E-Cigarette Effects on Markers of Cardiovascular and Pulmonary Disease

Cardiovascular Diseases Clinical Trial

Official title:

E-Cigarette Effects on Markers of Cardiovascular and Pulmonary Disease Risk (Aka CLUES - Cardiac and Lung E-cig Smoking Study)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03863509
• Other study ID #: 2017-1090
• Secondary ID: 1R01HL139331-01P
• Status: Completed
• Start date: March 5, 2019
• Est. completion date: March 9, 2022

Study information

• Verified date: August 2023
• Source: University of Wisconsin, Madison
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

This study is designed to enhance the understanding of the possible health effects of e-cigarette use by relating the acute and long-term use of e-cigarettes and conventional cigarettes ("products") to well-validated cardiovascular and pulmonary disease biomarkers. Participants will be enrolled in 3 groups: exclusive e-cigarette users, exclusive cigarette smokers, and a control group of never-users. Participants can expect up to 4 weeks of study participation.

Description:

E-cigarette use is increasing rapidly in the United States, especially amongst youth, underscoring the vital need to improve understanding of its health risks. Relevant data could inform policy, guide public health and clinical intervention efforts, and inform individuals who might use or who are using this product. This research will significantly enhance the understanding of the possible health effects of e-cigarette use by relating the acute and long-term use of e-cigarettes and conventional cigarettes ("products") to well-validated cardiovascular and pulmonary disease biomarkers. 3 different "use-groups" of participants will be enrolled: exclusive e-cigarette users (n=165), exclusive cigarette smokers (n=165), and a "control" group of never-users (n=110). These groups reflect the primary decisions that people can make regarding their future tobacco use: to continue to smoke cigarettes, to switch to e-cigarettes, or to avoid tobacco use entirely. It is essential that smokers and health care providers have accurate information on the health effect of these choices. [Additionally, 100 participants will be invited to be part of an epigenetics sub-study (50 E-cig users, 25 smokers and 25 controls), prior to smoking, an additional 16 ml of blood will be collected in Vacutainer cell separation tubes for peripheral blood monocyte (PBMC) Isolation containing sodium citrate.] Product use will be related to well-validated biomarkers that sensitively and reproducibly reflect mechanisms, injury, and/or future risk related to cardiovascular or pulmonary disease. Biomarkers will be related to: 1) acute product use in the laboratory (exposure challenges), 2) lifetime history of product use, and/or 3) real-time measures of product use in participants' daily lives. The primary cardiovascular biomarkers are brachial artery flow-mediated dilation (a measure of endothelial function) and carotid intima-media thickness, a measure of subclinical arterial injury and atherosclerosis. The primary pulmonary disease biomarkers will be measures of lung volumes and flow rates (Forced Expiatory Volume exhaled in the first second (FEV1), Forced vital capacity (FVC), FEV1/FVC) obtained by spirometry. Treadmill exercise stress testing will be performed (to assess aerobic fitness), electrocardiography (to measure heart rate variability, HRV), and measure heart rate, blood pressure, lipids, HgbA1c, and inflammation/oxidation markers (leukocyte count, C-reactive protein, urinary F2 isoprostanes and exhaled nitric oxide). This research will show how product use-groups differ in response to acute product use and long-term use as they are related to key cardiovascular and pulmonary biomarkers. Objective measures of product use include exhaled CO and plasma nicotine/cotinine and urinary nicotine/cotinine concentrations. History of product use within use-groups will be related to biomarker status. The proposed research will yield vital and comprehensive data regarding product use, subclinical arterial injury, atherosclerosis burden, arterial and pulmonary function, cardiac and aerobic fitness, cardiac autonomic regulation, systemic and pulmonary inflammation, and oxidative stress, as well as other key outcomes. These data will serve as a foundation for future longitudinal investigations of e-cigarette health effects and will inform public policy decisions, clinical intervention, and patient guidance regarding e-cigarettes.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 450
• Est. completion date: March 9, 2022
• Est. primary completion date: March 9, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• able to read and write English
• no plans to quit smoking and/or e-cig use in the next month
• not using cigars/smokeless/snus tobacco >/= 1 time per week
• having a stable pattern of current product use
• able to walk at least 2 blocks without assistance or stopping
• Specific to Exclusive Smokers:
• smokes daily
• >/= 5 cigs/day for last 6 months
• < 3 uses E-cigs in lifetime
• >/= 5 ppm carbon monoxide (CO)
• Cotinine > 100 ng/ml
• Specific to Exclusive E-cig users:
• </= 2 days per month cigarette use for last 6 months
• >/= 5 days per week E-cig use for last 3 months
• </= 4 ppm CO
• Cotinine > 100 ng/ml
• Specific to Never-users
• < 100 cigarettes in a lifetime, none for > 5 years
• < 3 E-cig uses in a lifetime
• </= 4 ppm CO
• Cotinine < 100 ng/ml

