Study of Chokeberry to Reduce Cardiovascular Disease Risk in Former Smokers

Study Overview
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Brief Summary
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The purpose of this project is to determine whether chokeberry polyphenols mitigate cardiovascular disease risk in former smokers.

Detailed Description
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More than 31% of Connecticut adults are former smokers, which may contribute to the high cardiovascular disease (CVD) risk in this state. Atherosclerosis, a hallmark of CVD, is a progressive life-long process. Chronic cigarette smoking increases atherosclerosis and CVD risk. While smoking cessation may lower CVD risk, former smokers still are at high CVD risk. The mechanisms by which smoking accelerates atherosclerosis formation are not fully understood. This knowledge gap prevents development of informed interventions to reduce CVD risk in former smokers. Previous work suggests smoking increases oxidative stress and leads to elevated CVD risk. Former smokers also have decreased antioxidants and markers of vascular function in the circulation, suggesting that despite cessation, smoking has a lingering adverse effect on CVD protective mechanisms. Chokeberry (Aronia melanocarpa) is a native Connecticut plant rich in polyphenol antioxidants and is a promising intervention for reducing CVD risk in former smokers. Chokeberries have diverse polyphenols such as anthocyanins, proanthocyanidins, resveratrol, quercetin, and chlorogenic acid. Chokeberry consumption improves dyslipidemia, inhibits inflammation, and reduces oxidative stress in humans and animals, all of which could contribute to the prevention of CVD in former smokers. Therefore, our central hypothesis is that dietary chokeberry polyphenols reduce CVD risk in former smokers by improving lipid profiles and inhibiting inflammation and oxidative stress. Our long-term goal is to define the mechanisms by which polyphenol antioxidants mitigate CVD risk. The overall goal of this project is to conduct a randomized placebo-controlled clinical trial to evaluate the cardio-protective effects of dietary chokeberry polyphenols in former smokers. Our objectives are to determine 1) the effect of chokeberry polyphenols on plasma cholesterol and triglyceride levels and on gene expression involved in cholesterol metabolism; 2) the extent to which chokeberry improves antioxidant and vascular function in former smokers; and 3) the association of bioavailability of chokeberry polyphenols to changes in biomarkers of CVD risk. Successful completion of this work will result in improved understanding of the role of dietary berry polyphenols to regulate lipid metabolism, inflammation and oxidative stress. Thus, this study will be an important step to developing dietary recommendations for individuals predisposed to CVD risk, particularly former smokers.

Official Title
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The Effect of Chokeberry Polyphenols on Biomarkers of Cardiovascular Disease and Antioxidant Defenses in Former Smokers

Conditions
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Cardiovascular Disease, Oxidative Stress

Intervention / Treatment
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* Dietary Supplement: Chokeberry Extract
* Dietary Supplement: Placebo capsule
* Dietary Supplement: Chokeberry extract capsule, acute


