Cardiovascular Clinical Trial
Official title:
A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study of the Effects of Chitin-Glucan on Oxidized Low-Density Lipoprotein (LDL)
Cardiovascular diseases (CVDs), especially atherosclerotic coronary heart disease and stroke, are the leading causes of death globally. Important risk factors for CVDs include elevated serum levels of total cholesterol, low-density lipoprotein(LDL)-cholesterol, triglycerides, and low high-density lipoprotein (HDL)-cholesterol. Elevated "oxidized" LDL, a pro-inflammatory villain, has also emerged as an important risk factor for the development of CVDs. There is a growing need to identify safe and effective nutritional interventions that offer a clinical benefit aimed at reducing one more of the risk factors for CVDs. Data from many studies in humans have shown various health benefits provided by dietary fiber intake, including an inverse association with the risk of developing cardiovascular disease. The primary purpose of this study is to determine whether daily consumption for 6 weeks of chitin-glucan, a fiber purified from a microorganism, is effective at reducing the amount of oxidized LDL in humans with borderline-to-high LDL-cholesterol. The effects of chitin-glucan on other cardiovascular risk factors will also be evaluated.
Cardiovascular diseases (CVDs), especially atherosclerotic coronary heart disease and
stroke, are the leading causes of death globally. Important risk factors for CVDs include
elevated serum levels of total cholesterol, low-density lipoprotein (LDL)-cholesterol,
triglycerides, and low high-density lipoprotein (HDL)-cholesterol levels. Oxidized LDL has
also been identified as a risk factor for CVDs. There is a growing need to identify safe and
effective interventions that offer a clinical benefit aimed at reducing one more of the risk
factors for CVDs.
Oxidized LDL is a unique plaque-specific protein produced in the arterial wall by the
oxidative modification of the apoB-100 moiety of native LDL mediated by reactive oxygen
species. Oxidized LDL is a powerful atherogenic protein, which is directly involved in the
initiation and progression of atherosclerosis, the main cause of coronary artery disease
(CAD). It is now widely believed that for native LDL to be atherogenic, it must be converted
to oxidized LDL. Oxidized LDL is found in atherosclerotic lesions and in the circulation,
but not in normal arteries. Oxidized LDL is both a biomarker of accelerated atherosclerosis
and a mediator of the atherosclerotic disease process. In 1998, Holvoet et al demonstrated
for the first time that elevated circulating levels of oxidized LDL were found in most
untreated patients with both stable CAD and acute coronary syndromes (unstable angina; acute
myocardial infarction). In this landmark study, oxidized LDL levels were measured in plasma
with an ELISA procedure using the oxidized LDL-specific, murine monoclonal antibody, 4E6.
Mercodia's commercially available oxidized LDL ELISA kits use Holvoet's monoclonal antibody,
4E6, which is specific for oxidatively modified LDL. The 4E6 antibody is directed against a
conformational epitope in the apoprotein(apo)B-100 moiety of LDL that is generated as a
consequence of aldehyde substitution of the lysine residues of apoB-100.
Data from epidemiological studies have shown various health benefits provided by dietary
fiber intake, including an inverse association with the risk of CVDs. As shown in several
well-controlled clinical trials, various water-soluble dietary fibers reduced total
cholesterol and LDL-cholesterol while HDL-cholesterol and triglycerides were not
significantly influenced. Recently, the European Food Safety Authority (EFSA) authorized a
health claim related to the maintenance of normal blood cholesterol concentrations for
soluble cereal fibres, particularly beta-glucans from oat and barley. The beta-glucans in
these cereals are non-starch polysaccharides consisting of (1→3,1→4)-beta-D-linked glucose
units.
Few studies have addressed potential favorable effects of beta-glucans from micro-organisms
on CVD risk factors. One clinical study examined the effects of yeast-derived beta-glucan, a
glucose polymer with beta-(1→3,1→6) linkages, on serum lipids in 15 hypercholesterolemic
obese men. At the end of the 8-week treatment period (15 g fiber/day in addition to the
normal diet), total cholesterol levels were decreased whereas HDL-cholesterol,
LDL-cholesterol and triglycerides did not differ significantly from the baseline values. A
number of animal studies showed that consumption of fungi or fungal extract can lower blood
cholesterol or reduce aortic atherosclerotic lesions in rabbits fed a high-cholesterol diet
or in atherosclerosis-susceptible apolipoprotein E-deficient mice fed a normal. It should be
noted that the fungal component(s) causing these effects have not been identified or
characterized (whole mushrooms or an impure extract were tested).
Chitin-glucan is a natural component of the cell wall of microscopic fungi. Chitin-glucan
can be regarded as an insoluble dietary fiber. In hamsters fed an atherogenic diet,
chitin-glucan mixed with food lowered plasma triglycerides and markedly reduced the
diet-induced formation of aortic fatty streak lesions. It also reduced aortic cholesterol,
cardiac superoxide anion production and hepatic malondialdehyde, and increased hepatic
antioxidant enzyme activities (glutathione peroxidase and superoxide dismutase). Although
oxidized LDL was not measured in this study, data from an early clinical trial indicated
that consumption of chitin-glucan for 28 days decreased circulating oxidized LDL by
approximately 26% in healthy, normo-cholesterolemic young males.
To confirm these results in a randomized, double-blind, placebo-controlled study using males
and females with broader inclusion criteria, chitin-glucan will be evaluated alone (at 1.5
and 4.5 grams per day), and in combination with olive extract (chitin-glucan at 1.5 gram per
day + olive extract at 135 mg per day). There is a large body of evidence that indicates
that olive oil recapitulates many of the beneficial effects on human health, including a
reduced risk for developing CVDs, that are reported for intake of the Mediterranean Diet.
Numerous studies performed in vitro and in vivo have concluded that polyphenolic compounds
present in extra virgin olive oil play an important role in the prevention of
atherosclerotic damage through their inhibition of LDL oxidation. Tyrosol and hydroxytyrosol
show dose-dependent activity in this regard and are considered potent antioxidants,
demonstrating activity in the micromolar range. Thus, there is a solid scientific and
clinical rationale to evaluate both chitin-glucan alone and in combination with olive
extract for their ability to reduce oxidized LDL.
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Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention
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