Easing the Pressure

A recent Centers for Disease Control and Prevention (CDC) study reported less than 2 percent of Americans meet the seven recommended heart-health targets that reduce the risk of heart disease.¹ Researchers from Emory University, Atlanta, and Harvard, Boston, reported if more people had normal blood pressure (under 120/80 mmHG), did not smoke, were physically active, had normal fasting blood glucose levels (below 100), kept their total cholesterol in check (below 200), had a healthy weight and ate a healthy diet, they could lower their risk of total and cardiovascular disease (CVD) mortality. People who met six of the seven goals had a 76-percent lower risk of heart-related death and a 51-percent lower risk of death from any cause, compared with those who met one or fewer.

The study used data from the National Health and Nutrition Examination Survey (NHANES) 1988 to 1994, 1999 to 2004 and 2005 to 2010, and the NHANES III Linked Mortality File (through 2006) that included 44,959 U.S. adults. CDC found some surprising, and disheartening, results. Between 1988 and 2010, the number of people eating a healthy diet declined, and the prevalence of obesity and abnormal fasting blood-glucose levels increased.

While it may seem somewhat positive, or at least not negative, that the proportion of adults with healthy untreated blood pressure and total cholesterol levels remained unchanged from 1988 to 2010, when we look at the number of health issues and heart-health awareness that has happened in the past 20 years, it seems like a steady number is in fact a defeated statistic.

Of the two measures that stayed the same since 1988cholesterol and blood pressureonly one is universally understood that too high is bad. Recent arguments have been made that high cholesterol levels aren't linked to heart disease, but pretty much all experts agree that hypertension is negative to health.

Blood pressure, the force against artery walls as the heart pumps blood through the body, is recorded as two numbers, systolic and diastolic. Systolic is the top number and measures the pressure in the arteries when the heart muscle contracts; diastolic is the bottom number, which measures the pressure in the arteries between heartbeats. Starting at age 20, the American Heart Association (AHA) recommends a yearly blood pressure screening if blood pressure is in the normal range (less than 120/80 mmHG). If it's higher, more frequent screenings may be necessary.

According to the AHA, about one in three (33.5 percent) U.S. adults has high blood pressure. This is equivalent to an estimated 76 million U.S. adults. AHA also says about 71 percent of hypertensive adults are taking antihypertensive drugs to control their blood pressure. Anti-hypertension drugs, such as diuretics and ACE inhibitors, come with their own set of risks that many would like to avoid, if possible.

Diuretics help flush water from the body; the theory is with less water and less salt in the blood, hypertension will be reduced. However, some worry about the dehydration that can occur with diuretics. In "The Magnesium Miracle," Carolyn Dean, M.D., said water loss can even cause high blood pressure because the body will hold on to whatever water it can by constricting blood vessels throughout the body. Other common side effects of diuretics include weakness, muscle cramps, joint pain and irregular heartbeat.

ACE inhibitors block the activity of the angiotensin-converting enzyme (ACE). ACE inhibitors work by decreasing chemicals that tighten blood vessels, such as angiotensin II, allowing for more blood flow, which means the heart can pump blood more efficiently. However, they are not without side effects; the most common are cough, elevated blood potassium levels, low blood pressure, dizziness, headache, drowsiness, weakness, abnormal taste (metallic or salty taste) and rash. Some extreme, but rare, side effects include kidney failure, allergic reactions, a decrease in white blood cells and angioedema (swelling of tissues).

The National Institutes of Health (NIH) said higher risk of high blood pressure is linked to those who are African American, obese, stressed, alcohol abusers, salt lovers, in a family with a history of hypertension, diabetics and smokers. Since there are no symptoms until high blood pressure severely damages the heart or brain, consumers may be less likely to address the issue. However, untreated hypertension can lead to several serious health concerns, such as bleeding from the aorta (the large blood vessel that supplies blood to the abdomen, pelvis and legs), kidney disease, heart attack/failure, poor blood supply to the legs, stroke and vision problems.

Over time, high blood pressure damages the blood vessel elasticity and may lead to blood vessel rupture and bleeding. When artery walls are thick and stiff, the risk for arteriosclerosis increases. Uncontrolled high blood pressure increases a person's stroke risk by four to six times, according to WebMD. A stroke occurs when blood flow to an area in the brain is cut off, and as a result, the brain cells, deprived of the oxygen and glucose needed to survive, die. High blood pressure also strains organ systems and can produce symptoms such as severe headaches and blurred vision.

