Role of Flavanols In Cardiovascular Function in Healthy Aging

Study Overview
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Brief Summary
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Groups of naturally occurring compounds called flavonoids are found in foods such as fruits and vegetables, red wine, tea, dark chocolate and cocoa products. Diets rich in flavonoids are associated with decreased risk for cardiovascular disease and major cardiovascular events (i.e. myocardial infarction) and have been shown to improve blood pressure, insulin sensitivity, and vascular function in a variety populations (Type II diabetes, elderly, smokers, etc.). The presumed beneficial effects of these compounds are thought to act through their inherent ability to scavenge free radicals. Specifically flavonoids scavenge superoxide anions which are free radicals that react with nitric oxide (NO) to produce peroxynitrite. The formation of peroxynitrite ultimately reduces the bioavailability of NO which is essential for vasodilation and thus vascular health and function. Normal aging is associated with impaired endothelial function, which presumably is due to less than optimal levels of NO bioavailability. Therefore, interventions that can increase NO bioavailability would be expected to improve microvascular function and vascular health in this population. The purpose of this study is to investigate the effects of dietary flavonoid supplementation on the vasodilatory capacity of the cutaneous vasculature, as well as on cerebral vascular reactivity and arterial stiffness in young and old humans. This study will test the hypothesis that acute dietary flavonoid treatment will improve impaired cutaneous vasodilatory capacity, cerebral vasomotor reactivity, and reduce arterial stiffness in older but not young humans.

Detailed Description
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Role of nitric oxide in vascular function. Nitric oxide (NO) is an important signaling molecule involved in many physiological processes. Of particular interest is its role in endothelial function and blood flow regulation. In response to heat or sheer stress against the walls of blood vessels, the endothelial layer of blood vessels releases NO, which causes smooth muscle in the vessel wall to relax and the vessel to dilate. Environmental heat-stress leads to an increase in skin blood flow to allow for improved heat loss from the body surface to the environment, and relies on NO. Normal aging reduces NO bioavailability leading to an impaired ability to increase skin blood flow in response to environmental heat-stress. Additionally, cerebral blood flow is reduced and arterial stiffness is increased in the normal aging process which is at least partially attributed to reductions in NO bioavailability. Effects of dietary flavonoids. As previously mentioned Flavonoids are a group of natural compounds found in vegetables, fruits, wine, tea, and cocoa. Flavanols are a subfamily of flavonoids, and are quantitatively the most important compound in flavonoid family in western diets. Flavanol intake has been shown to improve vascular health, as well as increase insulin sensitivity, decrease blood pressure, reduce platelet aggregation, and enhance cerebral blood flow. The basic chemical features of flavanol allows them to act as classic antioxidants to scavenge free-radicals decreasing oxidant level in cells. High levels of free radicals, especially superoxide, can reduce the bioavailability of NO and thus any NO-mediated actions. Cocoa and cocoa products are potent sources of flavanols, and therefore have been used extensively as a dietary intervention to study the effects of flavanol supplementation on various disease states. Impairments in vascular health in the normal aging process. The ability to increase skin blood flow in response to environmental heat-stress is lost with normal aging, especially when individuals exceed 65 years of age. An attenuated skin blood flow response during exposure to environmental heat stress would place these older individuals at an increased risk for heat-related illness or death. The ability to raise skin blood flow with rising skin temperature has been demonstrated to have a large nitric oxide component, so a deficit in NO bioavailability, which is also consistently observed in aging populations, could presumably lead to the attenuated skin blood flow response to heat stress. Furthermore, it is well documented that cerebral blood flow is reduced while arterial stiffness is increased in the normal aging process. In regard to the reduction in NO in aging populations, flavanol supplementation has been shown to decrease production of free radicals, which can scavenge and reduce NO levels thereby improving indices of vascular health including flow mediated vasodilation. Therefore, flavanol supplementation may maintain NO bioavailability at optimal levels, and provide a feasible way for aging populations to maintain vascular health and prevent heat-related illness and death. Significance: This study will address the mechanisms of impaired cutaneous and cerebral blood flow as well as increased arterial stiffness that can occur in aging populations. Furthermore, if the hypothesis is correct, findings from this study will provide evidence for the efficacy of flavanols to be used (as a simple and safe lifestyle intervention) to reverse or combat impaired vascular function that commonly occurs in older individuals.

Official Title
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Effects of Dietary Flavanols on Cutaneous, Peripheral, and Cerebral Vascular Function in Young and Old Humans

Conditions
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Aging

Intervention / Treatment
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* Dietary Supplement: High Flavanol first then Low Flavanol
* Dietary Supplement: Low Flavanol first then High Flavanol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and Females between 18 - 26 years old Males and Females between 65 - 80 years old Exclusion Criteria: cardiovascular disease metabolic disease neurological disease Pregnant lady Current smoker (or regularly smoked within last year) Currently taking medications known to effect the autonomic nervous system

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High Flavanol first then Low Flavanol<br>The measurements will be made on all study participants on two separate occasions; 1) before and 2 hours following consumption of a beverage with high flavanol content and 2) before and 2 hours following consumption of a beverage with low flavanol content. | Dietary Supplement: High Flavanol first then Low Flavanol<br>* The high flavanol trial will be performed following consumption of a beverage containing 1,050 mg of commercially available Cocoa Flavanols which will be mixed into 250 ml of distilled water. The subjects will consume this beverage and measurements will be performed 2 hours after consumption. The low flavanol trial will be performed following consumption of a beverage containing 0 mg of Cocoa Flavanols which will be mixed into 250 ml of distilled water. The subjects will consume this beverage and measurements will be performed 2 hours after consumption.<br>* Other names: dark chocolate beverage;|
| Experimental: Low Flavanol first then High Flavanol<br>The measurements will be made on all study participants on two separate occasions; 1) before and 2 hours following consumption of a beverage with low flavanol content and 2) before and 2 hours following consumption of a beverage with high flavanol content. | Dietary Supplement: Low Flavanol first then High Flavanol<br>* The low flavanol trial will be performed following consumption of a beverage containing 0 mg of Cocoa Flavanols which will be mixed into 250 ml of distilled water. The subjects will consume this beverage and measurements will be performed 2 hours after consumption. The high flavanol trial will be performed following consumption of a beverage containing 1,050 mg of commercially available Cocoa Flavanols which will be mixed into 250 ml of distilled water. The subjects will consume this beverage and measurements will be performed 2 hours after consumption.<br>* Other names: Mars Incorporated;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cutaneous Blood Flow Response to Local Heating of the Skin. | Local heating of the cutaneous vasculature to 42 degree C is commonly used to evoke a maximal skin blood flow response (only at the site of local heating). This response is almost entirely dependent on nitric oxide mediated vasodilation. | prior to (baseline) and 2 hours post beverage consumption | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pulse Wave Velocity / Arterial Stiffness | Assessment of pulse wave velocity in the common carotid artery and the femoral artery provides an index of arterial stiffness. | Prior to (baseline) and 2 hours following beverage consumption | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Nitric Oxide, Vascular Function, Aging, Blood Pressure, Arterial Stiffness, Cardiovascular Disease, Cerebral Blood Flow