In vitro and in vivo cardiac toxicity of flavored electronic nicotine delivery systems

Am J Physiol Heart Circ Physiol. 2021 Jan 1;320(1):H133-H143. doi: 10.1152/ajpheart.00283.2020. Epub 2020 Nov 20.


The usage of flavored electronic nicotine delivery systems (ENDS) is popular, specifically in the teen and young adult age-groups. The possible cardiac toxicity of the flavoring aspect of ENDS is largely unknown. Vaping, a form of electronic nicotine delivery, uses "e-liquid" to generate "e-vapor," an aerosolized mixture of nicotine and/or flavors. We report our investigation into the cardiotoxic effects of flavored e-liquids. E-vapors containing flavoring aldehydes such as vanillin and cinnamaldehyde, as indicated by mass spectrometry, were more toxic in HL-1 cardiomyocytes than fruit-flavored e-vapor. Exposure of human induced pluripotent stem cell-derived cardiomyocytes to cinnamaldehyde or vanillin-flavored e-vapor affected the beating frequency and prolonged the field potential duration of these cells more than fruit-flavored e-vapor. In addition, vanillin aldehyde-flavored e-vapor reduced the human ether-à-go-go-related gene (hERG)-encoded potassium current in transfected human embryonic kidney cells. In mice, inhalation exposure to vanillin aldehyde-flavored e-vapor for 10 wk caused increased sympathetic predominance in heart rate variability measurements. In vivo inducible ventricular tachycardia was significantly longer, and in optical mapping, the magnitude of ventricular action potential duration alternans was significantly larger in the vanillin aldehyde-flavored e-vapor-exposed mice than in controls. We conclude that the widely popular flavored ENDS are not harm free, and they have a potential for cardiac harm. More studies are needed to further assess their cardiac safety profile and long-term health effects.NEW & NOTEWORTHY The use of electronic nicotine delivery systems (ENDS) is not harm free. It is not known whether ENDS negatively affect cardiac electrophysiological function. Our study in cell lines and in mice shows that ENDS can compromise cardiac electrophysiology, leading to action potential instability and inducible ventricular arrhythmias. Further investigations are necessary to assess the long-term cardiac safety profile of ENDS products in humans and to better understand how individual components of ENDS affect cardiac toxicity.

Keywords: ENDS; arrhythmias; cardiac electrophysiology; electronic cigarettes; vaping.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Administration, Inhalation
  • Animals
  • Cardiotoxicity
  • ERG1 Potassium Channel / metabolism
  • Electronic Nicotine Delivery Systems*
  • Female
  • Flavoring Agents / administration & dosage
  • Flavoring Agents / toxicity*
  • HEK293 Cells
  • Heart Rate / drug effects*
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / metabolism
  • Nicotine / administration & dosage
  • Nicotine / toxicity*
  • Nicotinic Agonists / administration & dosage
  • Nicotinic Agonists / toxicity*
  • Tachycardia, Ventricular / chemically induced*
  • Tachycardia, Ventricular / metabolism
  • Tachycardia, Ventricular / physiopathology
  • Time Factors
  • Vaping / adverse effects*


  • ERG1 Potassium Channel
  • Flavoring Agents
  • KCNH2 protein, human
  • Nicotinic Agonists
  • Nicotine