To reduce risk, or reverse hypertension, NIH recommends people follow the seven steps noted in the CDC study. Eating a healthy diet and supplementing with the right ingredients can help keep blood pressure down, which opens an opportunity for natural product manufacturers to offer solutions, including dietary supplements and functional foods/beverages that help blood pressure stay in the normal range. So far, most consumers seem more interested in capsules and tablets in this category, but that doesnt mean they won't go for a healthy blood-pressure-maintaining drink in the future.

And because hypertension is usually not an isolated problem, including healthy ingredients that address many aspects of heart health, obesity and/or metabolic syndrome can work well in combination products.

However, manufacturers in the supplement business need to be sure to steer clear of drug claims, as FDA considers hypertension a disease, and supplements are not allowed to claim they treat, cure, prevent or mitigate diseases. Supplement manufacturers can use phrases such as, promotes healthy blood pressure," healthy blood pressure support" or "maintaining healthy blood pressure already within normal range" to communicate an ingredients benefits; however, statements like these should only be made after consulting with a knowledgeable attorney.

Using ingredients with clinical support can also help strengthen claims; thankfully, many studies have been performed in this area on a number of diet interventions.

Lifestyle

Research has shown adding exercise to any supplement routine will likely add to the blood pressure-reducing effect of any ingredient. In 2010, a study reported sedentary men and women, aged 55 years or older, who exercised using either low- or high-intensity endurance training for one hour three times a week reduced systolic blood pressure before, during and after exercise.² Another study found 16 weeks of resistance training reduced blood pressure and improved cardiovascular function in older men (aged 70 to 80) during moderate cycling exercise.³

A healthy diet is also crucial to controlling blood pressure. The DASH (Dietary Approaches to Stop Hypertension) diet is a dietary pattern promoted by the NIH and endorsed by the AHA, the 2010 Dietary Guidelines for Americans and the Mayo Clinic. It was also ranked as the best diet and the healthiest diet two years in a row by U.S. News & World Report. The diet focuses on fruits and vegetables, low-fat or non-fat dairy, and whole grains. The effects of this diet were studied in the DASH trial, with almost 500 normotensive or mildly hypertensive subjects, and showed it reduced blood pressure significantly.⁴ Mean systolic blood pressure and mean diastolic blood pressure decreased by 5.5 mmHG and 3.0 mmHG, respectively, in the total study cohort. Among the hypertensive subjects, the reductions were even greater; mean systolic blood pressure decreased by 11.4 mmHG, and mean diastolic blood pressure by 5.5 mmHG. In a follow-up study (DASH II), in which sodium intake was restricted to a maximum of 1.5 g/d, mean systolic blood pressure fell further in the normotensive subjects, by 7.1 mmHG.⁵

Minerals

A diet that emphasizes fruits, vegetables and low-fat dairy foods, such as the DASH diet, will be high in the minerals magnesium, potassium and calciumall factors that can contribute to reduced blood pressure. In 1985, Hypertension, an AHA journal, reported intakes of potassium, calcium, protein and milk were all inversely associated with blood pressure levels when examined one at a time controlling for other risk factors in an analysis of 8,000 Japanese men in Hawaii.⁶ The association of potassium intake with blood pressure was relatively stronger than the associations for other nutrients, but the intake of potassium was so highly correlated with intakes of calcium, milk and protein that it was not statistically possible to identify the independent association of potassium and blood pressure.

A 10-week multicenter, randomized, controlled trial comparing a prepared meal plan with a self-selected diet based on nutritionist counseling from the Hypertension Center at Cornell University, New York, concluded blood pressure is reduced with increased intake of minerals such as potassium, magnesium and calcium, perhaps by suppressive circulating calcium-regulating hormones in blood vessels.⁷

A 1999 study noted low magnesium may play a modest role in the development of hypertension.⁸ In 1992, Circulation, another AHA journal, reported increased intake of fiber and magnesium may contribute to the prevention of hypertension, after Harvard researchers examined the relationship of various nutritional factors with hypertension among 30,600 predominantly white U.S. male health professionals, 40 to 75 years old, without diagnosed hypertension.⁹ While age, weight and alcohol consumption were the strongest predictors for the development of hypertension, men with a fiber intake of more than 24 g/d were less likely to suffer from hypertension than those who ate fewer than 12 g/d. Dietary fiber, potassium and magnesium were also inversely related to baseline systolic and diastolic blood pressure, and to change in blood pressure during the follow-up among men who did not develop hypertension. Calcium was significantly associated with lower risk of hypertension only in lean men. Interestingly, that study found no significant association between hypertension and sodium.

