A new study from the University of Louisville shows the nicotine in certain types of e-cigarettes may be more harmful than others, increasing risk for irregular heartbeat, or heart arrhythmias.

A popular claim is that nicotine in e-cigarettes is relatively harmless, whereas additives and combustion products largely account for the harms of traditional cigarettes. The UofL research, which tested the effects of e-cigarettes with various types and doses of nicotine in animal models, showed that the nicotine form contained in pod-based e-cigarettes — nicotine salts — led to heart arrhythmias, particularly at higher doses.

In the study, published in , researchers compared heart rate and heart rate variability in mice exposed to vape aerosols containing different types of nicotine. The aerosols contained either freebase nicotine, used in older types of e-cigarettes; nicotine salts, used in Juul and other pod-based e-cigarettes; or racemic freebase nicotine, simulating the recently popularized synthetic nicotine; and their effects were compared to nicotine-free e-cigarette aerosols or air. In addition, the research team delivered increasing concentrations of the nicotine over time, from 1% to 2.5%, to 5%.

The nicotine salts induced cardiac arrhythmias more potently than freebase nicotine, and the cardiac arrhythmias increased with the higher concentrations of nicotine.

“This suggests the nicotine is harmful to the heart and counters popular claims that the nicotine itself is harmless,” said Alex Carll, assistant professor in UofL’s Department of Physiology and researcher with , who led the study. “Our findings provide new evidence that nicotine type and concentration modify the adverse cardiovascular effects of e-cigarette aerosols, which may have important regulatory implications.”

The study also revealed that the higher levels of nicotine salts increased sympathetic nervous system activity, also known as the fight-or-flight response, by stimulating the same receptor that is inhibited by beta blockers, heart medications which are prescribed to treat cardiac arrhythmias. In the autonomic nervous system, sympathetic dominance increases the fight-or-flight response in bodily functions, including heart rate.

“The nicotine in e-cigarettes causes irregular heartbeats (arrhythmias) in a dose-dependent manner by stimulating the very receptor that many heart medications are designed to inhibit,” Carll said.��

The findings conclude that inhalation of e-cig aerosols from nicotine-salt-containing e-liquids could increase cardiovascular risks by inducing sympathetic dominance and cardiac arrhythmias.

This work is part of a growing body of research on the potential toxicity and health impacts of e-cigarettes reported by the American Heart Association Tobacco Regulation and Addiction Center, for which UofL serves as the flagship institute. The team’s previous research found that exposure to e-cigarette aerosols containing certain flavors or solvent vehicles caused ventricular arrhythmias and other conduction irregularities in the heart, even without nicotine, leading Carll to speculate that the arrhythmias may not be the result of the nicotine alone, but also by the flavors and solvents included in the e-cigarettes.

The researchers concluded that, if these results are confirmed in humans, regulating nicotine salts through minimum pH standards or limits on acid additives in e-liquids may mitigate the public health risks of vaping.

Even without regulatory changes, however, the research suggests that users may reduce potential harm by opting for e-cigarettes with freebase nicotine instead of nicotine salts or using e-cigarettes with a lower nicotine content.

“Our findings demonstrate that short-term exposure to e-cigarettes can destabilize heart rhythm through specific chemicals within e-liquids,” said Alex Carll, assistant professor in the UofL Department of Physiology who led the study. “These findings suggest that e-cigarette use involving certain flavors or solvent vehicles may disrupt the heart’s electrical conduction and provoke arrhythmias. These effects could increase the risk for atrial or ventricular fibrillation and sudden cardiac arrest.”

The researchers tested the cardiac impacts of inhaled e-cigarette aerosols solely from the main two ingredients in e-liquids (nicotine-free propylene glycol and vegetable glycerin) or from flavored retail e-liquids containing nicotine. They found that for all e-cigarette aerosols, the animals’ heart rate slowed during puff exposures and sped up afterwards as heart rate variability declined, indicating fight-or-flight stress responses. In addition, e-cigarette puffs from a menthol-flavored e-liquid or from propylene glycol alone caused ventricular arrhythmias and other conduction irregularities in the heart.

Conducted in collaboration with Daniel Conklin and Aruni Bhatnagar, professors in the UofL Division of Environmental Medicine, this work adds to a growing body of research on the potential toxicity and health impacts of e-cigarettes reported by the American Heart Association Tobacco Regulation and Addiction Center, for which UofL serves as the flagship institute.

“The findings of this study are important because they provide fresh evidence that the use of e-cigarettes could interfere with normal heart rhythms – something we did not know before,” Bhatnagar said. “This is highly concerning given the rapid growth of e-cigarette use, particularly among young people.”

