Influence of Cooling Agents on the Arrhythmogenic and Autonomic Effects of Electronic Cigarettes in an in vivo Model

BACKGROUND: Despite the growing popularity of electronic cigarettes, evidence is mounting that vaping induces autonomic nervous system imbalance, cardiac arrhythmia, and potentially even cardiac arrest. The ingredients menthol, Wilkinson Sword (WS)-3, and WS-23 are cooling agents that enhance the appeal of electronic cigarettes (e-cigs) but bear unknown risks when inhaled. METHODS: We systematically evaluated how these coolants influence the impacts of e-cigs on cardiac and cellular electrophysiology in mice and human induced pluripotent stem cell-derived cardiomyocytes, respectively. Mice were exposed by inhalation to e-cig aerosols generated from standard e-liquid solvents and 2.5% nicotine benzoate (vehicle), or from vehicle plus menthol, WS-3, or WS-23, at increasing concentrations throughout exposure. Telemetry-derived electrocardiograms were analyzed for changes in heart rate, heart rate variability, morphology, and ventricular premature beat arrhythmias. Human induced pluripotent stem cell-derived cardiomyocytes were evaluated for the effects of serially increasing coolant concentrations on beat rate, electric field potential duration, and rate-corrected field potential duration from a newly validated formula, in the absence and presence of norepinephrine to simulate basal physiology and nicotine-evoked sympathoexcitation. RESULTS: Upon e-cig aerosol inhalation, all coolants acutely enhanced vehicle-induced autonomic imbalance, but only the synthetic coolants, WS-3 and WS-23, potentiated ventricular arrhythmogenesis. Ventricular premature beats during e-cig exposures correlated with sympathetic dominance and transient delays in ventricular repolarization measured by heart rate variability and QT interval corrected by RR interval, respectively; however, correlations were strongest for WS-23 despite no significant impact of coolants on nicotine intake. Conversely, in human induced pluripotent stem cell-derived cardiomyocytes, coolants did not affect basal physiology but slowed beat rate and shortened rate-corrected field potential duration during norepinephrine stimulation. CONCLUSIONS: Together, these data indicate that coolants dose-dependently enhance the arrhythmogenicity of e-cigs, likely through acute alterations in autonomic modulation and repolarization. Pending confirmation by human studies, these common nonnicotine additives may exacerbate e-cig cardiotoxicity and pose unique cardiovascular risks, particularly in those with arrhythmogenic susceptibility to sympathetic stimulation or slowed ventricular repolarization.