Cardiovascular disease (CVD) continues to be the leading cause of death worldwide. The primary risk factors for CVD are hyperlipidemia and hypertension (CDC 2011). Antioxidant-rich foods, such as blueberries, are high in phytochemicals such as flavonoids, polyphenols, anthocyanins and pterostilbene, are associated with a reduction in CVD risk and offer other benefits,including protection from oxidative stress and inflammation.

This white paper from ChromaDex Inc. provides more than you’ll likely want to know in an in depth overview of the evidence linking blueberries to CVD protection.  It highlights extensive research on a key ingredient in blueberries, pterostilbene which decreases the body’s synthesis of triglycerides and very low density lipoprotein (VLDL), helps to regulate total cholesterol levels and decreases blood pressure (Rimando 2005, Wiseman 2011).



Cardiovascular Disease

CVD includes hypertension, coronary heart disease, pulmonary heart disease (e.g., heart failure), stroke, atherosclerosis and other diseases of the blood vessels and circulatory system. According to the American Heart Association (AHA), more than one in three American adults has CVD. While CVD deaths have declined 30.6% from 1998 to 2008, it remains the leading cause of death, accounting for more than 800,000 deaths a year in the United States; someone in the United States dies every 39 seconds from cardiovascular disease.

About 150,000 of these deaths occur in people younger than 65 years old
(Roger 2012). The AHA’s heart disease and stroke statistics are as follows: the 2012 update estimated that more than 33.5 million U.S. adults have high total serum cholesterol levels (240 mg/dL or greater), and 76.4 million (33.5%) of U.S. adults suffer from hypertension, putting them at risk for a coronary event (Roger 2012).



Blueberries and CVD Risk Reduction

The Centers for Disease Control and Prevention (CDC) recommends that individuals make healthier lifestyle choices that include not smoking, taking part in daily physical activity and eating a diet that contains a variety of fruits and vegetables (CDC 2011). A diet rich in fruits and vegetables is important for preventing and managing CVD as items in these food groups contain phytochemicals that offer protection against both hyperlipidemia and hypertension. Human, animal and in vitro data linking phytochemicals to CVD protection are persuasive (Neto 2007).

Of all the fruits and vegetables, blueberries are known to have one of the highest antioxidant capacities. The phytochemicals in blueberries protect the body against the effects of free radicals (Neto 2007). As our bodies break down food, they produce by-products such as free radicals, which can attack healthy cells and may play a role in cardiovascular diseases. Oxidative and the production of free radicals, may be caused during metabolism and by environmental agents, such as tobacco smoke
(Sies 1997). Antioxidants remove free radicals and prevent these agents from initiating CVD (Neto 2007).

Antioxidants are being explored for use in dietary supplements and as additives for the prevention of many diseases, including cardiovascular disease and metabolic syndrome. Among all of the phytochemicals contained in blueberries, pterostilbene has significant cardio-protective potential.


Epidemiological and Clinical Studies

Many epidemiological studies have shown that a diet high in antioxidant-rich foods, such as blueberries, may reduce the risk of cardiovascular diseases. In the Kuopio Ischemic Heart Disease Risk Factor (KIHD) study, a prospective cohort study, 1,950 middle-aged Finnish men who had no history of CVD at baseline, were followed for an average of 12.8 years. The men who ate the highest amount of fruits, berries and vegetables (>408 g/day) had a significantly lower risk (relative risk = 0.43, 95% CI = 0.24 – 0.76, P = 0.004) of dying from CVD than men whose diets contained low amounts of fruits, berries and vegetables (<133 g/day) (Rissanen 2002).

Fruit and vegetable intake was also studied in 39,876 female health professionals who participated in the Women’s Health Study (WHS), randomized double-blind, placebo-controlled trial that evaluated the efficacy of low-dose aspirin and vitamin E in preventing CVD and cancer among women who did not have a history of either disease. A median intake of 10.2 servings per day of fruit and vegetables, which was ingested by 98% of the WHS participants who were followed for an average of five years, was associated with a relative risk of 0.68 (95% 0.51-0.92, P = 0.01) for CVD (Liu 2000).


Blueberries and Pterostilbene: Cardiovascular Benefits

The cardioprotective effect of berries, particularly blueberries, has garnered much attention. Among all fruits and vegetables, the blueberry is proving to be a “super-food” with substantial protective benefits against CVD. In a 2012 review, Arpita Basu,Ph.D., associate professor of nutritional science at Oklahoma State University, and Timothy J. Lyons, M.D., professor and chief, in the section of endocrinology and diabetes, Chickasaw chair in diabetes and director of the Harold Hamm Oklahoma Diabetes Center at the University of Oklahoma Health Sciences Center, note that emerging science supports the beneficial role of blueberries and other berries in the management of patients with metabolic syndrome, a group of medical conditions that increase the risk of cardiovascular disease.

In particular, Basu and Lyons cite data showing the ability of blueberries to lower hypertension, improve cholesterol, counterbalance oxidative stress and improve insulin sensitivity (Basu 2012). Basu et al. show that blueberries decrease cardiovascular risk factors in obese men and women with metabolic syndrome
in the single-blinded controlled study.

Forty-eight participants with metabolic syndrome, twenty-five in blueberry group and twenty-three in the control group, consumed a freeze-dried blueberry beverage or equivalent amounts of a controlled
beverage without blueberry for eight weeks. The blueberry group had a significantly lower systolic (- 6% vs – 1.5%, P = 0.003) and diastolic blood (-4 vs -1.2%, P = 0.04) pressures than the control group (Basu 2010). Blacker et al.showed that the phenolic compounds in blueberries reduced postprandial markers of oxidative stress.

Fourteen healthy young adults (18-27 years old) were divided into three groups of five people. One group ate a breakfast of cornflakes with a high dose of freeze-dried blueberry powder (75 g), another ate the cereal breakfast with a low blueberry dose (35 g) and a control group ate the cereal breakfast with sugar and ascorbic acid as found in seventy-five blueberries. Blood was taken beforehand and one, two and three hours after eating the breakfast to measure the oxidation radical absorbance capacity (ORAC). After one and two hours postprandial the high blueberry group had significantly higher increase in ORAC than the control group (P < 0.05) (Blacker 2012).

A cross-over study evaluating oxidative stress in men with cardiovascular risk factors found that drinking a wild-blueberry beverage, containing 25 g freeze-dried powder, reduced oxidative stress. In this study, eighteen men with mean age of 47.8 ± 9.7 years consumed the wild-blueberry drink for six weeks, and then switched to a placebo drink after a 6 week washout period. Consumption of the wild-blueberry drink resulted in significantly lower endogenous oxidized DNA bases (12.5 ± 5.6 % to 9.6 ± 3.5 %, P ≤0.01) and oxidative-induced DNA damage (45.8 ± 7.9 % to 37.2 ± 9.1 %, P ≤ 0.01) (Riso 2012).

Berries_coverA large prospective study looked at flavonoid subclasses in foods and measured their effects on hypertension in American men and women. The researchers recruited participants from three very large studies, the Nurses Health Studies I (meanage = 55 years) and II (mean age = 36 years) and the Health Professionals Follow-up Study (mean age = 56 years). In total,the researchers surveyed 133,914 female and 23,042 male health professionals every four years about their dietary intakes of flavonoids.

In the fourteen years the participants were followed, hypertension was reported by 29,018 women and 5,629
men. The researchers found that a higher intake of the anthocyanin, predominantly from blueberries and strawberries, was associated with a 8% reduced risk for hypertension (relative risk- 0.92, 95% CI – 0.86 – 0.98, P < 0.03), even after controlling for several other risk factors such as age, smoking, BMI, exercise, alcohol consumption, aspirin use, multivitamin use, and family history. The risk reduction was greatest among participants who were younger than 60 years old (relative risk – 0.88; 95% CI – 0.84, 0.93; P < 0.001) (Cassidy 2011).

