Inflammatory cardiovascular disease induced by autonomic effects of e-cigs

We are testing the idea that chronic use of nicotine through e-cigarette inhalation alters the activity of the involuntary or autonomic nervous system and also directly stimulates nicotinic receptors on inflammatory cells. Both processes increase inflammation and fibrosis and predispose to heart disease. We are concerned because e-cigarette (e-cig) popularity has increased dramatically over the past decade and has grown to include use by individuals with no prior history of cigarette smoking nor other nicotine use. There are very limited available data concerning the chronic effects of nicotine delivered by e-cigs, although there is evidence that blood nicotine levels and heart rate increases can be as high as those associated with conventional cigarettes. Cigarette smoking leads to dysregulation of the autonomic nervous system, altering the balance between its two divisions i.e. the sympathetic/vagal balance. Remarkably, the development of heart failure has also been associated with similar imbalance, increased sympathetic and decreased vagal tone.. Drugs that block increased sympathetic signaling (e.g., ?-adrenergic receptor blockers) are a mainstay of treatment in heart failure and there is suggestive evidence that increasing vagal activity is also therapeutically effective. Cardiovascular disease has been increasingly associated with enhanced inflammation, which can lead to fibrosis, stiffness and impaired contractile function of the heart. The question of whether altered cardiac inflammatory responses can occur as a result of e-cig use and if the autonomic nervous system is involved is of major significance for assessing the risks and attitudes regarding this behavior. Notably the few e-cig studies that have been conducted in non-human mammalian models do suggest that e-cig vapor alters systemic inflammatory and immune responses. In addition, there is evidence that nicotine acts directly on nicotinic receptors on macrophages—a major subset of inflammatory cells—and that altered sympathetic and vagal activities can affect cardiac inflammatory responses. It is not known whether there are autonomic nervous system effects of chronic e-cig use that affect cardiovascular function in animal models, nor have effects of e-cig use on cardiovascular and systemic inflammatory responses been considered. We will test the hypothesis that there are maladaptive consequences of chronic aerosolized nicotine exposure that are linked to inflammation and fibrosis and result in increased susceptibility of the heart to stress. We will do this using an apparatus to expose mice to e-cig vapor and avoid whole-body exposure. Our collaborator has published work using this InExpose system. We will examine the hypothesis that inflammation is increased by nicotine-containing e-cig inhalation using mice tested in this model, which achieves blood levels of cotinine—an established marker of nicotine intake—comparable to those achieved in humans. Proposed studies will assess systemic inflammatory responses, as well as those specifically occurring in the heart by measuring changes in expression of genes for pro-inflammatory factors (called chemokines and cytokines) and increases in the number of macrophages in the heart and blood. We will seek evidence that inflammatory changes result from alterations in the response of nicotinic receptors on macrophages and from changes in responses to sympathetic and parasympathetic nerve activity. Finally, we will determine whether in vivo imposition of sepsis using LPS to mimic bacterial infection, and of cardiac stresses by myocardial infarction with reperfusion, causes enhanced disease in mice exposed to chronic e-cig inhalation.