Synthetic cooling agents in e-cigarettes link to abnormal heartbeats

This study is the first to show that synthetic cooling agents in e-cigarettes may negatively affect heart health.

The U.S. restricts the sale of many flavored e-cigarettes (also called vapes), such as cotton candy flavors, to make e-cigarettes less enticing to children. However, most states have exceptions allowing menthol and other ingredients that give a cooling sensation when inhaled. These exceptions persist, and the FDA recently authorized the availability of certain flavored e‑cigarettes for adults, underscoring ongoing questions about how flavorings, cooling agents, such as WS-3 and WS-23 and product design affect cardiovascular health and youth use.

"Because synthetic coolants create a chilling sensation without flavor, they fall outside of e-cigarette restrictions that focus on 'characterizing flavors,'" said Alex Carll, Ph.D., M.S.P.H., principal investigator of the study and an associate professor of physiology in the department of physiology and the Christina Lee Brown Envirome Institute at the University of Louisville School of Medicine in Louisville, Kentucky. "Synthetic coolants WS-3 and WS-23 have become really popular in vapes, partly because they reduce harshness and make inhalation feel smoother."

In previous research, Carll and colleagues found that exposure to e-cigarette aerosols rapidly disrupted heart rhythm in mice, causing abnormal heartbeats that happened either too early or were completely skipped.

In this study, researchers conducted two types of laboratory tests. In the first, mice inhaled aerosols from e-cigarettes containing nicotine with or without cooling agents. Their heart's rhythm and conduction patterns were monitored during exposure. In the second test, lab-grown human heart cells were exposed to cooling agents and to noradrenaline to simultaneously mimic the impact of nicotine on stress hormones.

What are the key findings of the study?

• All of the cooling ingredients in e-cigarettes affected heart rate variability, which indicate stress responses that increase the risk for mistimed heartbeats, high blood pressure and other cardiovascular issues.
• Adding the synthetic coolants to e-cigarettes already containing nicotine and solvents increased irregular heartbeats in the mice, especially for WS-23, which tripled the number of premature heartbeats when compared to e-cigarettes containing just nicotine and solvents. With coolant exposures, these mistimed heartbeats corresponded with increased heart rate and a slower electrical recharge between beats.
• In human heart cells, the coolants did not change normal resting heart rhythm or recharge rate. However, when the cells were hormonally stressed, coolants slowed their rhythm and also sped up their recharge between heartbeats.
• In the mice, coolants did not significantly increase the amount of nicotine absorbed into the bloodstream after inhalation.

Alex Carll, Ph.D., M.S.P.H., principal investigator of the studyTogether, these findings suggest coolants could cause arrhythmias by making the heart electrically ready too soon or too late for the next beat. In general, we've seen tobacco-flavored vapes do not disrupt cardiac conduction in mice as much as vapes with either menthol or synthetic coolants. Coolants, especially WS-23, intensified the cardiovascular effects of e-cigarette exposures in the mice, causing more mistimed heartbeats and greater signs in heart rhythm of fight-or-flight stress responses, which in turn increase the risk of dangerous mis-timed heartbeats and sudden cardiac arrest."

Carll suggests that based on these results, policymakers review the current rules about coolants used in vapes.

"Coolants are added to e-cigarettes at very high levels, often more than nicotine or any other flavoring," he said. "Coolant levels in vapes should be considered for regulation, especially if further studies confirm that they increase the harmful effects of vaping on the heart."

The study leaves several open questions for future research. "It is still unclear how coolants in vapes affect people with higher risk for heart rhythm conditions. This includes pregnant women and those with hypertension, heart disease, obesity or Type 2 diabetes. We also don't know if the short-term effects of coolants lead to long-term harm," Carll said.

Menthol-flavored e-cigarette sales increased by 175.8% (from 30.7 million units to 84.7 million units) between 2019 and 2023. Sales of e-cigarettes with synthetic cooling ingredients, such as WS-3 or WS-23, increased 872.1% between 2020 to 2023, in the U.S., according to a 2024 report from the CDC Foundation and Truth Initiative.

"This research is timely since menthol and cooling flavors are becoming more popular," said Jason J. Rose, M.D., M.B.A., an associate professor of medicine and chief of the division of pulmonary, critical care & sleep medicine at the University of Maryland School of Medicine in Baltimore. Rose was the volunteer chair of the 2023 scientific statement writing group and was not involved in this research.

"It is important for parents to talk with their children to make sure they understand that no vaping or tobacco product is safe or risk-free, even if it has been authorized by the FDA," he added.

What are the details, background, design and limitations of the study?

• E-cigarettes are battery-operated devices that heat a liquid vaping solution to create an aerosol that is inhaled into the lungs. Most e-cigarettes include nicotine, the health-damaging and addictive component in traditional cigarettes. Other ingredients include solvents to create the vapor, and often cooling agents and flavors.
• Male mice were exposed to vape aerosol while various cardiac responses (heart rate, heart rate variability and the occurrence of premature beat arrhythmias) were monitored, and blood samples were collected for analysis. The vape aerosols contained 2.5% nicotine benzoate alone or with menthol, WS-3 or WS-23, at increasing concentrations.
• Lab-grown human cardiac cells were used for the second part of the analysis to understand the potential impact of cooling ingredients on heart cells in people.
• Study limitations include that mice may respond differently to the effects of cooling ingredients when compared to humans. In addition, male mice were selected for the research because it has been previously noted that they are more sensitive to e-cigarette impacts, therefore the results cannot be generalized to female mice.
• Coolants didn't significantly increase nicotine absorption in the mice, however, the small number of mice sampled for blood (5 per group) may not be enough for firm conclusions. "Importantly, lab-grown human heart cells often overlook the complicated interactions between the respiratory and cardiovascular systems in humans, therefore, more research is needed," Carll said.
• This study tested e-liquids that contain nicotine, solvents and sometimes coolants. In contrast, products available to the public that have coolants usually have many more ingredients, including flavoring and other additives.
• The short-term effects observed in this study may underestimate or differ from products with more ingredients, and the potential impact of long-term exposure requires more research.

Source:

American Heart Association

Journal reference: