Nitric Oxide Bioavailability in Chronic Obstructive Pulmonary Disease (COPD)
|First Received Date ICMJE||July 19, 2011|
|Last Updated Date||February 10, 2016|
|Start Date ICMJE||September 2010|
|Primary Completion Date||June 2015 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Flow-Mediated Dilation (FMD) [ Time Frame: 1-4 days ]
Brachial artery FMD induced by reactive hyperemia will be used to assess vascular endothelial function at baseline and several hours after each experimental intervention.
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||Complete list of historical versions of study NCT01398943 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
||Active Hyperemia Induced Flow-Mediated Dilation [ Time Frame: 1-4 days ]
Active hyperemia induced via localized exercise eliminates the systemic pulmonary limintation and allows for the assessment of skeletal muscle function.
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Nitric Oxide Bioavailability in Chronic Obstructive Pulmonary Disease (COPD)|
|Official Title ICMJE||Regulation of Nitric Oxide Bioavailability in Chronic Obstructive Pulmonary Disease: A Mechanistic Approach|
|Brief Summary||More patients with chronic obstructive pulmonary disease (COPD) die from cardiovascular disease than direct pulmonary complications. Inflammation and oxidative stress, characteristic in COPD, are likely contributors to the reduction in nitric oxide (NO) bioavailability and vascular endothelial dysfunction in COPD patients; however, this has yet to be determined. Thus, the overall objective of this proposal is to identify the role of NO bioavailability in contributing to vascular endothelial dysfunction in patients with COPD and to provide insight into the molecular mechanisms involved. Our central hypothesis is that inflammation and oxidative stress, both independently, contribute to the reduction in NO bioavailability and vascular endothelial dysfunction in patients with COPD.|
Testing All participants will initially be screened over the telephone to determine eligibility. After satisfying eligibility requirements, they will be asked to come in for a preliminary testing day. For each individual protocol, at least 2 study visits will be required (preliminary day and experimental day). The specific techniques for the study are underlined and presented below. Participants will arrive early on each testing day, having abstained from tobacco, vitamin supplementation, and exercise for at least 12 hours prior to investigation. Blood draws and measurements of vascular function will be performed at baseline and following each protocol (Aim 1A & B, 2A & B). The P.I., phlebotomist, or research assistant who is certified in drawing blood will collect a total blood sample equal to approximately 80ml (40ml pre and 40ml post), or about 5-6 tablespoons.
Prescreening-Phone Screening - A phone screening form will be used with participants who wish to be involved in the research study. The study will be explained to all subjects and if they wish to continue they will be asked for their contact information and determine if exclusions apply. Subjects who are eligible will be scheduled for the initial preliminary day of testing.
Preliminary Testing Day - All subjects will be asked to report to the laboratory following an overnight fast having abstained from exercise for at least 12 hours and vitamin supplementation for at least 72 hours prior to investigation. Following the initial telephone screening, all eligible subjects will sign a consent form and undergo a preliminary day of testing. The preliminary day will be utilized to assess 1) medical health history, 2) body composition, 3) pulmonary function, 4) maximal skeletal muscle function, 5) brachial ankle index as an assessment of peripheral vascular disease (PVD) and to familiarize each subject with the protocols of the study. Hematocrit and hemoglobin will be determined by finger stick to rule out anemia. A physical activity questionnaire (IPAQ) will be administered to all subjects to quantify physical activity status. Ankle-brachial index will be performed on all subjects to characterize the severity of peripheral artery disease (PAD).
Subject/Medical Information Form - This form summarizes information about the subject's contact information, personal information, family and medical history information, and height and weight. If there is any concern regarding any information presented in the medical health history form, the subject's physician or our medical director may be consulted. Completion of this questionnaire should take approximately 10 minutes.
Body Composition - Dual Energy X-ray Absorptiometry (DXA) is the latest technology in detecting bone mineral density, bone mineral content, and lean and fat mass. The DXA scan is a non-invasive & painless procedure and will be performed during the preliminary testing day. The DXA (Hologic Discovery W using Hologic Apex Software, 2.3.1) will be used to measure bone mineral density and body fat composition through the use of a very low level of radiation (Two scans is equivalent to three days of background radiation exposed from daily routines). Participants will be asked to remove all items that may contain metal including: jewelry, belts, shoes, ear and body piercings, etc. Gowns will be available for those who need to remove clothing. Participants will be instructed to lay on the padded platform and remain still until the platform stops moving. The DXA has been approved and performed in numerous protocols before (HAC#: 0901159, 0711123, etc.). Female participants will be advised that urine pregnancy testing will be done on prior to DXA testing to meet the inclusion criteria of only non-pregnant females in this study. Body Mass Index (BMI; kg/m2) will be calculated using height (m) measured to the nearest 0.1 cm and weight (kg) measured to the nearest 0.05 kg. Both height and weight will be taken without shoes and wearing as few clothes as possible. Waist to Hip Ratio (WHR) will be measured using an inelastic vinyl tape measure (Creative Health Products, Ann Arbor, MI). The site for the waist will be the horizontal plane, at the level of the narrowest part of the torso, between the 10th rib and the iliac crest; with the subject standing erect, arms by the side, and feet together, and relaxing their abdomen. The site for the hips will be the horizontal plane at the level of the maximal extension of the buttocks; with the subject standing erect. Three measurements will be taken to the nearest 0.1 cm at each site. The average of the three measurements will be used to calculate the WHR. The total duration of these assessments is approximately 45 minutes.
Pulmonary Function Test (PFT) - A routine pulmonary function test will be conducted on all subjects using spirometry. Each subject will be instructed to perform a forced expiration maneuver in which the subject will be asked to expire all the air into the spirometer as forcefully and rapidly as possible.