While sodium proponents have recently questioned the link between salt and hypertension, the CDC still says most Americans should consume less sodium (2,300 mg/d of sodium for most people, but 1,500 mg/d or less for those older than 51, who are African American, have high blood pressure, have diabetes or have chronic kidney disease). An October 2011 report from the CDC and NIH said 88 percent of the U.S. population consumes more than the recommended amount of salt per day.

The CDC recommendation is backed by research. A 2007 report from the American Medical Association (AMA) said the level of blood pressure, the incremental rise in blood pressure with age and the prevalence of hypertension are directly related to sodium intake.¹⁰ The association said it used observational studies and randomized controlled trials to document a consistent effect of sodium consumption on blood pressure, and said 1.3-g/d lower lifetime sodium intake translates into an approximately 5-mmHG smaller rise in systolic blood pressure as individuals advance from 25 to 55 years of age, a reduction estimated to save 150,000 lives annually.

And a review from 2000 found observational data indicated a reduction in dietary intake of sodium of 100 mmol/d (3 g of salt) lowered systolic blood pressure in subjects aged 50 to 65 years by 10 mmHg on average, which would reduce age-specific stroke mortality by an estimated 22 percent and mortality from heart disease by 16 percent.¹¹ In 2010, a review of ecological, population, prospective cohort and outcome trials found a modest reduction in population salt intake worldwide will result in a major improvement in public health.¹²

However, recent evidence showed sodium lowering does not improve overall heart health. In November 2011, a meta-analysis of more than 167 studies published in the American Journal of Hypertension suggested following a low-sodium diet actually may do more harm than good by triggering a negative chain reaction in the body that increases the risk of diabetes, stroke, heart attack and heart disease.¹³ Researchers from Copenhagen and Bispebjerg University Hospitals in Denmark found eating less than 2,800 mg/d of sodium helped lower blood pressure by 1 percent in people with normal blood pressure and 3.5 percent in those with high blood pressure. However, they also found reduced salt intake triggered a 2.5-percent rise in cholesterol and a 7-percent increase in triglycerides compared to people who were eating more than 3,450 mg/d. They also noted significant increases in levels of the enzyme renin, which regulates blood pressure, and the hormones noradrenaline and adrenaline, which affect blood pressure and heart rate.

Vitamin E

Vitamin E, found in nuts, which are also included in the DASH diet (four to five servings/week), is comprised of tocotrienols and tocopherols, and research has proven its beneficial effects on hypertension. A January 2012 study from Iran found vitamin E supplementation significantly improved blood pressure in diabetic rats.¹⁴ In humans, a randomized, double blind, placebo-controlled clinical trial conducted in 110 men with hypertension found combining vitamin C (1 g/d) with vitamin E (400 IU/d) reduced systolic, diastolic and mean arterial blood pressure after eight weeks compared to placebo-treated patients.¹⁵

Isolating the tocotrienols and using them in a full-spectrum complex can also benefit blood pressure health and reduce stroke riska major risk for those who have hypertension. A clinical trial found patients who supplemented with 160 mg/d or 320 mg/d palm tocotrienol complex (as Tocomin® from Carotech) for two months resulted in significant reduction in aortic systolic blood pressure.¹⁶ A previous study found spontaneous hypertensive rats that received gamma-tocotrienol experienced significantly reduced systolic blood pressure.¹⁷ Gamma-tocotrienol also prevented the expected increased blood pressure, reduce lipid peroxides and enhanced total antioxidant status including the superoxide dismutase (SOD) activity in these rats. In 2011, researchers from Australia reported examination of data from human, animal and in vitro studies showed tocotrienols normalized blood pressure as well as improved lipid profiles, reduced atherosclerotic lesions, decreased blood glucose and glycated hemoglobin concentrations, and inhibited adipogenesis in a metabolic syndrome model.¹⁸