The literature supports the theory that foods high in antioxidants can significantly affect the health of patients with cardiovascular disease by lowering hypertension and having marked effects on oxidative stress.

Proposed Mechanism of Action

Animal studies demonstrate the putative mechanism by which blueberries may decrease cardiovascular risk. Xieet al.showed that blueberries reduced pro-inflammatory markers of CVD, tumor necrosis factor-α(TNF-α) and interleukin-6 (IL-6), which are among the most potent cytokines linked to the development of atherosclerotic plaques.

In this study, apoE deficient (ApoE(-/-)) mice were fed a diet with or without 1% freeze-dried blueberries for five weeks. mRNA expression and serum levels of TNF –α and IL -6 were attenuated in the mice fed blueberries (p < 0.05). Sera from the mice fed blueberries inhibited the phosphorylation of the IkB, NF-к B, p65, MAPK p38 and JNK in murine macrophage cell line RAW 264.7, thereby preventing the activation of NF-кB and the MAPK pathways (Xie et al. 2011).

Xieet al.undertook another study to better understand the underlying mechanism of the ability of blueberries to reduce atherosclerotic lesion progression and found that in addition to their anti-inflammatory properties, blueberries inhibit gene expression and protein levels of scavenger receptor CD36 and SR-A expression in aorta and peritoneal macrophages (P < 0.05). These scavenger receptors are important in atherosclerotic foam cell development and the initiation of vascular lesions (Xie 2011).

Several animal studies have shown that blueberries improve endothelial function, reduce kidney damage and reduce blood pressure in hypertensive rats (Kalea 2010, Elks 2011). Kaleaet al. showed that wild blueberries improved endothelial function in hypertensive rats by modulating metabolic pathways, such as inhibiting COX-derived products in the aorta (Kalea 2010).

Elkset al.fed forty-eight male stroke-prone spontaneously-hypertensive rats a blueberry-enriched diet (2% w/w) and control diet for six or twelve weeks and found that the blueberry diet decreased systolic and diastolic blood pressures (P < 0.05) and helped to preserve renal function by maintaining higher glomerular filtration rate and renal blood flow and lower renal vascular resistance (P < 0.05) (Elks 2011). Another study showed that feeding 3% blueberry to normotensive and spontaneously-hypertensive stroke-prone rats for six weeks had a similar effect as angiotensin II-converting enzyme (ACE) inhibitors, which are used to treat hypertension in humans. The blueberries reduced ACE activity in the hypertensive rats by 12.4% (P< 0.05) compared to normotensive rats (Wiseman 2011).

Pterostilbene and CVD Risk Protection

Researchers are looking at the pharmacological activities of many fruits and vegetables in hopes that they can help address the epidemic of CVD. Studies are providing evidence that individual components of plant foods provide protection against cardiovascular disease, most notably pterostilbene, a stilbenoid antioxidant.

Pterostilbene is a natural analog of resveratrol and is found in certain fruits such as blueberries, cranberries, sparkleberries, loganberries and grapes. It belongs to a class of compounds called phytoalexins. Plants produce phytoalexins as part of their natural defense system against pathogens such as bacteria and fungi.

However, it is near impossible to consume from food sources the therapeutic amounts of pterostilbene needed to help prevent cardiovascular disease (Rimando 2005).

Although they belong to the same class of compounds, the structure of pterostilbene differs from resveratrol. Pterostilbene contains two methoxy groups and one hydroxyl group while resveratrol has three hydroxyl groups. Several papers have shown that this structural difference is important because the two methoxy groups make pterostilbene more lipophilic than resveratrol. Therefore, it is more easily absorbed by the body (Lin 2009). In addition, pterostilbene has a longer half-life in the blood than resveratrol (Aseni 2002).