Ankle Brachial Index (ABI) - This test is done by measuring the blood pressure in both the arm and near the ankle. The ABI is used to screen for peripheral vascular disease and will be used to control for confounding PVD in our subjects.
Flow-Mediated Dilation (FMD) - Subjects will lie in the supine position for 20 minutes to obtain hemodynamic steady state. A blood pressure cuff (Hokanson) will be placed around the forearm (distal to the Doppler transducer) and rapidly inflated to 250 mmHg for 5 minutes (circulatory arrest). Simultaneous ultrasound images of the vessel (B-mode) and Doppler waveforms will be collected 10 seconds prior to and for 2 minutes following deflation of the cuff. All B-mode images will be analyzed using automated edge detection software (Medical Imaging Applications), while intensity weighted velocity spectra segments will be saved to the GE Logiq 7 hard drive for off-line blood velocity waveform analysis. P.I. has utilized the traditional method of brachial artery flow-mediated dilation (FMD) induced by reactive hyperemia to assess vascular endothelial function in populations ranging from young healthy adults to older adults with pathological conditions47,58,59.
Carotid Artery Health (IMT) - Immediately following FMD assessments, B-mode ultrasonography will be used on both the right and left carotid arteries to determine the thickness of the intima-media interface. Automated edge detection software (Medical Imaging Applications) will be used for the analysis.
Carotid Artery Compliance (CAC) - After 20 minutes of rest in the supine position, carotid artery compliance will be determined non-invasively using high-resolution ultrasonography (Vivid 7, General Electric) and simultaneous applanation tonometry (Millar Instruments, Inc.) of the contralateral carotid artery [9,10,11]. Briefly, carotid artery diameters will be measured ~2 cm proximal to the carotid bulb with the transducer placed at a 90° angle to the vessel. Images will be recorded via frame grabber for subsequent off-line analysis of maximal diameters (i.e., systolic expansion) and minimal diameters (e.g., diastolic relaxation) corresponding to carotid artery pressure waveforms with vascular image analysis software (Medical Imaging Applications, LLC). High-fidelity carotid artery pressure waveforms will be recorded from the contralateral carotid artery with a pen-like applanation tonometer probe and recorded via data acquisition software (WinDaq, Inc). This technique provides waveforms with the same harmonic content as those obtained invasively in humans. The carotid blood pressure waveform will be calibrated to brachial mean and diastolic blood pressure as previously described [10, 11]. Dr. Pierce has ~3 years of experience in performing the carotid artery ultrasound and ~7 years performing applanation tonometry of the large arteries. He will be responsible for performing the ultrasound and training a research assistant to perform the applanation tonometry. All image and waveform analyses will be performed by the same investigator, who will be blinded to the identity of the subjects.
Active Hyperemia Induced Flow-Mediated Dilation (Skeletal Muscle Function) - Performing localized exercise eliminates the systemic pulmonary limitation and allows for skeletal muscle function in patients with COPD to be compared to healthy controls. During the preliminary day, each subject will undergo a graded maximal plantar flexion exercise test (lower leg) to volitional fatigue. For each treatment day, a similar graded exercise test will be performed in addition to obtaining absolute progressive work rates of 2, 4, and 6 watts for each subject. Each work rate will be performed for approximately 3 minutes to obtain steady state. Simultaneous B-mode images and Doppler waveforms to assess diameter and velocity of the popliteal artery(lower leg), respectively, will be collected for the last 45 seconds of each work rate. Heart rate and oxygen saturation will be assessed throughout the exercise.
Spygmocor - Pulse Wave Velocity (PWV) - A Spygmocor® device will be used at baseline and following each protocol to assess PWV. PWV analysis provides a non-invasive assessment of arterial stiffness. Increased arterial stiffness is known to be associated with cardiovascular disease [13, 14, 15]. The participant is required to lie in a resting position for approximately 30-45 minutes. The research assistant will place ECG electrode sensors at the carotid, femoral, radial and distal artery locations. A highly sensitive pen-like device, called a tonometer, is then gently applied to record the velocity of the blood flow between each of the points.
Blood Samples (pre and post protocols) - A 40 ml sample of venous blood will be drawn pre and post protocol by the P.I. or certified technician via sterile techniques and transferred into EDTA and SST tubes for analysis of HDL-cholesterol, total cholesterol, triglycerides, calculated LDL, and glucose by the Cholestech analyzer unit (Hayward, California) and other laboratory bioassays described below. When applicable (all protocols other than #3), to avoid multiple needle sticks a venous catheter will be placed into the subjects arm. Following each blood draw, and every 1-2 hours, approximately 3cc of injectable sterile saline will be flushed and locked into the catheter to maintain patency (saline block).
|Study Type ICMJE||Interventional|
|Study Phase||Not Provided|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double Blind (Participant, Investigator)
Primary Purpose: Prevention
|Condition ICMJE||Pulmonary Disease, Chronic Obstructive|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Completion Date||June 2015|
|Primary Completion Date||June 2015 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages||18 Years and older (Adult, Senior)|
|Accepts Healthy Volunteers||Yes|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT01398943|
|Other Study ID Numbers ICMJE||AHA00115CS|
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||Not Provided|
|Plan to Share Data||Yes|
|IPD Description||Not Provided|
|Responsible Party||Ryan Harris, Georgia Regents University|
|Study Sponsor ICMJE||Augusta University|
|Collaborators ICMJE||American Heart Association|
|PRS Account||Augusta University|
|Verification Date||February 2016|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP