine (as Pantesin®, from Daiichi Pharmaceutical) improved levels of LDL, VLDL and triglycerides, while increasing HDL.¹⁵⁸

But the ruler of the B vitamin heart army may be niacin (also called nicotinic acid), which was used as a treatment for dyslipidemia as early as the 1950s for improving HDL levels. One review noted niacin increases levels of HDL cholesterol and decreases LDL to its less atherogenic large particle size.¹⁵⁹ Further, niacin supplementation added to statin therapy has been shown to impede IMT progression and optimize lipid levels, including LDL, HDL and triglycerides.^160,161 A 2006 review agreed niacin helps optimize HDL and LDL lipid factors of atherosclerotic CVD risk, noting longer-release niacin delivery forms create less undesirable flush than immediate-release versions.¹⁶² In a case review paper published in late 2006, Robert Norris, M.D., University of Pennsylvania, Philadelphia, noted flush-free niacin forms are not effective substitutes for extended-release forms for uses related to lipid profile management.¹⁶³

Additional support for raising low HDL levels common to atherosclerosis and CVD comes from guggul, the oleogum resin of the Cammiphora mukul tree. In preclinical and clinical studies conducted in India, where the pharmacopoeia lists guggul for use in dyslipidemia, a standardized extract of guggul (as Gugulipid®, from Sabinsa) increased HDL levels, while decreasing TC, VLDL and triglycerides in healthy and hyperlipidemic subjects. A 2004 review cited accumulating evidence that guggul and its guggulsterone constituents lowers lipid factors in CVD and inhibits LDL oxidation.¹⁶⁴

Another herb from India , Cissus quadrangularis, has been found to reduce LDL as well as help control weight and blood sugar.¹⁶⁵ In the eight-week randomized, double blind, placebo-controlled study, overweight and obese subjects taking Cissus (as Cissus CQR-30, from Soy Labs) experience d reductions in TC, LDL, triglycerides, BMI and fasting blood glucose, in addition to a notable increase in HDL levels.

Showing there are always new research discoveries and theories in a field as complex as cardiovascular disease, recent research from University of Maastricht scientists revealed a new theory that calcium build-up in the arteries may contribute to CVD development and progression.¹⁶⁶ Studies show vitamin K2 (45m g /dasmenaquinone), but not K1 (phylloquinone), reduces arterial calcification by 50 percent.^167,168

The actions of many dietary ingredients in the realm of CVD and atherosclerosis are important for prevention of disease development and the devastating events that can occur in advanced stages of heart disease. According to the Centers for Disease Control (CDC), a 10-percent reduction in cholesterol correlates to a 20- to 30-percent reduction in incidence of CHD.

This alone is enough reason for formulators to take a long, hard look at the many natural compounds that can help control cholesterol levels, as well as other biomarkers and parameters of atherosclerosis. 

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