As e-cigarette use has grown nationwide, the potential advantages and harms of vaping have been debated. Since vaping does not involve combustion, it exposes users and bystanders to little if any carbon monoxide, tar or cancer-causing nitrosamines compared with conventional cigarettes. However, e-cigarettes can deliver aldehydes, particles and nicotine at levels comparable to combustible cigarettes. Vaping might help smokers quit combustible cigarettes, but the appeal and addictiveness of e-cigarettes may encourage youth to vape amidst unknown long-term risks or take up smoking. More than 25% of high schoolers and 10% of middle schoolers in the U.S. reported using e-cigarettes before the pandemic.

Additional research by Carll and Matthew Nystoriak, an associate professor of medicine at UofL, to determine the effects of vape flavorings on the heart recently received $3.6 million in research funding from the National Institutes of Health.

“Our team’s findings that specific ingredients in e-cigarette liquids promote arrhythmias indicates there is an urgent need for more research into the cardiac effects of these components in both animals and humans,” Carll said.

Perhaps early 20s? Maybe even 16?

“The average chronic smoker begins smoking at 13.7 years old,” says Daniel Conklin, PhD. “And if you know anything about averages, that’s … not good.”

Conklin, a professor of medicine at the University of Louisville, specializes in cardiovascular research and what environmental pollutants do to our bodies. At this month’s Beer with a Scientist, Conklin will discuss smoking and what we do (and don’t) know about the harm caused by electronic cigarettes.

“Essentially, we’re trying to separate fact from fiction. We’re currently part of an American Heart Association Tobacco Regulation Center to investigate emerging tobacco products and their potential to cause harm to the cardiovascular system,” Conklin said. “We’re trying to figure out the best way to regulate these products.”

Scientists have known that conventional tobacco products are associated with cardiovascular disease risk since the 1960s, Conklin said. However, with new technology comes a new generation of health risks and the emerging science showing what vaping does to the body may shock you.

Conklin’s talk will begin at 7 p.m. on Wednesday, May 15, at , 8023 Catherine Lane. A 30-minute presentation will be followed by an informal Q&A session.

“It’s a problem because the epidemiology shows that the more plaque you have, the more you increase your risk for having a heart attack,” Conklin said.

Conklin says e-cig cartridges are flavored, and that flavors like mango and blackberry pie appeal to the youth because they are more tasteful and fun than old-fashioned tobacco products. This creates the issue of developing a new generation of people addicted to nicotine products.

UofL Envirome Institute director Aruni Bhatnagar is overseeing the research. “It is important because you want to prevent a new generation of youth from being addicted to nicotine and nicotine products,” Bhatnagar said. “And, if there is a harm associated with the use these products, we should know what those harms are so that we can minimize it or we can appropriately regulate the use of tobacco products.”

UofL’s center specifically will receive $8.7 million as part of the national effort.��

Under the direction of Rose Marie Robertson, MD, the association’s deputy chief science and medical officer, and Aruni Bhatnagar, PhD, the Smith and Lucille Gibson Chair in Medicine at UofL, the Center examines the short- and long-term cardiovascular effects of tobacco products and the overall toxicity of tobacco products and their constituents.

The AHA Tobacco Regulation and Addiction Center received $20 million in its initial funding in 2013 through this same interagency partnership between the National Institutes of Health and the Food and Drug Administration as the FDA’s Center for Tobacco Products began its investment in the Tobacco Centers of Regulatory Science. The AHA Center is a multi-institutional network focused on creating a broad scientific base to inform the FDA’s regulation of tobacco product manufacturing, distribution and marketing.

The renewal grant awards were based on the scientific and technical merit of the applicant organizations. The AHA Tobacco Regulation and Addiction Center’s quality of research and productivity in its first five years created a strong foundation for future research and led to the renewed funding.

“We are honored to continue to be a part of this important national movement to protect the public health from the tragic consequences of tobacco product use that takes the lives of more than 480,000 Americans each year,” Robertson said. “In light of the fast-paced shifts in the landscape of new tobacco products, an accelerating trend of the use of these products by our nation’s children and an emerging generation of dual or poly-tobacco product users, the need for a better understanding of the health effects of these novel products has become even more imperative.”

During the past five years, more than 50 investigators from 12 institutions throughout the nation have collaborated on 82 publications from the center that examined topics such as the reasons behind the growing prevalence of adults and young adults who are vaping, the toxicity of flavoring chemicals used in e-cigarettes and the preliminary indicators of the growing use of poly-use, or the practice of using multiple tobacco products at the same time.

To date, researchers have found the use of tobacco products – such as traditional cigarettes, hookahs, smokeless tobacco, electronic cigarettes and e-hookahs – leads to a decrease in immune cells and prevents repair of damaged endothelial cells, increasing the risk of contracting secondary infections. Additionally, use of electronic hookahs can increase the risk of blood clots.

“Dr. Bhatnagar and his colleagues continue to demonstrate their leadership in the field of environmental cardiology, which obviously includes the use of tobacco,” said UofL President Neeli Bendapudi, PhD. “This renewal demonstrates the significance of the research being conducted and the potential impact it has on anyone who uses tobacco or similar products.��

“Hopefully it will impact those who are considering using tobacco both by providing information regarding health effects that can be used in health risk warnings, and also by providing FDA data regarding the toxicity of individual constituents within tobacco-derived aerosols.”

Research at the nine institutions – Boston University, Johns Hopkins University, ��New York University, University of Louisville, University of Mississippi Medical Center, Wake Forest University, Stanford University, University of Iowa and National Jewish Hospital – participating in the AHA Center over the next five years will focus on understanding the toxic potential of combustible and newer forms of tobacco products, identifying the biological markers of cardiovascular injury caused by components of tobacco products and assessing the risk of heart disease for different racial and ethnic groups of people from the use of newer tobacco products.

“Identifying the biomarkers of cardiovascular injury caused by tobacco use can lead to improved standards for testing of novel tobacco products and lead to policies regulating the level of harmful chemicals present in tobacco products, thus aiming to reduce the overall burden of cardiovascular injury in the general population,” Bhatnagar said.

The researchers hope to identify specific substances from tobacco products and in their smoke or aerosols that contribute to heart disease. This includes flavoring chemicals used in electronic nicotine delivery systems such as ��e-cigarettes, e-hookahs, JUUL and others, along with chemical solvents used in such products.

The center also has responsibility for training the next generation of tobacco regulatory scientists who will continue research into tobacco and its health effects. To this end, 23 people have been trained as fellows in tobacco regulatory science and 11 fellowship projects have been funded over the first 5 years. The center has also funded 12 short-term projects to study emerging topics of interest to tobacco regulation.

The renewed center has been designed to retain this flexibility to respond to FDA’s research needs in a shifting landscape of tobacco use through rapid-response research funding and independent fellowship grants that can enhance the center’s research database alongside its flagship projects.

Here are some highlights from Monday’s press conference:��

E-cigarettes come in all kinds of flavors, like mango, cotton candy or creme brûlée.��

But a new study from Boston University and the University of Louisville��shows inhaling those flavors could be bad for your cardiovascular health.��

Researchers found short-term exposure to some flavor additives may cause adverse health effects, such as blood vessel dysfunction that could lead to hypertension.

These results were published in a journal of the American Heart Association (AHA):.��

Daniel J. Conklin, PhD, a professor of cardiovascular medicine at UofL and an author on the study, said little is known about the health effects of e-cigarettes compared to what we know about regular cigarettes.

Despite many still containing nicotine and some with high levels of nicotine, such as JUUL, he said e-cigarette devices are often seen as a cessation tool or as a “safer” alternative because e-cigarettes contain fewer .

“But we can’t rule out risks for other diseases just because cancer risk is reduced,” he said.��

In 2016, the U.S. ��reported that 15.4 percent of adults said they had ever used an e-cigarette and 3.2 percent said they were current users.

But Conklin said e-cigarettes appear to have gained the most traction with teenagers and young adults. According to the , high school students use e-cigarettes more than adults and more than they use traditional cigarettes.

“That’s the most disconcerting aspect, because long-term tobacco use starts in the youth with addiction to nicotine,” he said. “So, many public health advocates are worried we’re looking at addicting a new generation.”

The “Flavor and Addiction to e-Cigarette and Tobacco Toxicity” trial — or FACTT — is carried out by the American Heart Association Tobacco Research and Addiction Center at UofL. Principal investigator for the trial is Sanjay Srivastava, PhD, who also currently has ongoing toxicological studies of tobacco and nicotine to identify which chemicals are harmful and can be regulated.

The center was established in 2013 with a $10.7 million grant from the NIH and FDA. Under the leadership of director Aruni Bhatnagar, PhD, the center conducts multidisciplinary research to help shape the manufacture, distribution and marketing of tobacco products as they are regulated by the FDA.

UofL is building a body of research in the potential hazards of electronic cigarettes. In 2014, Bhatnagar chaired the 10-member panel of national experts that developed the American Heart Association’s first-ever policy statement on e-cigarettes, citing the paucity of research that has been conducted on the effects of e-cigarettes on health.

Another researcher with the UofL center, Daniel Conklin, PhD, is currently researching links between e-cigarette ingredients and cardiovascular conditions; Earlier this year, Conklin was invited to present his first findings showing the link between e-cigarette ingredients and atherosclerosis, or plaque buildup in the arteries, by the American Association for the Advancement of Science for its Annual Meeting.

To be eligible for the FACTT trial, participants must not only be non-smokers, they also must be unmedicated and otherwise healthy. The trial requires a one-time visit for a blood draw at the center in the Delia Baxter Building at 580 S. Preston St. on the UofL Health Sciences Center campus.

Qualified participants will receive a $30 prepaid spending card. For more details and to sign up for the trial, contact the center at ATRAC@louisville.edu or 502-852-4236.