A study by Kapetoanovic et al. also showed that 80% of oral pterostilbene was
bioavailable, whereas only 20% of oral resveratrol was bioavailable (Kaptetanvic 2011).
In addition to its affects on hyperlipidemia and insulin sensitivity, pterostilbene has also shown to have antioxidant, anti-inflammatory and antiproliferative properties in a number of in vitro studies.

The peroxisome proliferator-activated receptor (PPAR) isoforms control gene expression by interacting with specific response elements in the promoter region of target genes (Tugwood 1996). PPAR-α is the primary isoform involved in the breakdown of fatty acids and lipids and in the activation of genes involved in fatty acid oxidation in the liver (Fruchart 2003).

Published reports have shown that pterostilbene functions as a PPAR-α activator, thereby decreasing the body’s synthesis of triglycerides and VLDLs, and helps regulate cholesterol levels (Rimando 2005). There have been mixed reports about the efficacy of resveratrol at PPAR-α activation (Rimando 2005; Inoue 2003). Although both are COX-2 inhibitors, pterostilbene achieves this inhibition at lower doses than resveratrol does (Hougee 2005).

Results from the first double-blind, placebo-controlled human trial of pterostilbene (pTeroPure®) were recently presented in a poster at the American Heart Association’s High Blood Pressure Research 2012 Scientific Sessions held in Washington, D.C.

In this prospective clinical trial, the researchers studied eighty adults with hypercholesterolemia (total cholesterol≥200 mg/dL and/or low-density lipoprotein cholesterol [LDL-C]≥100 mg/dL). The average age of the patients was 54 years old. Most of the participants were women (57/80; 71%) and Caucasian (56/80; 70%), and some had been diagnosed with hypertension (44/80; 55%). The participants were 18 years or older and were not taking any cholesterol therapy or their cholesterol medication was at a stable dose for at least two months prior to baseline laboratory testing. Most patients completed the study (73/80; 91%) (Riche 2012).

The eighty participants were randomized into one of four groups:

1. pterostilbene 125 mg twice daily,

2. pterostilbene 50 mg twice daily,

3. pterostilbene 50 mg + grape extract (GE) 100 mg twice daily, or

4. matching placebo twice daily for six to eight weeks.

All the patients received counseling about lifestyle interventions that could decrease their blood pressure and other cardiometabolic parameters.

The researchers measured blood pressure, body weight and lipids and adjusted the results for age, sex and race. They found that participants in the high-dose pterostilbene group had significantly reduced systolic (-7.8 mmHg; p<0.01) and diastolic blood pressure (-7.3 mmHg; p<0.001). The only change in lipids was an increase in LDL-C with pterostilbene monotherapy (+24.9 mg/dL; p<0.001), which was not seen in the grape extract combination group (p=0.47). The presence of a baseline cholesterol medication appeared to attenuate the LDL-C effects (Riche 2012).

In addition, patients not taking cholesterol medication (n=51) exhibited minor weight loss with pterostilbene (-0.59 kg/m2;P =0.014).

Conclusions and Recommendations

Blueberries have been shown to have numerous benefits, including protection from cardiovascular disease. Animal and human studies have suggested that increased consumption of blueberries improve cardiometabolic risk factors and hypertension, as well as provide protection against oxidative stress.

Eating a well-balanced diet that includes at least six servings of fruits and vegetables is a good way to maintain health. However, it is nearly impossible to consume from food sources the therapeutic amounts of pterostilbene needed to help prevent cardiovascular disease. pTeroPure, a synthesized form of pterostilbene, has been shown to reduce hypertension in adults with hypercholesterolemia in a clinical study (Riche 2012).

As evidence accumulates that supports the beneficial effects of pterostilbene, consumers will increasingly seek methods to incorporate this important compound into their diets. Animal and human studies to date have shown that a dose of 25-50 mg of pterostilbene each day for adults would be needed for cardioprotection (Rimando 2005). As it might be difficult for consumers to get an appropriate daily amount of pterostilbene from food sources alone for cardioprotection, food manufacturers should consider adding pTeroPure to their foods and beverages to help consumers achieve this daily goal.



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