On June 29-30, 2015, the NHLBI, with co-funding from the NIH Office of Disease Prevention, sponsored a workshop in Bethesda, Maryland, on Cardiovascular and Pulmonary Disease and the Emergence of e-cigarettes. The goal of the meeting was to identify specific gaps in existing research evidence that, if closed, would clarify the acute and chronic pulmonary and cardiovascular health effects of e-cigarette use.
Electronic cigarettes, or e-cigarettes, are battery-powered devices that vaporize a liquid typically containing propylene glycol (PG) and vegetable glycerine (VG) as a vehicle, and nicotine and other constituents such as flavorings and irritants. Users inhale the aerosol. Although it is well known that traditional cigarette use causes multiple cardiovascular and pulmonary diseases, the health implications of e-cigarettes, now a multi-billion dollar market, are largely unknown. E-cigarettes are currently unregulated at the Federal level in the US, and are being perceived by the public as a safer alternative to smoking. There has been limited research to date in the US concerning the cardiopulmonary health effects of e-cigarettes, and many gaps remain. E-cigarette use is growing exponentially in the US, and new evidence that it poses a danger to pulmonary and/or cardiovascular health, together with the potential for addiction and wide-spread use, could indicate an impending and serious public health concern. For this reason, the Division of Lung Diseases and Division of Cardiovascular Sciences at NHLBI conducted a workshop to identify key areas of needed research, as well as opportunities and challenges to conducting research in this area.
Summary of Presentations and Discussions
Drs. Jim Kiley, Director of the Division of Lung Diseases and Mike Lauer, Director of the Division of Cardiovascular Sciences, provided opening remarks to participants, which underscored the importance and relevance of the topic to the NHLBI. The workshop co-Chairs, Drs. Aruni Bhatnagar and Jonathan Samet, each gave opening addresses. Dr. Samet provided a conceptual organizational model, describing various aspects of e-cigarette use to be considered when evaluating mechanistic links to risk for cardiovascular and pulmonary disease. This model formed the basis for subsequent workshop sessions, which included discussions of device characteristics and constituents, health effects of specific constituents such as nicotine and flavorings, user profiles and patterns of use, dosimetry and nicotine exposure, environmental effects and second and third hand exposure, cardiovascular and pulmonary health effects, and risk assessment. Participants were charged with identifying challenges and opportunities in these areas of research, and highlighting specific research gaps.
The meeting organizers, Drs. Lisa Postow and Catherine Stoney, provided the context for the meeting and outlined the goals. Overall recommendations from the group are provided below, followed by specific gap areas identified in each of the workshop sessions.
Consensus and Recommendations
Most Pressing Challenges and Opportunities
- There is a large variety of e-cigarette products on the market, resulting in variability in characteristics such as atomizers, wicking materials, e-liquids, PG/VG ratios, flavorings, and nicotine. Some of this variety is due to differences among product generations, so early research in this area may not be applicable to current devices being used and marketed. A research-grade e-cigarette is needed to standardize research approaches.
- Children and youth, pregnant women, and those with preexisting disease are potentially vulnerable and represent particularly important groups to target with regard to cardiovascular and pulmonary effects of e-cigarettes.
- Development of best practices for animal experiments with e-cigarettes is needed, including accepted methods for animal exposures and a determination of whether animal exposures can reliably reflect the effects of secondhand exposure of e-cigarettes.
- The collection of e-cigarette use data in cohort and clinical trials, disease registries, Electronic Health Records, and other databases through the use of standardized questionnaires and the use of rapid surveillance strategies should be encouraged.
- Standardized survey questions should be developed to capture e-cigarette usage in existing and future NHLBI cohorts and clinical trials.
- Biomarkers of exposure to toxins or potential toxins and biomarkers of cardiopulmonary harm are needed; metabolomics may be a useful strategy.
- Studies of cardiopulmonary effects of e-cigarettes will benefit from a team science approach, incorporating expertise in aerosols, physiology, dosimetry, behavior, flavorings, and other relevant areas.
- Studies testing the effects of inhaled nicotine on cardiovascular and pulmonary systems are needed at both the cell/molecular and the organ/tissue levels.
- The use of cessation studies as a platform for clinical investigations of e-cigarette effects on cardiopulmonary health should be encouraged.
Devices and Constituent Characteristics
The great variety of e-cigarette devices, constituents, heating temperatures, and usage behaviors were discussed. All of these factors influence the nature of the aerosolized product, including the size and chemical nature of the inhaled particles. The complexity of these issues and rapidly changing nature of e-cigarette market should be considered in future research efforts.
- What are the characteristics of aerosol particles resulting from e-cigarette use?
- How and where are aerosol particles deposited in the airways?
- What is contained in e-cigarette aerosols? To what extent do impurities related to solvents and nicotine, metal particles, flavorings, and by-products of heating such as carbonyls contribute to aerosol composition?
- What is the health impact, if any, of additives that are now being incorporated into e-cigarette products to mimic the experience of traditional smoking?
- How can we develop biomarkers of exposure to e-cigarettes?
Health Effects of Constituents
Health and behavioral effects of flavorings and nicotine were addressed in greater detail. While little is known, there are many possible ways that inhaled flavorings might affect the respiratory or cardiovascular system. Nicotine has known effects on the cardiovascular system, and in utero exposure to nicotine has a profound influence on lung development.
- What are the cardiovascular and pulmonary risks, if any, of flavorings as delivered through e-cigarettes?
- What are the long-term effects of nicotine exposure through e-cigarette use?
- What are the risks to the developing fetus when a pregnant woman uses e-cigarettes?
