Abstract 19102: E-Cigarettes Induce Persistent Cardiac Autonomic Dysfunction and Molecular Signatures of Dilated and Arrhythmogenic Cardiomyopathy

Abstract

Introduction: Evidence is mounting that use of e-cigarettes (e-cigs) promotes cardiopulmonary injury and dysfunction, but the long-term consequences remain unclear. Consumption of menthol e-cigs has surged amid imminent bans on combustible menthol cigarettes and cigars. Recently, we found e-cig aerosols with menthol (but not tobacco) flavor acutely induced spontaneous ventricular arrhythmias in mice. Hypothesis: Menthol e-cigs induces persistent cardiac autonomic imbalance. Methods: Adult C57BL/6J male mice with electrocardiogram (ECG) and blood pressure (BP) telemeters were exposed for 4 weeks to menthol e-cig aerosols (JUUL, 180 puffs/day, 5 days/week; n=8) or filtered air (Air; n=7) and challenged with restraint stress to determine cardiovascular reactivity to stress. Hearts (n=5/group) were collected immediately after final exposure for phosphoproteomics. Results: Menthol e-cig exposures increased HR, decreased HR variability, and evoked ventricular premature beats only on exposure day 1, but consistently increased BP throughout the 20-day exposure (+16 mmHg systolic BP vs. Air). Additional exposures in females (n=4) recapitulated these acute effects. Pre-treatment with atenolol (n=4 males) abolished e-cig-induced arrhythmias, suggesting β 1 -adrenergic mediation of e-cig-induced arrhythmias. After 4-week JUUL Menthol exposure, mice had basal sinus bradycardia and impaired stress reactivity, characterized by reduced maximal HR and rapid recovery to baseline. All three effects persisted up to 3 weeks following cessation and were accompanied by prolonged ventricular repolarization (QT c ). Phosphoproteomic analysis revealed upregulation of protein kinase A signaling, and mitochondrial dysfunction in e-cig-exposed mice. Phosphoproteins associated with dilated & arrhythmogenic cardiomyopathy (ATP2A2, FN1, CACNB2, PFKM, ADCY6, and PRKAR1A) were differentially regulated in e-cig-exposed mice. Conclusions: We demonstrate that menthol e-cigs induce persistent cardiac autonomic imbalance associated with molecular signatures of dilated & arrhythmogenic cardiomyopathy. Autonomic imbalance and cardiac electrical dysfunction may contribute to the long-term health effects of repeated use of e-cigarettes.