Exclusion Criteria:

• current use of a smoking cessation medication
• women who are pregnant or plan to get pregnant in the coming month
• women who might be pregnant
• incarcerated individuals
• history of sarcoidosis in past 5 years, or active interstitial lung/pulmonary fibrosis
• history of positive Coronavirus-19 test

Related Conditions & MeSH terms

• Cardiovascular Diseases
• E-Cigarette Use
• Lung Diseases
• Pulmonary Disease
• Tobacco Use

Intervention

Behavioral:
• Cigarettes
smokes daily
• E-Cigarettes
E-cigarette usage >/= 5 days/week

Locations

Country	Name	City	State
United States	University of Wisconsin	Madison	Wisconsin

Sponsors (4)

Lead Sponsor	Collaborator
University of Wisconsin, Madison	National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), University of Wisconsin Center for Tobacco Research and Intervention

Country where clinical trial is conducted

United States, 

References & Publications (1)

Tattersall MC, Hughey CM, Piasecki TM, Korcarz CE, Hansen KM, Ott NR, Sandbo N, Fiore MC, Baker TB, Stein JH. Cardiovascular and Pulmonary Responses to Acute Use of Electronic Nicotine Delivery Systems and Combustible Cigarettes in Long-term Users. Chest. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Brachial Artery Flow-Mediated Dilation (FMD)- Pre Challenge	Brachial Artery Flow-Mediated Dilation is a primary cardiovascular biomarker and a measure of endothelial function that will be assessed before and after an acute exposure challenge. These are pre-challenge values.; Ultrasound based changes in brachial artery diameter after a forearm cuff occlusion (250mmHg) for 5 minutes. FMD is the percent change in brachial diameter measured 60 to 90 seconds post cuff release compared to its resting diameter. A higher % dilation is an indication of better endothelial function.	V2 up to 4 weeks from enrollment visit, fasting
Primary	Forced Expiratory Volume (FEV1)- Pre Challenge	FEV1 is a primary measure of pulmonary disease obtained by spirometry that will be assessed before and after an acute exposure challenge. These are per-challenge values	V2 up to 4 weeks from enrollment visit , fasting, pre challenge session
Primary	Carotid Intima-Media Thickness (IMT)	Carotid Intima-Media Thickness is a cardiovascular biomarker and a measure of sub-clinical arterial injury and atherosclerosis as a result of chronic exposure. IMT will be measured via ultrasonography.	V2 up to 4 weeks from enrollment visit, only done pre-challenge
Primary	Changes in Systolic Blood Pressure Pre- and Post-challenge.	Visit 2 was scheduled up to 4 weeks from enrollment visit, fasting.. They came in the morning after 8 hours of fasting and refraining from nicotine products. Systolic blood pressure (left brachial artery using an oscillometric method) was measured supine, after 10 minutes rest ("Pre") and repeated after they underwent smoking or vaping changes. The "post challenge" blood pressures were recorded 15-20 minutes post end of exposure. For controls, all measurements were repeated in the same order after a 10 minute break.	During Visit 2 (1 - 4 weeks post enrollment) before and after smoking/vaping challenge and for controls after a 10 minute break
Primary	Changes in Diastolic Blood Pressure Pre- and Post-challenge.	Participants returned for V2 up to 4 weeks from enrollment visit, fasting. They came in the morning after 8 hours of fasting and refraining from nicotine products. Diastolic blood pressure (left brachial artery using an oscillometric method) was measured supine, after 10 minutes rest ("Pre") and repeated after they underwent smoking or vaping changes. The "post challenge" blood pressures were recorded 15-20 minutes post end of exposure. For controls, all measurements were repeated in the same order after a 10 minute break.	before and after smoking/vaping challenge during Visit 2 (up to 4 weeks from enrollment)