Tocotrienols may help protect the brain for those with hypertension, according to recent research. A 2000 study found alpha-tocotrienol (from Tocomin) was 1,000 times more potent than alpha-tocopherol in protecting the brain cells from glutamate-induced neuron death. ¹⁹ Glutamate, a nonessential amino acid, can accumulate outside cells when brain injury or disease occurs, causing calcium ions to enter cells and leading to neuron damage. Stroke journal, also from the AHA, published a study in 2005 that found oral supplementation of Tocomin SupraBio led to more protection against stroke-induced injury in spontaneously hypertensive rats compared to rats that did not receive the supplement. This study demonstrated the palm tocotrienol complex acted on key molecular checkpoints (c-Src and 12-Lipoxygenase) to protect against glutamate- and stroke-induced neurodegeneration and ultimately may protect against stroke.²⁰

In a paper published in the Journal of Neurochemistry in 2006, professor Chandan Sen of the Ohio State University Medical Center, and a team of researchers, found at lower doses, tocotrienols helped reduce cell death associated with toxicity caused by homocysteic acid, which in excess can cause vascular and neuronal lesions associated with CVD. Sen and his team also found a higher concentration of tocotrienols reduces free-radical activity and the resulting neurotoxicity caused by the fatty acid linoleic acid.²¹ In another study published in 2006, Sen, in collaboration with professor Pramod Khosla, Wayne State University, reported women who took 400 mg/d of Tocovid SupraBio soft gel capsules (formulated from Tocomin SupraBio 20-percent) had 12 to 30 times higher peak plasma tocotrienol levels than those needed to completely prevent stroke-related neurodegeneration two, four, six and eight hours post supplementation.²²

In April 2011, a pre-clinical study from Sen and his team found oral supplementation with tocotrienols reduced overall brain tissue damage, prevented loss of neural connections and helped sustain blood flow in the brains of dogs that had strokes.²³ The researchers found 24 hours after a stroke, lesions indicating brain tissue damage were about 80 percent smaller in dogs that received supplementation than were the lesions in dogs that received no intervention. Tocotrienols also prevented loss of white matter fiber tract connectivity. Imaging tests showed the treated animals brains had better blood flow at the stroke site as compared to untreated dogs brains, a difference attributed to tiny collateral blood vessels ability to improve circulation in the brain when blood flow stopped in more substantial vessels.

Plant Pressure Reducers

Holding out an olive branch to heart health, olive leave extract has been shown to be beneficial for a number of heart-related indices, including blood pressure. Frutaroms Benolea® (EFLA® 943), an olive leaf extract produced with the patented hyperpure technology, demonstrated both its blood pressure reduction and lipid-lowering effect in an unpublished randomized, double blind study on 232 volunteers with stage-1 hypertension During the eight-week treatment period, participants took a Benolea 500-mg caplet two/d or a 12.5-mg tablet of Captopril (a pharmaceutical used to treat hypertension) two/d. Dietary advice was also given to help participants manage their hypertension. Both Benolea and Captopril lowered systolic blood pressure compared to baseline. The reduction in the Benolea group was slightly smaller than in the Captopril group; however, in subjects with higher initial systolic blood pressure (greater than 145 mmHg), the reduction in systolic blood pressure appeared equal with Benolea as with Captopril.

Epidemiological evidence has indicated regular intake of fruit and vegetables and beverages such as red wine and tea, which contain high levels of polyphenols, are associated with a reduced risk of CVDs, including hypertension. A French review of vitro and in vivo evidence from July 2011 said the beneficial effect of polyphenol-rich natural products has been attributable, at least in part, to their direct effect on blood vessels, and in particular on endothelial cells.²⁴ That study also noted polyphenols from tea, grapes, berries and plants have been shown to activate endothelial cells to increase the formation of potent vasoprotective factors including nitric oxide (NO). Further, the review said experimental and clinical studies have also indicated chronic intake of several polyphenol-rich natural products improved endothelial dysfunction and decreased vascular oxidative stress associated with hypertension.