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Former smoker (previously smoked ≥3 cigarettes/day for at least 1 year, cessation for at least 6 months Healthy male or female between 18-65 y Serum clinical ranges no more than mildly elevated (serum cholesterol <240 mg/dL) and serum triglyceride (<150 mg/dL) Resting blood pressure <140/90 mm Hg Stable body weight (±5 lb) for last 2 months BMI ranges within normal and overweight (18.5-39 kg/m2) Willing to maintain normal exercise level (<7 h/wk) Willing to avoid exercise 24 h prior to blood sampling Willing to ingest a dietary chokeberry supplement or placebo (500 mg/d) daily for 12 wks. Exclusion Criteria: Previous diagnoses of CVD, diabetes, or arthritis (except for osteo-arthritis) Currently being treated for cancer (i.e., chemotherapy, radiation therapy) Women with prescribed estrogen replacement therapy Practicing slimming diet Practicing vegetarian diet Currently taking vitamin or mineral supplements or plant pills Alcohol consumption exceeding the definition of moderate drinking (2 drinks/day or a total of 12/week for men or 1 drink/day or a total of 7/week for women)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Color-matched rice powder pill<br>Color-matched rice powder pill | Dietary Supplement: Placebo capsule<br>* Color-matched rice powder pill, 2 x 250 mg/day for 12 weeks<br>|
| Active Comparator: Chokeberry extract capsule<br>Chokeberry extract capsule | Dietary Supplement: Chokeberry Extract<br>* Consumption of 2 x 250 mg chokeberry extract capsules daily for 12 weeks.<br>|
| Experimental: Chokeberry extract capsule (acute)<br>Chokeberry extract capsule pharmacokinetics | Dietary Supplement: Chokeberry extract capsule, acute<br>* Chokeberry extract capsule, 2 x 250 mg, one-time dose.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| LDL Cholesterol | Change in LDL cholesterol from baseline after chronic supplementation. Not determined in Chokeberry Extract Capsule (Acute) arm as this arm was a one-time dose. | Baseline, 6 weeks, 12 weeks of intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Cholesterol | Change in fasting total cholesterol from baseline after chronic supplementation. Not determined in Chokeberry Extract Capsule (Acute) arm as this arm was a one-time dose. | 6 and 12 weeks after supplementation | 
| HDL-cholesterol | Change in fasting plasma cholesterol from baseline after chronic supplemenation. Not determined in Chokeberry Extract Capsule (Acute) arm as this arm was a one-time dose. | 6 and 12 weeks after supplementation | 
| Triglycerides | Change in fasting plasma triglycerides from baseline after chronic supplementation. Not determined in Chokeberry Extract Capsule (Acute) arm as this arm was a one-time dose. | 6 and 12 weeks after supplementation | 
| Resting Systolic Blood Pressure | Change in resting systolic blood pressure after chronic supplementation. Not determined in Chokeberry Extract Capsule (Acute) arm as this arm was a one-time dose. | Baseline, 6 weeks, and 12 weeks following intervention | 
| Resting Diastolic Blood Pressure | Change in resting diastolic blood pressure after chronic supplementation. Not determined in Chokeberry Extract Capsule (Acute) arm as this arm was a one-time dose. | Baseline, 6 weeks, and 12 weeks following intervention | 
| Urinary F2-isoprostanes | Change in resting urinary F2-isoprostanes after chronic supplementation. Not determined in Chokeberry Extract Capsule (Acute) arm as this arm was a one-time dose. | Baseline and 12 weeks following intervention | 
| 3-hydroxy-3-methyl-glutaryl Coenzyme A Reductase (HMGR) | Monocyte messenger ribonucleic acid (mRNA) expression normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) after chronic supplementation. Not determined in Chokeberry Extract Capsule (Acute) arm as this arm was a one-time dose. | Baseline, 12 wk | 
| LDL Receptor (LDLR) | Monocyte LDL receptor mRNA normalized to glyceraldehyde-3-phosphate dehydrogenase after chronic supplementation. Not determined in Chokeberry Extract Capsule (Acute) arm as this arm was a one-time dose. | Change from baseline at 12 weeks | 
| LDL Receptor (LDLR) Protein | Monocyte LDL receptor protein by Western blot, normalized to β-actin after chronic supplementation. Not determined in Chokeberry Extract Capsule (Acute) arm as this arm was a one-time dose. | Baseline, 12 weeks | 
| Plasma Area Under the Curve of Chokeberry Polyphenols and Their Metabolites. | Plasma area under the curve of chokeberry polyphenols and their metabolites. Measurement (time 0) began at study baseline. Not determined in chronic arms (Color-matched Rice Powder Pill or Chokeberry Extract Capsule). | 0, 0.5, 1, 2, 4, 6, 9, 12, and 24 hours following dose | 
| Urinary Excretion of Polyphenols | Urinary excretion of polyphenols, from 0 to 24 h after consumption of extract, area under the curve (AUC) in Chokeberry Extract Capsule (acute) arm only. | 0 to 24 h after consumption of extract | 