Primary	Changes in Heart Rate Pre- and Post-challenge.	Visit 2 was scheduled up to 4 weeks from enrollment visit, fasting. Participants attended fasting and refraining from nicotine products for at least 8 hours prior. All visits were in the morning. Pre-challenge heart rate measured supine, after 10 minutes rest from blood pressure monitor (dinamap). The post challenge heart rates were recorded 15-20 minutes post end of exposure to smoking or vaping challenge completion or in the case of controls after a 10 minute break.	Before and after smoking/vaping challenge during Visit 2 (up to 4 weeks from enrollment)
Primary	Changes in Brachial Artery Diameter Pre- and Post-challenge	Visit 2 was scheduled up to 4 weeks from enrollment visit. Participants attended fasting and refraining from nicotine products for at least 8 hours prior. All visits were in the morning. Pre-challenge brachial artery diameter imaged with ultrasound after resting supine for 10 minutes before and repeated 15-20 minutes after smoking/vaping challenge ended. or in the case of controls after a 10 minute break.	before and after smoking/vaping challenge during Visit 2 (up to 4 weeks from enrollment)
Primary	Changes in Brachial Artery Flow Mediated Dilation (FMD) Pre- and Post-challenge	Visit 2 was scheduled up to 4 weeks from enrollment visit. Participants attended fasting and refraining from nicotine products for at least 8 hours prior. All visits were in the morning. Pre-challenge ultrasound of brachial artery diameter imaged with ultrasound after resting supine for 10 minutes before and repeated 15-20 minutes after smoking/vaping challenge ended. or in the case of controls after a 10 minute break. The FMD protocol includes measuring % change in resting diameter after 60-90 seconds post fore-arm cuff occlusion release.	Testing was done after 10 minutes rest and fasting for pre- and post-challenge. The post challenge FMD were recorded 15-20 minuted after end of exposure (up to 4 weeks from enrollment)
Primary	Changes in Percent of Sequential Heart Cycles That Differ by More Than 50 ms From Each Other in Length (PNN50, %) Pre- and Post-challenge	Expressed as a percentage of beats (supine recordings had be 5 minutes or longer to be valid). We used the SphygmoCor system for these recordings (Atcor medical). Participants attended V2 1-2 weeks after enrollment visit. They came in the morning fasting and refraining from nicotine for at least 8 hours. Heart rate variability was recorded supine for 10 minutes or more, pre and post smoking/vaping challenge. For controls is was repeated after a 10-minute break.	During V2 (scheduled up to 4 weeks from enrollment) and obtained after 10 minutes of supine rest, before and after smoking/vaping challenge
Primary	Changes in Root Mean Square of Successive Differences Between Normal Heart Beats (RMSSD, ms) Pre- and Post-challenge	Participants attended V2 up to 4 weeks after enrollment visit. They came in the morning fasting and refraining from nicotine for at least 8 hours. Heart rate variability was recorded supine for 10 minutes or more, pre and post smoking/vaping challenge. For controls it was repeated after a 10 minute break.	heart rate variability recordings of at least 10 minutes per-challenge and 15 minutes post-challenge (up to 4 weeks from enrollment)
Primary	Changes in Heart Rate Variability Standing Ratio Pre- and Postchallenge	We used the SphygmoCor system for these recordings (Atcor medical). Participants attended V2 up to 4 weeks after enrollment visit. They came in the morning fasting and refraining from nicotine for at least 8 hours. Heart rate variability standing ratio was assessed pre and post smoking/vaping challenge. For controls is was repeated after a 10-minute break. Ratio between maximal heart rate after abrupt standing from a supine position and the subsequent lowest heart rate value within 40 seconds of peak.	Ratio was measured pre- and post- smoking/vaping challenge after completion of the 10 minutes of heart rate variability measures (up to 4 weeks from enrollment)
