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- Resveratrol
- Cardiovascular Disease
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Date:
02-15-2018 | HC# 061737-586
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Re: Review of the Cardioprotective Effects of Resveratrol Reveals Inconsistent Findings in Clinical Trials, with Positive Results in Preclinical Trials
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. Multiple dietary supplements do not affect metabolic
and cardiovascular health. Aging (Albany
NY). 2014;6(2):149-157.
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