Cardiovascular Effects of Inhalable Tobacco Product Dual Use

PROJECT SUMMARY The introduction of e-cigarettes (e-cigs) was portrayed by the tobacco industry, and expected by the public, to result in an alternative to smoking cigarettes that attenuated or even eliminated their harmful effects. However, while this may be the case in some circumstances, an increasing body of literature indicates that e- cig use can cause some of the same (and some additional) adverse cardiovascular toxicity and health effects as those caused by smoking. This is apparent for both liquid-based e-cigs and heated tobacco products, and in some cases, involves adverse effects that are not dependent on nicotine itself. Over the past decade, this research group has conducted a considerable amount of research in humans and animals to determine what properties of smoking and other inhalational nicotine products accounted for these adverse effects to inform the FDA about their toxicity. The results from those studies clearly indicate that no single constituent is responsible for the adverse vascular effects, and that both adverse vascular and cardiac effects result from exposure to a wide range of these products individually. Conversely, smoking and e-cig use result in distinct profiles of circulating inflammatory mediators, suggesting that they have overlapping effects via non- overlapping causes, with e-cig use causing some endothelial problems not caused by smoking. This suggests that using both cigarettes and e-cigs could result in synergistic adverse effects; i.e., dual use is worse than exclusive use of either product. This stands in contrast to the common assumption by the general public, and by the FDA in recent Marketing Granted Orders for e-cigs and heated tobacco products, that dual use would confer health benefits to smokers. The similarity of physiological effects, despite disparate underlying mechanisms, supports the need to better understand interacting cardiovascular effects of dual use, such as cigarettes + e-cigs. The overarching hypothesis is that at least some adverse cardiovascular effects of smoking and e-cig use stem from distinct underlying causes of harm; therefore, dual use may be worse than exclusive smoking. In the current landscape of multiple products, dual/poly-use is relatively common; therefore, the health effects of a tobacco product should be understood in the context of other prevalent inhalational product use patterns. This project will investigate the cardiovascular effects of dual use on the human, rat, and cellular levels, focusing on whether dual use increases, decreases, or has the same adverse cardiovascular effects as exclusive use of either product. These goals will be accomplished through the following Specific Aims: (1) Understand cardiovascular health effects of dual use of a wide range of nicotine delivery products on vascular and cardiac function in rats. (2) Understand cardiovascular health effects of smoking and e-cig dual use in humans. (3) Identify patterns of circulating biomarkers specific to exclusive or dual use. This project addresses the Health Effects and Toxicity FDA Scientific Domains of interest.