Grapes, as called out in the French review, contain polyphenolic compounds that can cause an endothelium-dependent relaxation of blood vessels, allowing for more blood flow and reduced blood pressure. A 2004 study reported consuming Concord grape juice for eight weeks reduced systolic blood pressure by 7.2 mmHG and diastolic blood pressure by 6.2 mmHG in hypertensive patients.²⁵

MegaNatural® BP, a patented grape seed extract produced by Polyphenolics, a division of Constellation Brands Inc., helps support blood pressure levels that are already within normal range, helps support normal arterial function and supports normal endothelium cell function. In a University of California Davis study, MegaNatural BP lowered both the systolic and diastolic blood pressures compared to placebo in subjects with metabolic syndrome.²⁶ Those in the MegaNatural BP group experienced a reduction in average systolic blood pressure of 12 mmHG and average diastolic blood pressure of 8 mmHG. In a second unpublished study from UC-Davis, participants with prehypertension who took 300 mg/d of MegaNatural BP for eight weeks reduced their systolic blood pressure by 8 mm and diastolic blood pressure by 5 mmHG.

Tomatoes have also been known to help reduce blood pressure, most likely due to their carotenoids, such as lycopene and beta carotene, and vitamin E content. When researchers took tomato extract (as Lyc-O-Mato from LycoRed) and gave it to subjects with hypertension, but who did not require antihypertensive or lipid-lowering drug therapy, it significantly reduced blood pressure.²⁷ In a single blind, placebo-controlled trial, patients entered a four-week placebo period, then an eight-week treatment period with 250 mg/d of Lyc-O-Mato, and a four-week control period with placebo. Systolic blood pressure decreased from 144 to 134 mmHG, and diastolic blood pressure decreased from 87.4 to 83.4 mmHG. No changes in blood pressure were demonstrated during placebo periods.

Three years later, that same group of researchers found Lyc-O-Mato, when given to patients treated with low doses of ACE inhibitors, calcium channel blockers or their combination with low-dose diuretics, reduced blood pressure by more than 10 mmHg systolic and more than 5 mmHg diastolic pressure.²⁸

Pycnogenol® is an antioxidant plant extract from the bark of the French maritime pine (Pinus pinaster) that has shown blood pressure benefits. French maritime pine consists of a mixture of bioflavonoids, procyanidins, catechin, taxifolin and phenolcarbonic acids.

In a double blind, randomized, crossover study, Pycnogenol, 200 mg/d, or placebo was provided to 11 subjects (seven men and four women) with systolic blood pressure of 140 to 159 mmHG and/or diastolic blood pressure of 90 to 99 mmHG for eight weeks.²⁹ Researchers noted a significant decrease in the systolic blood pressure during Pycnogenol supplementation. However, Pycnogenols lowering of diastolic blood pressure did not reach statistical significance when compared to placebo. Working on another blood pressure compound, this study found Pycnogenol supplementation decreased serum thromboxane concentration; thromboxane is a vasoconstrictor and a potent hypertensive agent.

A 2004 placebo-controlled, double blind, parallel group study from China found patients who supplemented with 100 mg/d Pycnogenol for 12 weeks decreased endothelin-1 concentrations (a potent vasoconstrictor peptide) significantly compared to placebo, while concentrations of 6-keto prostaglandin F1a (the metabolite of prostacyclin, an effective vasodilator) in plasma were significantly higher compared to placebo.³⁰ Values for NO in plasma increased in both groups, signifying the possibility for increased blood flow, but the differences were not significant.

A 2010 study published in Hypertension noted a small reduction in systolic blood pressure was observed in spontaneously hypertensive rats that supplemented with either Pycnogenol or melatonin.³¹ Both natural ingredients also improved artery structure and endothelial function.

A 2010 Italian study compared a combination of Pycnogenol and the ACE inhibitor ramipril.³² One group of 26 hypertensive patients with early signs of renal function problems was medicated with 10 mg/d ramipril; a second group of 29 patients took Pycnogenol in addition to the ACE inhibitor over a period of six months. At trial end, a lowered systolic and diastolic blood pressure was found in both groups, with a significant further reduction of diastolic pressure in the group given Pycnogenol in addition to ramipril.

Combining Pycnogenol with Kaneka's coenzyme Q10 (CoQ10, as PycnoQ10® from Horphag) taken by stable heart failure patients as an adjunct to medical treatment, significantly decreased systolic and diastolic pressure as well as decreased heart rate in 12 weeks.³³ Systolic and diastolic pressure was notably lowered with PycnoQ10 from 139.2 to 133.2 mmHg and 82.3 to 77.3 mmHg, versus 140.3 to 139.5 mmHg and 83.4 to 81.2 mmHg in the control group. That study also found the combination increased the blood volume ejected with each beat (signifies a stronger heart) and reduced respiratory rates.

CoQ10

CoQ10, a compound that acts as an electron carrier in the mitochondrial electron transport chain, can work alone as an alternative treatment to hypertensive drugs, according to research. A 12-week randomized, double blind, placebo-controlled trial in a cohort of 46 men and 37 women with isolated systolic hypertension found 60 mg twice/d of oral CoQ10 reduced systolic blood pressure by 17.8 +/- 7.3 mmHG.³⁴ And a 2002 study from Australia found CoQ10 supplementation of 100 mg twice/d improved blood pressure in subjects with type 2 diabetes; CoQ10 significantly decreased systolic (-6.1+/-2.6 mmHg) and diastolic (-2.9+/-1.4 mmHg) blood pressure.³⁵ A year later, a review from the same Australian researchers concluded the limited data available from animal and human intervention studies are generally consistent with a benefit of CoQ10 on vascular function and blood pressure.³⁶

Dairy and Protein

Low-fat dairy is also a highlight of the DASH diet, and epidemiological studies suggest milk consumption and dietary intake of dairy proteins are inversely related to the risk for hypertension. The most studied mechanism underlying the antihypertensive effects of milk peptides is via ACE inhibition, according to a 2007 review.³⁷ An analysis from the first National Health and Nutrition Examination Survey (NHANES I), a cross-sectional study with more 10,000 subjects, found low consumption of milk products was associated with a high incidence of hypertension.³⁸

Intervention studies have also investigated the effects of milk and milk products on blood pressure. A six-month crossover study of blood pressure and serum lipids in 50 free-living volunteers, found 1,150 mg/d of supplemental calcium via yogurt, cottage cheese and milk reduced systolic blood pressure (120 +/- 1.5 to 115 +/- 1.5 mmHG) more than 32 oz/d of orange juice (118 +/- 1.7 to 117 +/- 1.6 mmHG).³⁹ And eight weeks of drinking one quart of 2-percent fortified skim milk reduced systolic and diastolic blood pressure; the low-cholesterol subgroup had a greater decrease in diastolic blood pressure than the high-cholesterol group.⁴⁰

Epidemiological studies also suggest protein intake is inversely related to the risk for hypertension. In fact, a review of epidemiologic evidence from Tulane University, New Orleans, said observational studies identified an inverse relationship between dietary fiber and protein intake and blood pressure, and noted the relationship was demonstrated in both cross-sectional and prospective cohort studies and among various populations.⁴¹

A systematic review of 46 published scientific literature on dietary protein (from various sources) and blood pressure from The Netherlands said biomarker studies and randomized controlled trials indicated a beneficial effect of protein on blood pressure.⁴² According to results in observational studies, the researchers said this beneficial effect may be mainly driven by plant protein.

Enzymes

Certain enzymes can create reactions within the digestive system that lead to lower blood pressure. For instance, Aminogen®, Triarcos patented proteolytic digestive enzyme, when added to a whey protein, only slightly increased systolic blood pressure and decreased diastolic blood pressure, whereas subjects taking whey protein without Aminogen had an increase in systolic and diastolic blood pressure that approached significance.⁴³

Reducing blood pressure can lead to a host of benefits, especially a reduced risk for heart disease and stroke. Adding healthful ingredients, such as magnesium, vitamin E, grape extract and CoQ10, along with a good diet and plenty of exercise can rein in hypertension before devastation occurs.

Heart of the Matter

For more on heart health supplements and the marketing behind them:

Visit INSIDER's free online Heart Health Content Library for articles such as "Jekyll and Hyde are Vying for Your Heart: The HDL and LDL Battle" and "The Other Side of Heart Health: Circulation."

Attend the SuppySide MarketPlace Education session, "Health Conditions: Cardiovascular Health," with speaker Tom Vierhile, innovation insights director, Datamonitor, Wednesday, May 9, from 9 to 11 a.m., Javits Center, New York. Vierhile will discuss how dietary supplements and healthy eating habits can work together to reduce the risk of a coronary event.

References listed on the next page.

References:

1.       Yang Q et al. "Trends in Cardiovascular Health Metrics and Associations With All-Cause and CVD Mortality Among US Adults." JAMA. 2012 Mar 16.