Primary	Changes in Predicted Forced Expiatory Volume in 1 Second (FEV1, %) Pre- and Post-challenge	maximum amount of air that the subject can forcibly expel during the first second following maximal inhalation, expressed as a percentage of the predicted normal values in the population. Participants attended V2 1-4 weeks after enrollment. They came in the morning, fasting and refraining from nicotine exposure for at least 8 hours prior. Pre-challenge spirometry was performed sitting before all other tests and repeated within 15 minutes after smoking/vaping challenge.	before and after smoking/vaping challenge during Visit 2 (1-4 weeks after enrollment visit)
Primary	Changes in Forced Vital Capacity (FVC, %) Pre- and Post-Challenge.	Amount of air that can be forcibly exhaled after taking the deepest breath possible expressed as a predicted percentage from the normal population. Participants attended V2 1-4 weeks after enrollment. They came in the morning, fasting and refraining from nicotine exposure for at least 8 hours prior. Pre-challenge spirometry was performed sitting before all other tests and repeated within 15 minutes after smoking/vaping challenge.	before and after smoking/vaping challenge during Visit 2 Visit 2 which was scheduled 1 to 4 weeks from enrollment visit, fasting
Primary	Changes in Ratio Between Predicted Forced Expiatory Volume in First Second and Predicted Total Vital Capacity (FEV1/FVC Ratio) Pre- and Post-challenge	The post challenge spirometry was recorded <15 minutes post end of exposure. Participants attended V2 1-4 weeks after enrollment. They came in the morning, fasting and refraining from nicotine exposure for at least 8 hours prior. Pre-challenge spirometry was performed sitting before all other tests and repeated within 15 minutes after smoking/vaping challenge.	before and after smoking/vaping challenge during Visit 2 (1-4 weeks after enrollment visit)
Primary	Changes in Percent Predicted Forced Expiratory Flow at 25 and 75% of the Pulmonary Volume (FEF 25-75, %) Pre and Pos-challenge	Participants attended Visit 2 (1-4 weeks after enrollment visit). They came in the morning, fasting and refraining from nicotine exposure for at least 8 hours prior. Pre-challenge spirometry was performed sitting before all other tests and repeated within 15 minutes after smoking/vaping challenge.	Spirometry performed pre-challenge and within 15 minutes post-challenge (up to 4 weeks from enrollment)
Primary	Changes in Fractional Exhaled Nitric Oxide (FeNO, Ppb) Pre- and Post-challenge	Participants attended V2 1-4 weeks after enrollment. They came in the morning, fasting and refraining from nicotine exposure for at least 8 hours prior. Pre-challenge FeNO was obtained sitting and repeated within 15 minutes after smoking/vaping challenge.	before and after less than 15 minutes from smoking/ vaping product (up to 4 weeks from enrollment)
Secondary	Heart Rate (HR)	Heart Rate pre-acute exposure challenge was obtained after resting supine for 10 minutes during V2 in the morning, fasting and refraining from nicotine exposure for at least 8 hours prior.	Participants attended V2 generally 1-4 weeks after enrollment with a window that allowed up to 4 weeks after enrollment
Secondary	Heart Rate Variability (HRV) - Pre Product Use Challenge	Heart Rate Variability PNN50(%) measured before an exposure challenge. Participants attended visit 2 fasting and refraining from nicotine for at least 8 hours.	V2 two was generally scheduled 1-4 weeks after enrollment visit with a window up to 4 weeks. HRV measures obtained after resting supine for 10 minutes
Secondary	Systolic Blood Pressure (BP)	Blood Pressure measured using the oscillometric technique before an acute exposure challenge following standardized protocol. After resting supine for 10 minutes blood pressure was measured on both arms and the average of the last two values was used.	V2 was up to 4 weeks from enrollment visit, after resting supine for 10 minutes
