TRDRP-funded study shows e-cigarettes can cause abnormal ventricular repolarization, a predictor of sudden death.
Smoking kills about half[i][ii] of the 34 million Americans who partake,[iii] and is the most prevalent modifiable risk factor for heart disease and sudden death from cardiac events in the U.S. Eighty percent of former smokers and 70% of current smokers have turned to electronic cigarettes (e-cigarettes) as a cessation strategy,[iv] despite not being approved as such by the U.S. Food & Drug Administration (FDA), and with conflicting evidence regarding their effectiveness for this purpose.[v]
“Our previous findings suggested that electronic cigarettes are less lethal or potentially have fewer adverse effects compared to combusted commercial tobacco,”[vi] says Holly Middlekauff, Physician and Professor of Medicine at UCLA’s David Geffen School of Medicine. However, her latest study, published in April 2023 in the American Journal of Physiology’s Heart and Circulatory Physiology,[vii] “gives us pause.”
Sudden death is one adverse outcome that can result from smoking combustible cigarettes. And the way combustible cigarettes lead to sudden death is by making electrical changes in the heart, known as ventricular repolarization, a key stage in electrical cardiac activity. It’s been demonstrated that small disturbances to this essential stage of the heartbeat can trigger arrythmias. These changes are easily detectable on the echocardiogram (EKG) “We know that combustible cigarettes have an abnormal effect on the electrocardiogram, [specifically] on this repolarization that has been associated with sudden death,” says Middlekauff. “How about electronic cigarettes?” Her team’s study set out to find the answer.
The researchers recruited 110 participants between the ages of 21 and 45, about half biological male and half female, all nonobese, with no known health problems, and who were not pregnant, not competitive athletes, not taking prescription medications other than birth control, and were not smoking marijuana or taking illicit drugs. Participants were divided into three cohorts based on their tobacco use: combustible tobacco cigarette smokers, e-cigarette users, and non-users. The combustible tobacco cigarette cohort included individuals who had smoked tobacco cigarettes for more than one year, with or without the concomitant use of e-cigarettes. The electronic cigarette cohort was made up of people who had used exclusively e-cigarettes for more than one year, and who had not smoked combustible tobacco cigarettes for more than a year prior to the study. The non-user cohort were those who had not smoked combustible tobacco cigarettes or used e-cigarettes for at least one year.
All research was done in a quiet, temperature-controlled room at the University of California Los Angeles (UCLA) Human Physiology Laboratory. Participants were asked to lie down on a recliner with a footrest and 10 electrodes were placed on their chest following standard echocardiogram (EKG) protocol. Blood was drawn for baseline levels of nicotine and cotinine — a metabolite of nicotine — and then the EKG recorded for five minutes while the room was kept quiet. After this time, the footrest was abruptly lowered, and they were asked to stand up and remain still, an action known to increase cardiac sympathetic nerve activity. This action has been shown to unmask abnormal ventricular repolarization.
Next, the EKG was detached and the person was led to a balcony where they were asked to do one of the following activities, in random order for each person. People in the combustible tobacco cohort were asked to smoke either a combustible cigarette, a JUUL e-cigarette with 5% nicotine, a research no-nicotine cigarette, or an empty straw. People in the e-cigarette cohort were asked to take 3-second puffs every 30 seconds for 15 minutes on either a mint-flavored e-cigarette (JUUL) with 5% nicotine, a mint-flavored e-cigarette (JUUL) with 0% nicotine, or an empty straw. Afterwards, an EKG was recorded for 5 minutes while lying down in the recliner, followed again by abrupt standing.
“This was concerning because…this abnormal prolongation of the measurement on the EKG was indicative of a potential risk factor for sudden death,” says Middlekauff. “This finding, interestingly, was just present in the men, not in the women. It was a very significant change in the men and then the women did not show this abnormality at all.”
There's a documented difference in ventricular repolarization, as measured by the QT interval, between males and females says Middlekauff. Unlike males, pre-menopausal women have almost no risk of myocardial infarction or sudden cardiac death, except if they smoke or have diabetes. However, women who smoke have much higher mortality from cardiac events than men. “Smoking erases that sex benefit.”
