Date on Master's Thesis/Doctoral Dissertation

8-2023

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Physiology and Biophysics

Degree Program

Physiology and Biophysics, PhD

Committee Chair

Carll, Alex

Committee Co-Chair (if applicable)

Bhatnagar, Aruni

Committee Member

Bhatnagar, Aruni

Committee Member

Joshua, Irving

Committee Member

Schuschke, Dale

Committee Member

Maldonado, Claudio

Author's Keywords

Ventricular premature beat; heart rate variability; electrocardiogram; nicotine; synthetic cooling agent

Abstract

Introduction. Accumulating evidence indicates that exposure to electronic cigarettes (e-cigs) promotes sympathetic dominance and electrophysiologic instability in the heart, potentially culminating in arrhythmogenesis. E-liquids contain various formulations of nicotine and flavorings, but the effects of specific e-liquid constituents and their concentrations on e-cig-induced autonomic imbalance and electrical dysfunction are unresolved. To that end, we tested the hypothesis that e-cigs modify cardiac autonomic balance and ventricular arrhythmogenesis in mice dependent on e-liquid constituent type and concentration. Methods. Using a crossover design and a serial exposure regimen, ECG-telemetered male C57BL/6J mice underwent whole-body exposure to e-cig aerosols generated from e-liquids containing different cooling agents or nicotine formulations. On a given exposure day, mice were exposed to either increasing coolant concentrations (0.25%, 1%, and 2.5%) or increasing nicotine concentrations (1%, 2.5%, and 5%) for three 18 min exposure cycles (9 min puffing phase followed by 9 min washout phase) per concentration with time-matched periods for filtered air (FA) and vehicle controls. Spontaneous ventricular premature beat (VPB) incidence rates, heart rate, and heart rate variability (HRV) were quantified and compared between exposures. Atenolol was used to test the role of β1-adrenergic activation in e-cig induced changes in autonomic balance. Results. Exposure to 1% menthol and racemic nicotine at 2.5% and 5% reduced heart rate and increased HRV, suggesting parasympathetic dominance. Conversely, exposure to 5% nicotine salt and WS-3 and WS-23 at 2.5% elevated heart rate and decreased HRV, indicating sympathetic dominance, and also increased VPBs. Pretreatment with atenolol abolished the heart rate elevations and HRV declines during exposure to nicotine salt, signifying β1-adrenergic mediation of e-cig-induced sympathetic dominance. Conclusions. Exposure to e-cig aerosols containing commercially relevant levels of synthetic cooling agents and nicotine salts may enhance the cardiac risks of vaping by promoting sympathetic dominance and ventricular arrhythmias. Importantly, β1-adrenergic activation mediates nicotine salt-evoked increases in sympathetic influence. These findings may aid the design of human studies or inform tobacco regulatory initiatives that reduce the public health risks of vaping.

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