User Profile and Patterns of Use
E-cigarette use is growing rapidly, particularly among current smokers and youth. There is concern that youth usage may promote later tobacco smoking behavior. There is a great need for better, more rapid, and more frequent surveillance of use by youth and older, sicker populations.
- Can standardized questionnaires be developed to document use and use patterns of e-cigarettes?
- Can electronic health records be used to study use patterns and to correlate use with health outcomes?
- How can we better collect information about use patterns in those with cardiovascular or pulmonary diseases?
- Do non-smokers who use e-cigarettes become conventional cigarette users?
- How should dual use (use of both e-cigarettes and other tobacco products) be taken into account when studying e-cigarette users?
- What are e-cigarette usage patterns like during pregnancy?
Dosimetry and Nicotine Exposure
How the lung is exposed to e-cigarette particles will determine how well nicotine is delivered to the user and how airways are exposed to potentially toxic constituents. Device and e-liquid characteristics as well as user behavior influence nicotine dose, and in some cases nicotine dose can exceed that from tobacco cigarette delivery. The nature of aerosol particles from e-cigarettes is immensely complex. Some particles may result from condensation of vapor on ambient air particles, while some particles will be liquid droplets. Many questions also remain regarding lung deposition of particles from e-cigarettes and how they might affect health.
- Can plasma nicotine concentration be predicted from puff topography and device information?
- Where are components of e-cigarettes, such as nicotine, flavorings, metals, and others, getting deposited in the lung, and what are the predictors of locations of deposition?
- How do such factors as device design, concentration of ambient air particles, and temperature of the oral cavity affect the nature of aerosols that form upon inhalation?
- Do individual particles of a heterogeneous aerosol mixture contain different compositions of constituents?
- Is particle deposition altered by disease in the lung?
Second and Third Hand Exposure
There is no side-stream aerosol from e-cigarettes, but user exhalation does expose others to aerosols. There is an epidemiological link between particulate matter air pollution and risks for cardiovascular and pulmonary events. Therefore, any additional particulate matter in the air might have toxic cardiopulmonary effects. Secondhand nicotine exposure might have additional significant effects on bystanders, particularly pregnant women.
- How quickly do e-cigarette particles dissipate in the environment?
- How can the health effects of secondhand exposures best be studied using animal models?
- What are the health effects when children, pregnant women, and others live with e-cigarette users?
Cardiovascular and Pulmonary Effects of E-cigarettes
Some research suggests that there may be pulmonary and cardiovascular health effects of e-cigarettes in animals. There is a great need for early biomarkers of future harm, particularly for diseases that take decades to develop like chronic lung diseases. Individuals with pre-existing diseases might be particularly at risk, but might also comprise a sensitized group for whom possible harm can be detected more rapidly than for the general population.
- What are the acute and chronic effects of e-cigarette use for those with cardiopulmonary disease (cardiovascular disease, asthma, COPD, etc)
- What are the cardiovascular and pulmonary effects of e-cigarettes in youth?
- What is the effect of flavorings, propylene glycol, vegetable glycerine, and nicotine, on airways and the cardiovascular system?
- Does the rate of lung function decline change when smokers of conventional cigarettes change to the exclusive use of e-cigarettes?
- What are the acute and chronic effects of e-cigarettes on endothelial function, the sympathetic nervous system, and pathways of angiogenesis?
- Are inflammatory pathways affected by e-cigarette use?
Potential harms and benefits might be associated with e-cigarette use. Research is necessary to untangle the overall public health consequences of growing e-cigarette use in the US.
- What are the effects of e-cigarette use in youth, in terms of addiction and cardiopulmonary harm?
- How does the growing market for e-cigarettes affect usage of traditional cigarettes?
- Aruni Bhatnagar, MD, University of Louisville, Kentucky, Co-Chair
- Jonathan Samet, MD, University of Southern California, California, Co-Chair
- R. Graham Barr, MD, DrPH, Columbia University, NY
- Neal L. Benowitz, MD, University of California San Francisco, CA
- Pamela I. Clark, BSN, MSPH, PhD, University of Maryland, MD
- Christian H. Coyle, PhD, FDA Center for Tobacco Products
- Pamela Dalton, MPH, PhD, Monell Chemical Senses Center,
- Claire Doerschuk, MD, The University of North Carolina at Chapel Hill, NC
- M. Bradley Drummond, MD, Johns Hopkins University, MD
- Elizabeth L. Durmowicz, MD, FDA Center for Tobacco Products
- Thomas Eissenberg, PhD, Virginia Commonwealth University, VA
- Peter Ganz, MD, University of California San Francisco, CA
- Diane Gold, MD, MPH, Harvard Medical School, MA
- Maciej Goniewicz, PhD, PharmD, Roswell Park Cancer Institute, NY
- Nadia Hansel, MD, PhD, Johns Hopkins University, MD
- Philip K. Hopke, PhD, Clarkson University, NY
- Brian A. King, PhD, MPH, Centers for Disease Control and Prevention
- Suchitra Krishnan-Sarin, PhD, Yale School of Medicine, CT
- Timothy R. McAuley, MS, PhD, Consulting for Health, Air, Nature, & a Greener Environment, NY
- Murray Mittleman, MD, DrPH, Harvard Medical School, MA
- Nancy Rigotti, MD, Massachusetts General Hospital, MA
- Michelle R. Staudt, PhD, Weill Cornell Medical College, NY
- Eliot R. Spindel, MD, PhD, Oregon Health and Science University, OR
- Rachel Widome, PhD, MHS, University of Minnesota, MN
- Lisa Postow, PhD, DLD
- Catherine Stoney, PhD, DCVS
- James Kiley, PhD, DLD
- Michael Lauer, MD, DCVS