The team tried to tease out what factors in electronic cigarettes were responsible for the abnormal ventricular repolarization. Was it the increased heart rate after sudden standing? Was it the nicotine? Statistically, they couldn't attribute it to either. A preclinical study in mice found a sex difference where electronic cigarettes caused a higher rate of arrhythmias in males, but, again, those researchers were unable to ascribe the effect to nicotine.[viii]
“There's probably something else in electronic cigarettes that has this adverse effect,” says Middlekauff. “When the solvents [such as propylene glycol and glycerin] are heated, they generate aldehydes, and some have adverse effects on the heart and other organs in the body. So it may be heating of just the solvent itself or… it may be this combination of chemicals that are present in electronic cigarette aerosol.”
The present study results have important implications for the use of e-cigarettes as a cessation tool. “If somebody who smokes tobacco cigarettes is thinking of using electronic cigarettes for smoking cessation, they should realize that there's potential risk in doing so, especially males,” says Middlekauff.
“In women who smoke tobacco cigarettes, this finding has suggested that electronic cigarettes would be a safe harm reduction strategy,” adds Middlekauff, emphasizing that they should be used for “only the shortest period of time possible… because of the other associated risks—and a lot of them are unknown.” Repeating this study with postmenopausal women could yield very different results. Additionally, because the sex difference issue was analyzed post hoc, the findings need to be verified in a prospective study.
“The take home message is that electronic cigarettes are not harmless,” says Middlekauff. ‘If somebody who smokes tobacco cigarettes is thinking of using electronic cigarettes for smoking cessation, they should realize that there is potential risk in doing so, especially males.”
Middlekauff’s team is interested in researching electronic cigarettes as a smoking cessation tool in groups that have large disparities in tobacco use and in cardiovascular death related to tobacco. “We're doing a study of people living with HIV—who smoke at a greater rate than the general population—comparing [ventricular repolarization] and some other parameters after the use of tobacco cigarettes, electronic cigarettes, and control.” The study is also funded by TRDRP.
Electronic Cigarettes and Sudden Death (One Pager)
Written by Wendee Nicole Holtcamp
MEDIA CONTACT
trdrp@ucop.edu
[i] Tobacco [Fact Sheet]. 24 May 2022. Geneva, Switzerland: World Health Organization. https://www.who.int/news-room/fact-sheets/detail/tobacco#:~:text=Key%20facts,exposed%20to%20second%2Dhand%20smoke.
[ii] Centers for Disease Control and Prevention. Office on Smoking and Health. Sustaining State Programs for Tobacco Control: State Data Highlights, 2006. https://stacks.cdc.gov/view/cdc/11827
[iii] Cornelius ME, Wang TW, Jamal A, et al. Tobacco Product Use Among Adults — United States, 2019. MMWR Morb Mortal Wkly Rep 2020; 71(11);397–405. http://dx.doi.org/10.15585/mmwr.mm7111a1.
[iv] Mayer M, Reyes-Guzman C, Grana R, et al. Demographic Characteristics, Cigarette Smoking, and E-Cigarette Use Among US Adults. JAMA Netw Open. 2020;3(10):e2020694. doi:10.1001/jamanetworkopen.2020.20694. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2771440.
[v] Chen R, Pierce JP, Leas EC, et al. Effectiveness of E-Cigarettes as Aids for Smoking Cessation: Evidence from the PATH Study Cohort, 2017-2019. Tob Control. 2022; tobaccocontrol-2021-056901. doi:10.1136/tobaccocontrol-2021-056901. https://tobaccocontrol.bmj.com/content/early/2022/01/11/tobaccocontrol-2021-056901.
[vi] Ruedisueli I, Lakhani K, Nguyen R, et al. Electronic Cigarettes Prolong Ventricular Repolarization in People Who Smoke Tobacco Cigarettes: Implications for Harm Reduction. Am J Physiol Heart Circ Physiol. 2023;324(6):H821–H832. doi:10.1152/ajpheart.00057.2023. https://journals.physiology.org/doi/full/10.1152/ajpheart.00057.2023
[vii] Ip M, Diamantakos E, Haptonstall K, et al. Tobacco and Electronic Cigarettes Adversely Impact ECG Indexes of Ventricular Repolarization: Implication for Sudden Death Risk. Am J Physiol Heart Circ Physiol. 2020;318(5):H1176–H1184. doi:10.1152/ajpheart.00738.2019. https://journals.physiology.org/doi/full/10.1152/ajpheart.00738.2019.
[viii] Carll AP, Arab C, Salatini R, et al. E-cigarettes and their Lone Constituents Induce Cardiac Arrhythmia and Conduction Defects in Mice. Nat Commun. 2022;13(1):6088. doi:10.1038/s41467-022-33203-1. https://www.nature.com/articles/s41467-022-33203-1.
