Re: Review of the Cardioprotective Effects of Resveratrol Reveals Inconsistent Findings in Clinical Trials, with Positive Results in Preclinical Trials

Resveratrol Cardiovascular Disease Date: 02-15-2018 HC# 061737-586 Cho S, Namkoong K, Shin M, et al. Cardiovascular protective effects and clinical applications of resveratrol. J Med Food. 2017;20(4):323-334. Cardiovascular diseases (CVDs) are the most common cause of death worldwide. These authors reviewed the potential effects of resveratrol, a natural compound found in red grapes (Vitis vinifera, Vitaceae) and other fruits, in the development of CVDs and described the evidence on the mechanisms of those effects. Five beneficial effects of resveratrol are reviewed, namely, antiatherogenic, anti-inflammatory, antihypertensive, cardioprotective, and metabolic modulation. Inflammation of the arterial wall, or atherosclerosis, is caused by endothelial damage induced by cytokines responding to hemodynamic and redox stress conditions. Macrophages, a type of white blood cell, play a key role in the development of atherosclerosis. Resveratrol affects many of the chemical compounds involved in macrophage lipid metabolism; it activates endothelial nitric oxide synthase (eNOS), increases high-density lipoprotein efflux, and downregulates endothelin 1 gene—actions that are linked to its antiatherogenic effects. Low-grade inflammation associated with age increases the incidence of both stroke and coronary artery disease. Nitric oxide (NO) helps maintain endothelial cell function. Endothelium-derived NO protects the cardiovascular system during aging, as shown in a study in which mice deficient for the eNOS gene displayed premature cardiac aging and early mortality. Hypertension increases the risk for CVDs. Researchers suggest that resveratrol reduces blood pressure through vasodilatation, antioxidative processes, and neovascularization, with various molecules responsible for each of these processes. Cardioprotective effects of resveratrol have been reported in animal studies. Its protective effects against cardiac hypertrophy are explained by several mechanisms. It protects cardiac muscle cells by decreasing oxidative stress, autophagy, apoptosis, and cardiac fibrosis. The authors caution that "despite the encouraging results in animal models, clinical trials that provide support for the beneficial effects of resveratrol in human subjects are rare to date." Affecting almost one-fourth of the world's population, metabolic syndrome is associated with the risk for CVD and diabetes mellitus. The complex pathophysiology of metabolic syndrome has been only partly explained, with insulin thought to play an important role in the syndrome. Because low potency and stability limit the use of resveratrol, various derivatives have been synthesized to increase its efficiency and stability. In a previous study, the authors described the derivative HS-1793 as a strong cardioprotective drug with enhanced stability and efficiency.1 Human clinical studies have reported on the effects of resveratrol on CVDs. These authors reviewed 20 clinical trials, with 909 subjects, investigating the cardiovascular protective effects of resveratrol. Dosages ranged from 8 mg/kg to 2,000 mg/kg daily. The antiatherosclerotic effect of resveratrol is supported by large clinical trials. Among the studies reporting a beneficial effect is a trial of 75 patients who were undergoing primary prevention of CVDs with statin treatment and who were treated with resveratrol (350 mg daily of resveratrol-enriched grape extract containing 8 mg resveratrol). The investigators reported a 20% decrease in oxidized low-density lipoprotein (LDL) and a 4.5% decrease of LDL cholesterol in those patients.2 In a study of 24 healthy obese men treated with 500 mg resveratrol daily for 28 days, no effects were seen on blood pressure or lipid profile.3 Because other studies found no effect on the lipid profile and some found beneficial effects, the authors write, "[C]linical trials investigating the effect of resveratrol on plasma lipid profile in human subjects remain unclear … ." Clinical studies on the effect of resveratrol on blood pressure reported that doses of resveratrol at 150 mg or more daily significantly reduced systolic blood pressure but did not affect diastolic blood pressure in healthy subjects. Furthermore, one study found that lower doses of resveratrol had no effect on blood pressure. The authors suggest that the antihypertensive effects of resveratrol might be more effective in patients with high blood pressure. In 40 patients with stable coronary artery disease after myocardial infarction, one study reported improved cardiac function after supplementation of 10 mg resveratrol daily for 90 days4; resveratrol helped reduce LDL and improved flow-mediated dilatation and left ventricle diastolic function. In another clinical study of 166 patients with stable angina pectoris, the administration of 20 mg/d resveratrol, calcium fructoborate, and their combination for 60 days improved several markers of coronary artery disease.5 Among the clinical trials investigating the effects of resveratrol on metabolic syndrome are studies in which treatments of resveratrol at doses of 150 mg daily in 11 healthy obese men and 500 mg daily in 50 healthy adult smokers6 reduced plasma triglyceride levels. In the study of the 11 healthy obese men, resveratrol also elevated intramyocellular lipid levels and decreased intrahepatic lipid content, glucose, triglycerides, alanine aminotransferase, and inflammation markers. In healthy, nonobese subjects, however, resveratrol along with other dietary supplements did not affect cardiometabolic risk factors.7 The authors conclude that findings from clinical studies on the cardioprotective effects of resveratrol "are either inconsistent or not as promising as the preclinical findings," suggesting that "conflicting findings between different clinical trials are due to major differences in research protocols, because the relationships between dosage, bioavailability, and physiological response may result in different conclusions in resveratrol effects." This study was supported by grants from the Priority Research Centers Program of the National Research Foundation of Korea, which is funded by the Ministry of Education, Science and Technology of the Republic of Korea. ―Shari Henson References 1Jeong SH, Hanh TM, Kim HK, et al. HS-1793, a recently developed resveratrol analogue protects rat heart against hypoxia/reoxygenation injury via attenuating mitochondrial damage. Bioorg Med Chem Lett. 2013;23(14):4225-4229. 2Tomé-Carneiro J, Gonzálvez M, Larrosa M, et al. Consumption of a grape extract supplement containing resveratrol decreases oxidized LDL and ApoB in patients undergoing primary prevention of cardiovascular disease: a triple-blind, 6-month follow-up, placebo-controlled, randomized trial. Mol Nutr Food Res. 2012;56(5):810-821. 3Poulsen MM, Vestergaard PF, Clasen BF, et al. High-dose resveratrol supplementation in obese men: an investigator-initiated, randomized, placebo-controlled clinical trial of substrate metabolism, insulin sensitivity, and body composition. Diabetes. 2013;62(4):1186-1195. 4Magyar K, Halmosi R, Palfi A, et al. Cardioprotection by resveratrol: a human clinical trial in patients with stable coronary artery disease. Clin Hemorheol Microcirc. 2012;50(3):179-187. 5Militaru C, Donoiu I, Craciun A, Scorei ID, Bulearca AM, Scorei RI. Oral resveratrol and calcium fructoborate supplementation in subjects with stable angina pectoris: effects on lipid profiles, inflammation markers, and quality of life. Nutrition. 2013;29(1):178-183. 6Bo S, Ciccone G, Castiglione A, et al. Anti-inflammatory and antioxidant effects of resveratrol in healthy smokers a randomized, double-blind, placebo-controlled, cross-over trial. Curr Med Chem. 2013;20(10):1323-1331. 7Soare A, Weiss EP, Holloszy JO, Fontana L. 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