Endothelial Dysfunction
Conditions
Keywords
smoking cessation, gamma-tocopherol, nicotine-replacement therapy, oxidative stress
Brief summary
Cigarette smoking is a significant risk factor for cardiovascular disease (CVD) and is the leading cause of premature mortality in the US. The detrimental effects of smoking on vascular dysfunction are attributed to the effects of smoke itself and the inflammatory responses it induces. Smoking cessation restores vascular function by alleviating these stress responses. However, smoking cessation with nicotine replacement therapy (NRT), the prevailing approach to mitigate tobacco dependence, fails to allow full restoration of vascular function. Thus, a critical public health problem exists to understand how NRT prevents restoration of vascular function and how these NRT-mediated impairments can be overcome by using gamma-tocopherol (g-T) as an innovative co-therapy. The objective of this study is to conduct a clinical intervention trial that aims to reduce CVD risk by defining how smoking cessation and g-T restore vascular function. The hypothesis is that smoking cessation and dietary g-T supplementation will synergistically restore smoking-induced impairments in vascular function by ameliorating oxidative/nitrosative stress responses, and that g-T will facilitate full restoration of vascular function otherwise precluded by NRT. A placebo-controlled, g-T intervention study will be conducted in cigarette smokers undergoing nicotine-free or NRT smoking cessation. Prior to and after 24 h and 7 days of placebo or g-T administration, vascular function will be evaluated using a non-invasive ultrasound technique and an array of antioxidants and biomarkers for vascular inflammation and oxidative/nitrosative stress responses will be assessed. Collectively, these studies will help identify how vascular function is regulated in individuals undergoing smoking cessation, and whether g-T can be used as a strategy to better improve vascular function during smoking cessation.
Detailed description
While it is well known that smoking cessation reduces the risk of cardiovascular disease (CVD), the rate in which CVD risk is normalized is relatively slow. This suggests a need to better define co-therapies that target oxidative stress and inflammatory responses that otherwise impair vascular function. In this randomized placebo-controlled clinical study, smokers undergoing smoking cessation with or without nicotine replacement therapy will receive dietary supplementation of gamma-tocopherol (500 mg/day) or placebo for 7 days. Their vascular function and biomarkers of CVD risk (inflammatory proteins, antioxidants, oxidized lipids) will be assessed prior to, and at 1 day and 7 days during smoking cessation with and without gamma-tocopherol supplementation to define potential mechanisms by which gamma-tocopherol may accelerate the restoration of vascular function and assist in reducing CVD risk.
Interventions
Participants will quit smoking with nicotine patches
Participants will take gamma-tocopherol (500 mg/d) supplements for 7 days
Participants will take placebo for 7 days
Participants will quit smoking without any pharmacological aids
Sponsors
Study design
Eligibility
Inclusion criteria
* male or female between 18-60 y, * premenopausal status for women * healthy, verified by serum clinical chemistry * stable body weight (±5 lbs) for 2-mo and BMI 19-30 kg/m2 * non-nutritional supplement user for \>2-mo * free of known diseases including diabetes, CVD, cancer, infections, HIV/AIDS, hepatitis, and bleeding disorders * resting blood pressure \<140/90 mm Hg; * smokers (≥10 cigarettes/d, ≥1 year) * maintaining normal exercise patterns (\<7 h/week) and willingness to avoid exercise 24 h prior to blood sampling and vascular testing * willingness to ingest a dietary vitamin E supplement (gamma-tocopherol; 500 mg/d) or a placebo (composed of tocopherol-free corn oil) daily for 1 week.
Exclusion criteria
* serum chemistry outside normal limits * alcohol consumption \>3 drinks/d or \>10 drinks per week * nutritional supplement user with past 2 months * \>7 hours/week of exercise * use of any pharmacological therapy to treat high cholesterol or high blood pressure * pregnancy, lactation, or initiation or change in hormonal birth control within the previous 3 mo * use of vasoactive compounds (e.g. erectile dysfunction medication, omega 3-fatty acids, niacin) * suffering from major psychiatric illnesses * currently using non-nicotine aids or drugs to quit smoking; or 10) allergy to adhesive tape.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change in Brachial Artery Flow-mediated Dilation at Day 7 From Day 0 | Day 0 and 7 of intervention | Flow-mediated dilation (FMD) of the brachial artery is measured to assess vascular endothelial function. FMD is obtained by monitoring change in vessel diameter before and after brachial artery occlusion with a blood pressure cuff. The unit of FMD is % and is calculated using the following equation: FMD = \[(peak dilation at post occlusion - vessel diameter at preocclusion)/vessel diameter at preocclusion\]\*100. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change From Baseline in Plasma Gamma-tocopherol (Vitamin E) at Day 7 From Day 0. | Day 0 and 7 of intervention | Plasma measurements of gamma-tocopherol was assessed in response to smoking cessation and in combination with gamma-tocopherol (vitamin E) supplementation. |
| Absolute Change From Baseline in Plasma Malondialdehyde at Day 7 From Day 0. | Day 0 and 7 of intervention | Plasma measurements of malondialdehyde, a marker of lipid peroxidation was assessed in response to smoking cessation and in combination with gamma-tocopherol (vitamin E) supplementation |
Countries
United States
Participant flow
Recruitment details
Recruitment took place in and around the community surrounding the University of Connecticut. Recruitment occurred from 2010-2011.
Pre-assignment details
Health status of participants was determined from a comprehensive metabolic panel as well as circulating lipid levels. Individuals having serum chemistries outside of acceptable limits were not enrolled.