| Adiponectin | Fasting plasma adiponectin after chronic consumption. Not determined in Chokeberry Extract Capsule (Acute) arm as this arm was a one-time dose. | Baseline, 6 weeks, 12 weeks | 
| Interleukin-1 Beta | Fasting plasma interleukin-1 beta after chronic consumption. Not determined in Chokeberry Extract Capsule (Acute) arm as this arm was a one-time dose. | Baseline, 6 weeks, 12 weeks | 
| Interleukin-6 | Fasting plasma interleukin-6 after chronic supplementation. Not determined in Chokeberry Extract Capsule (Acute) arm as this arm was a one-time dose. | Baseline, 6 weeks, 12 weeks | 
| Monocyte Chemoattractant Protein-1 | Fasting plasma monocyte chemoattractant protein-1 after chronic supplementation. Not determined in Chokeberry Extract Capsule (Acute) arm as this arm was a one-time dose. | Baseline, 6 weeks, 12 weeks | 
| Tumor Necrosis Factor-alpha | Fasting plasma Tumor necrosis factor-alpha after chronic supplementation. Not determined in Chokeberry Extract Capsule (Acute) arm as this arm was a one-time dose. | Baseline, 6 weeks, 12 weeks | 
| C-reactive Protein | Fasting plasma C-reactive protein after chronic supplementation. Not determined in Chokeberry Extract Capsule (Acute) arm as this arm was a one-time dose. | Baseline, 6 weeks, 12 weeks | 
| Intercellular Adhesion Molecule 1 | Fasting plasma intercellular adhesion molecule 1 after chronic supplementation. Not determined in Chokeberry Extract Capsule (Acute) arm as this arm was a one-time dose. | Baseline, 6 weeks, 12 weeks | 
| Soluble Vascular Cell Adhesion Molecule 1 | Fasting plasma soluble vascular cell adhesion molecule 1 after chronic consumption. Not determined in Chokeberry Extract Capsule (Acute) arm as this arm was a one-time dose. | Baseline, 6 weeks, 12 weeks | 
| P-selectin | Fasting plasma P-selectin after chronic supplementation. Not determined in Chokeberry Extract Capsule (Acute) arm as this arm was a one-time dose. | Baseline, 6 weeks, 12 weeks | 
| Total Antioxidant Capacity | Fasting plasma total antioxidant capacity after chronic supplementation. Not determined in Chokeberry Extract Capsule (Acute) arm as this arm was a one-time dose. | Baseline, 6 weeks, 12 weeks | 
| Catalase Activity | Catalase activity after chronic supplementation. Not determined in Chokeberry Extract Capsule (Acute) arm as this arm was a one-time dose. | Baseline, 6 weeks, 12 weeks | 
| Glutathione Peroxidase Activity | Fasting plasma glutathione peroxidase activity after chronic supplementation. Not determined in Chokeberry Extract Capsule (Acute) arm as this arm was a one-time dose. | Baseline, 6 weeks, 12 weeks | 
| Superoxide Dismutase Activity | Fasting plasma superoxide dismutase after chronic supplementation. Not determined in Chokeberry Extract Capsule (Acute) arm as this arm was a one-time dose. | Baseline, 6 weeks, 12 weeks | 
| Urinary Polyphenol Excretion | Overnight urinary polyphenol excretion after chronic supplementation. Not determined in Chokeberry Extract Capsule (Acute) arm as this arm was a one-time dose. | 12 weeks | 
| Energy-adjusted Nutrient Intake: Carbohydrate, Protein, Fat, Fiber | Energy-adjusted intake based on 3-day dietary recalls, determined by the average of baseline and 12 weeks. Not determined in Chokeberry Extract Capsule (Acute) arm as this arm was a one-time dose. | Baseline, 12 weeks | 
| Energy Intake | Energy intake reported from 3-day dietary recalls at baseline and 12 weeks, determined by the average of baseline and 12 weeks. Not determined in Chokeberry Extract Capsule (Acute) arm as this arm was a one-time dose. | Baseline, 12 weeks | 
| Energy-adjusted Micronutrient Intake | Energy-adjusted micronutrient intake from 3-day dietary recalls at baseline and 12 weeks. Values reported as the average of baseline and 12 weeks. Not determined in Chokeberry Extract Capsule (Acute) arm as this arm was a one-time dose. | Baseline, 12 weeks | 
| Polyphenol Intake | Energy-adjusted polyphenol intake assessed by 3-day dietary recalls at baseline and 12 weeks, values determined by average of baseline and 12 weeks. Not determined in Chokeberry Extract Capsule (Acute) arm as this arm was a one-time dose. | Baseline, 12 weeks | 
| Intake of Dietary Antioxidant Capacity | Energy-adjusted intake of dietary antioxidant capacity determined by 3-day dietary recalls at baseline and 12 weeks. Values reported as average of baseline and 12 weeks. Not determined in Chokeberry Extract Capsule (Acute) arm as this arm was a one-time dose. | Baseline, 12 weeks | 
| Energy-adjusted Vitamin A Intake | Energy-adjusted vitamin A intake from 3-day dietary recalls at baseline and 12 weeks. Values reported as the average of baseline and 12 weeks. Not determined in Chokeberry Extract Capsule (Acute) arm as this arm was a one-time dose. | Baseline, 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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aronia, LDL cholesterol, polyphenols, bioavailability, oxidative stress