Secondary	Forced Vital Capacity (FVC)	Forced Vital Capacity is a measure of how much air can be exhaled forcefully obtained by spirometry pre acute exposure challenge.	recordings obtained during V2 in the morning, fasting and refraining from nicotine for at least 8 hours. This visit was generally 1-2 weeks after enrollment date with a window up to 4 weeks
Secondary	Fractional Exhaled Nitric Oxide (FeNO)	Fractional Exhaled Nitric Oxide is a measure of airway inflammation measured before an acute exposure challenge.	recordings obtained during V2 in the morning, fasting and refraining from nicotine for at least 8 hours. This visit was generally 1-2 weeks after enrollment date with a window up to 4 weeks
Secondary	Autonomic Measures - RMSSD	Root mean square of standard deviation of rr intervals. Obtained fasting and refraining from nicotine exposure using the Sphymocor system. We used 10 or more minutes of supine data to derive heart rate variability measures.	v2 was generally 1-2 weeks after enrollment visit, with a window up to 4 weeks from V1
Secondary	Arterial Pulse Wave Analysis (PWA), Augmentation Index (at 75 Bpm, %)	Analysis of radial pressure wave forms allows for non-invasive estimation of central aortic pressures, accounting for pressure amplification and the amplitude of the arterial pulse wave as it moves through arteries away from the heart. The Atcor Sphygmacor system can derive central aortic pressures from radial tracings using a validated transfer function. This computation is performed using the pulse wave analysis (PWA) mode. Pulse Wave Analysis via radial tonometry was obtained as a measure of chronic exposure.	v2 was generally 1-2 weeks after enrollment visit, with a window up to 4 weeks from V1
Secondary	Exercise Treadmill Stress Test (ETT)-Peak METS	An ETT to determine exercise capacity will be completed as a measure of chronic exposure. Peak metabolic equivalents (METs, 1 MET=3.5 ml O2 uptake/kg body weight/minute) were determined at all exercise stages, peak exercise, and 1-minute post-exercise.	Treadmill test done only once at the end of v2 after completion of all other post-challenge assessment tests. V2 was scheduled 1-4 weeks from enrollment vist
Secondary	Diastolic Blood Pressure (DBP)	During V2, Diastolic Blood Pressure was measured using the oscillometric technique before an acute exposure challenge following a standardized protocol. After resting supine for 10 minutes blood pressure was measured on both arms and the average of the last two values was used. Participants attended v2 in the morning, fasting and refraining from nicotine products for at least 8 hours.	V2 was generally 1-2 weeks after enrollment with a window up to 4 weeks from V1, recorded after resting supine for 10 minutes
Secondary	Peak Rate Pressure Product (RPP, Peak Heart Rate Multiplied by Peak Systolic Blood Pressure)	Peak RPP was calculated by multiplying maximun heart rate during exercise by systolic blood pressure as a reliable assessment of cardiac workload	During V2 (1-4 weeks after enrollment visit) the treadmill stress test was done last, following Nicotine-containing product challenge (users) or pretend 10 minute exposure for controls
Secondary	Heart Rate Reserve (%)	Measure of maximal exercise capacity adjusted for age, calculated as max heart rate during treadmill divided by (220 minus the participant's age in yrs)	During V2 (1-4 weeks after enrollment visit) the treadmill stress test was done last, following Nicotine-containing product challenge (users) or 10 minute pretend exposure for never-users
Secondary	60 Seconds Heart Rate Recovery (Beats Per Minute)	Difference in heart rate 60 seconds post treadmill minus maximal heart rate during treadmill..	During V2 (1-4 weeks after enrollment visit) the treadmill stress test was done last, following Nicotine-containing product challenge (users) or pretend 10 minute exposure for controls

External Links

•   link to full manuscript with published results for this trial