Participants by arm
| Arm | Count |
|---|---|
| Supplement + Smoking Cessation Individuals will ingest gamma-tocopherol (500 mg/d) for 7 days while undergoing smoking cessation without any aids | 14 |
| Placebo + Smoking Cessation Individuals will ingest placebo for 7 days while undergoing smoking cessation without any aids | 16 |
| Supplement + Nicotine Replacement Therapy Individuals will ingest gamma-tocopherol (500 mg/d) for 7 days while undergoing smoking cessation with the use of NRT | 13 |
| Placebo + Nicotine Replacement Therapy Individuals will ingest placebo for 7 days while undergoing smoking cessation with the use of NRT | 13 |
| Total | 56 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Protocol Violation | 2 | 2 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 1 | 1 | 1 |
Baseline characteristics
| Characteristic | Placebo + Smoking Cessation | Supplement + Nicotine Replacement Therapy | Supplement + Smoking Cessation | Placebo + Nicotine Replacement Therapy | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants | 13 Participants | 14 Participants | 13 Participants | 56 Participants |
| Age, Continuous | 22 years STANDARD_DEVIATION 4 | 26 years STANDARD_DEVIATION 8 | 22 years STANDARD_DEVIATION 4 | 25 years STANDARD_DEVIATION 8 | 24 years STANDARD_DEVIATION 6 |
| Region of Enrollment United States | 16 participants | 13 participants | 14 participants | 13 participants | 56 participants |
| Sex: Female, Male Female | 5 Participants | 5 Participants | 5 Participants | 4 Participants | 19 Participants |
| Sex: Female, Male Male | 11 Participants | 8 Participants | 9 Participants | 9 Participants | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 14 | 0 / 16 | 0 / 13 | 0 / 13 |
| serious Total, serious adverse events | 0 / 14 | 0 / 16 | 0 / 13 | 0 / 13 |
Outcome results
Absolute Change in Brachial Artery Flow-mediated Dilation at Day 7 From Day 0
Flow-mediated dilation (FMD) of the brachial artery is measured to assess vascular endothelial function. FMD is obtained by monitoring change in vessel diameter before and after brachial artery occlusion with a blood pressure cuff. The unit of FMD is % and is calculated using the following equation: FMD = \[(peak dilation at post occlusion - vessel diameter at preocclusion)/vessel diameter at preocclusion\]\*100.
Time frame: Day 0 and 7 of intervention
Population: Analysis was performed on all participants completing the 7 d intervention
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dietary Supplement + Smoking Cessation | Absolute Change in Brachial Artery Flow-mediated Dilation at Day 7 From Day 0 | 4.08 % of preocclusion diameter | Standard Error 0.61 |
| Placebo + Smoking Cessation | Absolute Change in Brachial Artery Flow-mediated Dilation at Day 7 From Day 0 | 2.77 % of preocclusion diameter | Standard Error 0.35 |
| Dietary Supplement + Nicotine Replacement Therapy | Absolute Change in Brachial Artery Flow-mediated Dilation at Day 7 From Day 0 | 2.97 % of preocclusion diameter | Standard Error 0.51 |
| Placebo + Nicotine Replacement Therapy | Absolute Change in Brachial Artery Flow-mediated Dilation at Day 7 From Day 0 | 2.66 % of preocclusion diameter | Standard Error 0.44 |
Absolute Change From Baseline in Plasma Gamma-tocopherol (Vitamin E) at Day 7 From Day 0.
Plasma measurements of gamma-tocopherol was assessed in response to smoking cessation and in combination with gamma-tocopherol (vitamin E) supplementation.
Time frame: Day 0 and 7 of intervention
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dietary Supplement + Smoking Cessation | Absolute Change From Baseline in Plasma Gamma-tocopherol (Vitamin E) at Day 7 From Day 0. | 7.30 microM | Standard Error 0.98 |
| Placebo + Smoking Cessation | Absolute Change From Baseline in Plasma Gamma-tocopherol (Vitamin E) at Day 7 From Day 0. | -0.10 microM | Standard Error 0.21 |
| Dietary Supplement + Nicotine Replacement Therapy | Absolute Change From Baseline in Plasma Gamma-tocopherol (Vitamin E) at Day 7 From Day 0. | 7.28 microM | Standard Error 1.57 |
| Placebo + Nicotine Replacement Therapy | Absolute Change From Baseline in Plasma Gamma-tocopherol (Vitamin E) at Day 7 From Day 0. | -0.24 microM | Standard Error 0.13 |
Absolute Change From Baseline in Plasma Malondialdehyde at Day 7 From Day 0.
Plasma measurements of malondialdehyde, a marker of lipid peroxidation was assessed in response to smoking cessation and in combination with gamma-tocopherol (vitamin E) supplementation
Time frame: Day 0 and 7 of intervention
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dietary Supplement + Smoking Cessation | Absolute Change From Baseline in Plasma Malondialdehyde at Day 7 From Day 0. | -0.08 microM | Standard Error 0.05 |
| Placebo + Smoking Cessation | Absolute Change From Baseline in Plasma Malondialdehyde at Day 7 From Day 0. | -0.06 microM | Standard Error 0.03 |
| Dietary Supplement + Nicotine Replacement Therapy | Absolute Change From Baseline in Plasma Malondialdehyde at Day 7 From Day 0. | -0.04 microM | Standard Error 0.04 |
| Placebo + Nicotine Replacement Therapy | Absolute Change From Baseline in Plasma Malondialdehyde at Day 7 From Day 0. | -0.07 microM | Standard Error 0.02 |