Date on Master's Thesis/Doctoral Dissertation

12-2019

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Physiology and Biophysics

Degree Program

Physiology and Biophysics, PhD

Committee Chair

Bhatnagar, Aruni

Committee Co-Chair (if applicable)

Carll, Alex

Committee Member

DeFilippis, Andrew

Committee Member

Joshua, Irving

Committee Member

Schuschke, Dale

Author's Keywords

cigarette; nicotine; electrocardiogram, beta-blocker; catecholamines

Abstract

Cigarette smoking is a leading cause of preventable disease and premature death worldwide. The adverse effects of cigarette smoking, including proarrhythmia, are related to the mixture of chemicals, including nicotine (which sustains tobacco addiction). However, it remains unclear which individual tobacco smoke constituents and biological pathways mediate this increased risk. The purpose of this research was to explore the chronic effects of cigarette smoking, as well as compare the acute effects of nicotine and cigarette smoking, and the possible role of β-adrenoreceptors, on human cardiac electrophysiology. Chapter 1 is a comprehensive literature review of (a) the ex vivo and in vivo effects of nicotine and non-nicotine constituents of cigarette smoking on cardiac ion channels, (b) the direct and indirect effects of the autonomic nervous system on cardiac electrophysiology, and (c) studies of acute and chronic effects of cigarette smoking in humans. Chapter 2 consists of two studies in which we used cotinine levels to investigate the differences in baseline cardiac electrocardiogram between chronic smokers and non-smokers, and to define smoking status and its burden. We also explored the relationship between urinary catecholamines, cotinine, and electrocardiographic changes. Chapter 3 features the 2 x 2 factorial experimental study designed to compare the acute effects of cigarette smoking and nicotine, with and without a β-blocker (propranolol). We found that chronic cigarette smoking was associated with a shortened PR segment at baseline, and that dopamine possibly mediates this effect. There was also (corrected) QT interval shortening with increased cotinine levels. This experimental study revealed that the non-nicotine constituents in cigarette smoking were mainly responsible for PR segment shortening, through β-adrenoreceptors. Other evidence revealed that, although nicotine in cigarette smoke is primarily responsible for sympathetic activation and (corrected) QT interval shortening, it is the non-nicotine constituents that depress the ST segment. Collectively, acute and chronic exposure studies indicate that smoking may promote cardiac arrhythmia, primarily via β-adrenoreceptors, causing acceleration of dromotropy and ischemia (non-nicotine mediated), and ventricular repolarization (nicotine-mediated). This research elucidated a major physiological mechanism driving the effect of cigarette smoking and nicotine on cardiac electrophysiology. Consequently, these findings will inform U.S. Food and Drug Administration of tobacco and nicotine-containing products’ impact on the human cardiac electrical system, and potentially help regulate alternative forms of nicotine delivery and protect public health.

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