2.       Cornelissen VA et al. " Effects of aerobic training intensity on resting, exercise and post-exercise blood pressure, heart rate and heart-rate variability." J Hum Hypertens. 2010 Mar;24(3):175-82.

3.       Lovell DI, Cuneo R, Gass GC. "Resistance training reduces the blood pressure response of older men during submaximum aerobic exercise." Blood Press Monit. 2009 Aug;14(4):137-44.

4.       Appel LJ et al. "A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group." N Engl J Med. 1997;336:111724.

5.       Sacks FM, Svetkey LP, Vollmer WM, Appel LJ, Bray GA, Harsha D, Obarzanek E, Conlin PR, Miller ER 3rd, et al. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH diet). DASH-Sodium Collaborative Research Group. N Engl J Med. 2001;344:310.

6.       Reed D et al. " Diet, blood pressure, and multicollinearity." Hypertension. 1985 May-Jun;7(3 Pt 1):405-10.

7.       Resnick LM et al. "Factors affecting blood pressure responses to diet: the Vanguard study." Am J Hypertens. 2000 Sep;13(9):956-65.

8.       Peacock JM et al. "Relationship of serum and dietary magnesium to incident hypertension: the Atherosclerosis Risk in Communities (ARIC) Study." Ann Epidemiol. 1999 Apr;9(3):159-65.

9.       Ascherio A et al. "A prospective study of nutritional factors and hypertension among US men." Circulation. 1992 Nov;86(5):1475-84.

10.   Dickinson BD et al. "Reducing the population burden of cardiovascular disease by reducing sodium intake: a report of the Council on Science and Public Health." Arch Intern Med. 2007 Jul 23;167(14):1460-8.

11.   Law M. "Salt, blood pressure and cardiovascular diseases. J Cardiovasc Risk. 2000 Feb;7(1):5-8.

12.   He FJ, MacGregor GA. " Reducing population salt intake worldwide: from evidence to implementation." Prog Cardiovasc Dis. 2010 Mar-Apr;52(5):363-82

13.   Graudal NA, Hubeck-Graudal T, Jürgens G." Effects of low-sodium diet vs. high-sodium diet on blood pressure, renin, aldosterone, catecholamines, cholesterol, and triglyceride (Cochrane Review)."  Am J Hypertens. 2012 Jan;25(1):1-15. doi: 10.1038/ajh.2011.210.

14.   Shirpoor A et al. "Decreased blood pressure with corresponding decrease in adhesive molecules in diabetic rats caused by vitamin E administration." J Diabetes. 2012 Jan 11. doi: 10.1111/j.1753-0407.2012.00184.x.

15.   Rodrigo R et al. "Decrease in oxidative stress through supplementation of vitamins C and E is associated with a reduction in blood pressure in patients with essential hypertension"2008 Clin Sci (Lond). 2008 May;114(10):625-34.

16.   Rasool AHG, et al. "Dose dependent elevation of plasma tocotrienol levels and its effect on arterial compliance, plasma total antioxidant status, and lipid profile in healthy humans supplemented with tocotrienol rich vitamin E." J. Nutr Sci Vitaminol 5, no. 6 (2006): 473-478.

17.   Newaz MA, Nawal NN. "Effect of gamma-tocotrienol on blood pressure, lipid peroxidation and total antioxidant status in spontaneously hypertensive rats." Clin Exp Hypen 21, no. 8 (1999): 1297-1313.

18.   Wong Weng-Yew and Lindsay Brown. "Nutrapharmacology of Tocotrienols for Metabolic Syndrome." Current Pharmaceutical Design, Jul 2011:

19.   Sen CK, et al. "Molecular Basis of Vitamin E Action: Tocotrienol potently inhibits glutamate-induced pp60c-Src kinase and death of HT4 neuronal cells." The Journal of Biological Chemistry 275, no. 17 (2000): 13049-13055.

20.   Khanna S, et al. "Neuroprotective Properties of the Natural Vitamin E alpha-Tocotrienol." Stroke 36 (2005): e144-e152.

21.   Khanna S, et al. "Characterization of the potent neuroprotective properties of the natural vitamin E alpha-tocotrienol." Journal of Neurochemistry 98, no. 5 (2006): 1474-1486.

22.   Khosla P, et al. "Postprandial Levels of the Natural Vitamin E Tocotrienol in Human Circulation." Antioxidants & Redox Signaling 8, no. 5-6 (2006): 1059-1068.

