Cardiopulmonary Complications of Electronic Cigarettes

Background:

The invention of electronic cigarettes (E-CIGs) in 2003 upended the trajectory of a decades-long public health campaign against cigarette smoking. Promoted as a safer method of inhaling nicotine compared to cigarettes and as smoking cessation tools, E-CIGs have substantially grown in popularity with rates of uptake now exceeding those of cigarette smoking. Surveys estimate that 5.8% of Canadians 15 years and older have used E-CIGs in the last 30 days. Young Canadians appear particularly susceptible: 13.6% of youths aged 15-19 and 19.7% aged 20-24 report past 30 day E-CIG use. Despite this rapid growth, questions remain as to their long-term safety. In 2019, an outbreak in the United States of acute lung injury related to E-CIGs (later termed E-cigarette or Vaping Use-Associated Lung Injury or EVALI) served as a warning that these devices were not benign. As Canadians increasingly reach for E-CIGs, especially at younger ages and not just for the purposes of smoking cessation, greater clarity into the pulmonary toxicities of E-CIG use is urgently needed.

E-CIG use has been linked to cardiopulmonary risks with potential long-term consequences for health. Even mild reductions in cardiopulmonary function during young adulthood are associated with increased risk of disease, morbidity, and all-cause mortality, underscoring the importance of protecting cardiopulmonary health. Recent work has shown that E-CIG use is associated with reduced exercise capacity (V̇O2peak), increased exertional dyspnea and greater ventilatory inefficiency. Additionally, emerging evidence linking E-CIG use with greater ventilation/perfusion heterogeneity and blunted pulmonary diffusing capacity for carbon monoxide (DLCO) recruitment during a volume-loading challenge suggests the presence of pulmonary vascular dysfunction. However, the mechanisms behind these findings remain largely unknown.

DLCO is a pivotal component of gas exchange and acid-base balance. Indeed, increases in lung diffusing capacity are critical to meeting the elevated metabolic demands during exercise and subsequently preventing a diffusion limitation, excessive increases in alveolar-arterial oxygen difference and possibly exercise induced arterial hypoxemia. Furthermore, reduced DLCO in those with respiratory diseases, such as chronic obstructive pulmonary disease, contributes to exercise intolerance and arterial hypoxemia. Physiological stressors such as exercise and controlled alterations in central blood volume (CBV) provide a means of challenging the cardiopulmonary system to reveal early dysfunction. Exercise increases cardiac output and pulmonary blood flow, requiring proportional increases in DLCO secondary to its components pulmonary capillary blood volume (VC) and membrane diffusing capacity (DM) to maintain efficient gas exchange. Similarly, lower body positive and negative pressure (LBPP/LBNP) transiently manipulate CBV, enabling assessment of pulmonary vascular responsiveness under controlled loading conditions. Evaluating DLCO during these stressors may therefore uncover abnormalities that are not detectable at rest, providing novel insight into the early pulmonary consequences of chronic E-CIG use. Additionally, as many individuals also consume cannabis, the investigators will also recruit a cannabis use only and a combined E-CIG and cannabis group.

Purposes/Objectives and Hypotheses:

The purpose of the current study is to:

1. Describe the relationship between pulmonary vascular structural and functional parameters with exercise tolerance in E-CIG users, and
2. Examine if blunted resting DLCO recruitment in E-CIG users can be normalized by increasing pulmonary blood volume through LBPP.

The investigators hypothesize that:

1. E-CIG users will show a blunted DLCO response to exercise, particularly in females, and that impaired pulmonary vascular structure/function is associated with exercise intolerance in E-CIG users, and
2. Increasing central blood volume via LBPP will normalize resting DLCO in E-CIG users.

Participant Selection:

The study design includes a cohort of individuals aged 12-40 years who have consented to be contacted from previous studies.

Inclusion criteria for the adolescent and adult cohorts are as follows:

Adolescent Cohort:

1. Participants aged ≥12 and \<18 years
2. Control group: \< 100 lifetime cigarettes, \< 200 lifetime E-CIG puffs, and no cannabis exposure
3. E-CIG Use Only: currently using E-CIGs every day or some days
4. Cannabis Use: cannabis smoking history of > 1 joint-year
5. Combined E-CIG and Cannabis Use: adolescents who meet both #3 and #4

Adult Cohort:

1. Participants aged 18-40 years
2. Control group: \< 100 lifetime cigarettes, \< 200 lifetime E-CIG puffs, and no cannabis exposure
3. E-CIG Use Only: currently using E-CIGs every day or some days
4. Cannabis Use: cannabis smoking history of > 1 joint-year
5. Combined E-CIG and Cannabis Use: adults who meet both #3 and #4

Research Method/Procedures:

All visits will happen on separate days with at least 24 hours between visits.

Visit 1: Screening:

The participant will undergo a venous blood draw to measure cotinine and THC, and complete detailed questionnaires regarding demographic, medical, E-CIG and other substance use. The investigators will then perform pulmonary function tests on each participant. Finally, the participant will complete a graded exercise test (V̇O2max, expired gas analyses, operating lung volumes) on an upright cycle ergometer to volitional exhaustion with measurement of heart rate and blood pressure. Evaluation of dyspnea including intensity and unpleasantness will be performed at each workload. Further, reasons for test termination, dyspnea, and qualitative descriptors of dyspnea will be evaluated at peak exercise. Hemoglobin (Hb) concentration will be measured via finger prick prior to and following completion of exercise testing.

At the end of the visit, participants will be provided with an activity monitor to quantify physical activity. They will be instructed to wear the device 24-hours per day for seven consecutive days and return it to the research coordinator at the end of the monitoring period.

Fitbit wear compliance will be monitored by reviewing the recorded activity data and wear time following the 7-day monitoring period. The Fitbit data allows for clear differentiation of when the device is not worn. Participants will be instructed to wear the Fitbit for the duration of the monitoring period, except when removal is necessary (e.g., charging, water-related activities, contact sports). Brief periods of non-wear will be permitted, and participants will be instructed to put the device back on as soon as possible. The research team will review the data for periods of non-wear or missing data and will assess data completeness and integrity prior to analysis.

Visit 2: DLCO with Rest and Exercise:

Exercise will be used as a physiological stressor to increase central blood volume. The participant will perform DLCO maneuvers at rest and during exercise at varying exercise intensities between \~20%-100% of their V̇O2max. Participants will also be equipped with a continuous blood pressure monitor, a brachial blood pressure cuff, an electrocardiogram, and a thoracic impedance device. At each stage participants will also breathe on a mouthpiece for two minutes to collect metabolic data: ventilation (V̇E), oxygen consumption (V̇O2), and carbon dioxide production (V̇CO2). Cardiovascular parameters (blood pressure, peripheral venous pressure, heart rate, thoracic impedance) will be measured continuously. Hb via finger prick will also be measured at each intensity.

As per recommendations , participants will perform standard DLCO breath-hold maneuvers for 6 seconds, and maneuvers will be performed twice at each intensity. A washout period of at least 4 minutes at rest and 2 minutes between each breath hold during exercise will be completed to ensure adequate recovery and blood gas equilibration. Participants will not complete more than 15 DLCO breath holds during each experimental visit.

Visit 3: Central Blood Volume Manipulation and DLCO:

The participant will perform the DLCO test at various levels of LBNP/LBPP ranging from -80 mmHg to +40 mmHg. Changes in central blood volume during LBNP are equivalent to standing upright (-80 mmHg LBNP), and changes in central blood volume during LBPP are equivalent to lying down with the participant's feet above their head (+40 mmHg LBPP). For the LBNP/LBPP trials, participants will lie supine with their lower body (from the iliac crest to their toes) inside the pressure chamber. The participant's lower body will be sealed within the differential pressure chamber using a neoprene skirt to prevent any air leakage from the insides of the chamber. Negative and positive pressures are induced by a vacuum pump that either reduces or increases atmospheric pressure inside the chamber in a controlled and precise manner. The vacuum pump is controlled by a trained member of the research team, and chamber pressure is continuously monitored via a digital manometer.

Participants will be equipped with a continuous blood pressure monitor, a brachial blood pressure cuff, an electrocardiogram, and a thoracic impedance device. Each stage of LBPP/LBNP will begin with two minutes of stabilization followed by two DLCO breath-hold maneuvers. At each stage, participants will also breathe on a mouthpiece for two minutes to collect metabolic data, and oscillometry measurements will be completed twice per stage. Cardiovascular parameters will be measured continuously. Hb via finger prick will be measured prior to the first pressure stage and again at the transition between LBNP and LBPP conditions.

Participants will not complete more than 15 breath holds during the experimental visit. As per recommendations, participants will perform standard DLCO breath-hold maneuvers for 6 seconds, and maneuvers will be performed twice at each stage. A washout period of at least 4 minutes between each breath hold will be completed to ensure adequate recovery and blood gas equilibration.

Visit 4: Ultrasound with Exercise and LBPP/LBNP:

Participants will complete the same interventions as visit 3 (exercise at \~20%-100% of their V̇O2max) and visit 4 (LBNP/LBPP -80 to +40 mmHg). At each stage of exercise and LBNP/LBPP, a trained sonographer will obtain images of the heart via echocardiography.

Visit 5: Blood Volume Measurement Participants from the adult cohort only will undergo a carbon monoxide rebreathe protocol to estimate blood volume. A certified technician will insert an IV catheter into an antecubital vein to collect serial blood samples. While lying supine, participants will inhale a bolus of carbon monoxide (0.7-1.0 mL/kg bodyweight) mixed with 100% oxygen on a rebreathing circuit for two minutes and will then continue to rest for eight additional minutes. Venous blood samples measuring carboxyhemoglobin before the rebreathe and at eight and 10 minutes after the rebreathe will allow the calculation of blood volume.

Visit 6: Computed Tomography:

Participants from the adult cohort only will report to a Medical Imaging Centre for the CT scan. Following a briefing by the Medical Imaging Centre staff, participants will lie supine on the CT scanner and the region of interest in the chest will be obtained. The participant will remain as still as possible and inhale to total lung capacity and hold their breath. During the breath hold, images will be acquired. The participant will then empty their lungs as far as they can and imaging will be repeated.