Re: Review of Studies of Grape Products Documents Bioactivities that May Reduce Risk of Cardiovascular Disease

Grape (Vitis vinifera, Vitaceae) Polyphenols Cardiovascular Disease Diabetes Date: 09-15-2017 HC# 021742-576 Rasines-Perea Z, Teissedre P-L. Grape polyphenols' effects in human cardiovascular diseases and diabetes. Molecules. January 1, 2017;22(1):68. doi: 10.3390/molecules22010068. Polyphenols, the most abundant secondary metabolites in plants, include flavonoids and non-flavonoids. Dietary intake of polyphenols varies greatly and is difficult to quantify. Polyphenols are poorly characterized in foods and their quantity may vary depending on factors including plant genetics and preparation and storage methods. Epidemiological and clinical studies report that moderate consumption of alcoholic drinks, including wine and juice from grapes (Vitis vinifera, Vitaceae) and from Concord grapes (V. labrusca), affects antioxidant capacity, lipid profiles, and blood coagulation and may reduce incidence of cardiovascular disease (CVD) and total mortality. Type 2 diabetes is often associated with CVD and heart failure, sharing many risk factors. Several studies of grapes and their components, mainly polyphenols and especially resveratrol (RES), have examined the relationship between grape consumption and CVD. The authors review the published benefits of grape polyphenols related to CVD and diabetes but do not describe their search strategy. High blood pressure (BP) is the largest proximal risk factor for CVD; depending upon age, systolic BP (SBP) that is lowered by only 2 mm Hg can be associated with meaningful reductions in CVD mortality. Antihypertensives were the most prescribed drugs in the United States in 2012 and 2013, but hypertension can also be reduced with diet. Studies with grapes that included BP measurements have mostly been conducted in cohorts with prehypertensive average baseline BP, but some have included subjects with metabolic syndrome, with above-average vascular risk, and/or mild to moderate hypertension. Decreases in SBP have been reported with grape seed extract (GSE) supplementation and some report similar drops in diastolic BP (DBP). A meta-analysis of nine randomized controlled trials (RCTs) found that GSE significantly lowered SBP by −1.54 mm Hg (P=0.02) but had no significant effect on DBP. However, some individual RCTs have reported far larger effects. One RCT with a dosage of 150 mg, the lowest of all the RCTs, significantly dropped SBP by −11 mm Hg and DBP by −7 mm Hg compared to placebo. This study used a uniquely processed GSE with a patented composition called MegaNatural®-BP (Polyphenolics; Madera, California). One cited RCT found decreases in SBP and DBP in both the GSE and placebo groups, with a larger decrease in the former. Some trials in people with normal or near-normal BP found no significant BP changes. More RCTs are needed to determine the effect of grape polyphenols on BP, but they show the most promise in those with higher BP. High plasma levels of low-density lipoprotein cholesterol (LDL-C) and low levels of high-density lipoprotein cholesterol (HDL-C) are risk factors for CVD. Polyphenols affect hepatic cholesterol and lipoprotein metabolism by reducing cholesterol absorption and delivery of cholesterol to the liver, thus reducing plasma cholesterol. Polyphenols also affect apolipoproteins (apo) A and B, modify very-low-density lipoprotein (VLDL) particles, and reduce plasma triglyceride (TG) levels, possibly by boosting lipoprotein lipase (LPL) activity. Studies report reductions in total cholesterol (TC), LDL-C, and apo B-100, as well as higher apo A-1 and HDL-C, in healthy individuals and patients undergoing hemodialysis after 14 days of supplementation with 100 mL/d concentrated Bobal* grape juice. Studies with Concord grape juice found increases in TG levels and no changes in TC, HDL-C, or LDL-C. Other studies report varying results with different products and study populations. A study using a GSE product (MegaNatural-Gold; Polyphenolics) found TC, LDL-C, and HDL-C significantly decreased (TC and LDL-C, P<0.01; HDL-C, P<0.05) after three weeks in eight patients with hypercholesterolemia and remained unchanged in nine subjects with normal lipid levels. A crossover RCT with 45 overweight and slightly obese men and women found no difference in HDL-C or LDL-C with 150 mg/d RES or placebo for four weeks. In a double-blind RCT with 40 post-infarction patients, 10 mg/d RES for three months resulted in improvements in endothelial function measured by flow-mediated vasodilation and LDL-C levels (both P<0.05). Grape polyphenols slow LDL oxidation and thus atherosclerosis. Two studies in patients undergoing hemodialysis who consumed 100 mL/d concentrated Bobal grape juice for 14 days found decreases in oxidized LDL (ox-LDL) of 35% and 65%, respectively. Studies using Concord grape juice have reported increases in LDL velocity and, in one case, a 9% reduction in LDL oxidation. In one study, Concord grape juice significantly reduced thiobarbituric acid reactive substances (TBARS) compared to water. One study of GSE found significantly reduced TBARS levels and prolonged lag time for LDL oxidation; another, no change in ox-LDL after supplementation with 1000 mg/d GSE for six weeks. A six-month, triple-blinded RCT of RES-enriched GSE supplementation in 75 patients for primary prevention of CVD found decreased LDL-C (P=0.04), apo B (P=0.014), and ox-LDL (P=0.001); RES was said to be necessary for these effects. Reduced superoxide anion production, involved in formation of ox-LDL, has been found for neutrophils and platelets in different studies of purple grape juice and Concord grape juice. Regarding F2-isoprostanes, an indicator of oxidative stress, conflicting results are reported, with some studies finding decreased levels and others no change or even increased levels. Two studies of the effect of grape supplementation on DNA damage as a marker of oxidative stress found significant decreases in lymphocyte DNA damage for different products in different patient cohorts. Four studies of platelet activation and one of atrial fibrillation suggest more CVD-related benefits of grapes. In one of the former, white grape juice inhibited platelet aggregation more than red grape juice. Six studies reported findings indicating the potential role of grape polyphenols, particularly anthocyanins, flavan-3-ols, and RES, in reducing risk of diabetes. In one, both alcoholic and dealcoholized red wine significantly improved insulin levels over baseline; gin (often flavored with juniper [Juniperus communis, Cupressaceae] berry) did not. Larger, better-quality studies are needed and justified. —Mariann Garner-Wizard *The Bobal variety of V. vinifera comes from the Utiel-Requena region, Valencia, Spain.