23.   Rink C, et al. "Tocotrienol vitamin E protects against preclinical canine ischemic stroke by inducing arteriogenesis." Journal of Cerebral Blood Flow & Metabolism 31 (2011): 2218-2230.

24.   Schini-Kerth VB et al. " Vascular protection by natural product-derived polyphenols: in vitro and in vivo evidence. Planta Med. 2011 Jul;77(11):1161-7.

25.   Park YK, Kim JS, Kang MH. "Concord grape juice supplementation reduces blood pressure in Korean hypertensive men: double-blind, placebo controlled intervention trial." Biofactors. 2004;22(1-4):145-7.

26.   Sivaprakasapillai B et al. " Effect of grape seed extract on blood pressure in subjects with the metabolic syndrome." Metabolism. 2009 Dec;58(12):1743-6.

27.   Engelhard YN, Gazer B, Paran E. " Natural antioxidants from tomato extract reduce blood pressure in patients with grade-1 hypertension: a double-blind, placebo-controlled pilot study. Am Heart J. 2006 Jan;151(1):100.

28.   Paran E et al. "The effects of natural antioxidants from tomato extract in treated but uncontrolled hypertensive patients." Cardiovasc Drugs Ther. 2009 Apr;23(2):145-51.

29.   Saeed Hosseini et al. " A randomized, double-blind, placebo-controlled, prospective, 16 week crossover study to determine the role of Pycnogenol in modifying blood pressure in mildly hypertensive patients" Nut. Res.2001 Sept; 21(9):1251-60.

30.   Liu X et al. " Pycnogenol, French maritime pine bark extract, improves endothelial function of hypertensive patients." Life Sci. 2004 Jan 2;74(7):855-62.

31.   Rezzani R, et al. Effects of melatonin and Pycnogenol on small artery structure and function in spontaneously hypertensive rats. Hypertension. 2010 Jun;55(6):1373-80.

32.   Cesarone MR, et al.  Kidney flow and function in hypertension: protective effects of pycnogenol in hypertensive participants--a controlled study." J Cardiovasc Pharmacol Ther. 2010 Mar;15(1):41-6.

33.   Belcaro G et al "Investigation of Pycnogenol® in combination with coenzymeQ10 in heart failure patients (NYHA II/III)." Panminerva Med. 2010 Jun;52(2 Suppl 1):21-5.

34.   Burke BE, Neuenschwander R, Olson RD. "Randomized, double-blind, placebo-controlled trial of coenzyme Q10 in isolated systolic hypertension. South Med J. 2001 Nov;94(11):1112-7."

35.   Hodgson JM et al. "Coenzyme Q10 improves blood pressure and glycaemic control: a controlled trial in subjects with type 2 diabetes." Eur J Clin Nutr. 2002 Nov;56(11):1137-42.

36.   Hodgson JM, Watts GF. "Can coenzyme Q10 improve vascular function and blood pressure? Potential for effective therapeutic reduction in vascular oxidative stress." Biofactors. 2003;18(1-4):129-36.

37.   Jauhiainen T, Korpela R. Milk peptides and blood pressure. J Nutr March 2007 137:825S.

38.   McCarron DA et al. " Blood pressure and nutrient intake in the United States." Science. 1984 Jun 29;224(4656):1392-8.

39.   Bierenbaum ML et al. "Dietary calcium. A method of lowering blood pressure." Am J Hypertens. 1988 Jul;1(3 Pt 3):149S-152S.

40.   Buonopane GJ et al. " Effect of skim milk supplementation on blood cholesterol concentration, blood pressure, and triglycerides in a free-living human population." J Am Coll Nutr. 1992 Feb;11(1):56-67.

41.   He J, Whelton PK. " Effect of dietary fiber and protein intake on blood pressure: a review of epidemiologic evidence." Exp Hypertens. 1999 Jul-Aug;21(5-6):785-96.

42.   Altorf-van der Kuil W et al. "Dietary protein and blood pressure: a systematic review." PLoS One. 2010 Aug 11;5(8):e12102.

43.   Anderson, ML. A Double‐Blind Clinical Study to Investigate the Effects of a Fungal Protease Enzyme System on Metabolic, Hepato‐renal, and Cardiovascular Parameters Following 30 Days of Supplementation in Active, Healthy Men. Food Dig Dec 2011.