Alex Carll, an associate professor in the Department of Physiology, studies the impacts of ingredients in vape liquids in the laboratory. Rodrigo Cavallazzi, professor of medicine in the Division of Pulmonary, Critical Care and Sleep Disorders, treats patients as director of the medical intensive care unit at UofL Health – UofL Hospital.

UofL News spoke with Carll and Cavallazzi about their findings and insights to understand how work in the laboratory echoes patients’ experience with e-cigarettes.

UofL News: Dr. Carll, what is the focus of your research and what have you discovered about the effects of vaping?

Alex Carll: We test the impacts of inhaled electronic cigarette aerosols on heart function and blood pressure.��We have found that exposures to these aerosols in mice can rapidly disrupt heart rhythm, causing abnormal heart beats that occur either prematurely or are skipped.

Our studies in animal models indicate that vaping likely causes cardiac arrhythmias (abnormal heart beats) and does so by causing fight-or-flight stress responses. It increases blood pressure in humans and mice, as well. These abnormal heart beats can increase risk for fatal arrhythmias and sudden cardiac death, which have recently been associated with vaping in young adult patients.

Another mouse study from our group indicates that vaping during pregnancy may cause peripartum arrhythmias, with these effects continuing well after e-cigarette cessation.

UofL News: Dr. Cavallazzi, have you seen these types of effects in your patients?

Rodrigo Cavallazzi: When I see patients, my focus is more on the respiratory system, but it is definitely conceivable that patients who vape have several consequences to their cardiovascular system, including arrhythmias, based on the load of nicotine and other potentially toxic chemical substances��they are exposed to through vaping.��

UofL News: What are the symptoms you most often see in patients who vape?

Cavallazzi: I see respiratory symptoms such as cough, shortness of breath, chest tightness and wheezing, which I am certain can be attributed to vaping in some patients. I also see exacerbation of underlying lung diseases such as asthma and COPD.

Some of these patients end up in the ICU. I have seen a few patients with acute respiratory failure that I believe was due to a very serious condition called “e-cigarette or vaping product use-associated lung injury” (EVALI). These patients develop acute respiratory failure that sometimes resembles severe pneumonia or a severe Covid-19 infection. The medical literature indicates that this happens when tetrahydrocannabinol (THC, the principal��psychoactive constituent��of��cannabis) is added to an e-cigarette device and is��contaminated with vitamin E acetate. It also has been reported in patients inhaling nicotine only.

The effects mentioned in Dr. Carll’s studies seem to corroborate what other authors have written on the cardiovascular effects of inhaled nicotine and other potentially toxic chemical substances through e-cigarettes.��

UofL News: Dr. Carll, have you been involved in any human studies?

Carll: Yes, my lab has published two population studies detailing smoking’s adverse impacts on cardiac conduction, and we have associated some of our observations with long-term cardiovascular mortality.

Our population studies in smokers showed correlations between cotinine in the blood, a biomarker indicating nicotine exposure, and electrocardiogram (ECG) abnormalities. Some of these ECG abnormalities in smokers corresponded with over a 25-year follow-up period. Additionally, some of the ECG effects associated with smoking and nicotine corresponded with changes in the fight-or-flight stress hormones norepinephrine, epinephrine and dopamine. Dopamine itself also appeared responsible for shortening in the time between atrial and ventricular contraction.

I also have been involved in a yet-unpublished clinical trial focused on preventing smoking’s adverse impacts on heart conduction.

UofL News: Dr. Cavallazzi, how would the effects that Dr. Carll documented in the lab affect patients?

Cavallazzi: As a clinician, the chronic cardiovascular effects of combustible cigarette smoking I often see are myocardial infarction,��stroke and peripheral vascular disease. The latter manifests as difficulty walking and erectile dysfunction.

UofL News: How does the knowledge we have about the effects of cigarette smoking translate to vaping? And what do you tell your patients about the health impacts of vaping and smoking?

Cavallazzi: I tell them��the truth. Combustible cigarette smoking increases the risk of lung cancer development by 15 to 30 times. Up to 50% of people who smoke combustible cigarettes develop COPD. This is a much higher figure than previously thought.

Combustible cigarette smoking increases the risk of a heart attack by 4 to 7 times and increases the risk of other cancers and conditions, including peripheral vascular disease and stroke.

We are now starting to understand the risks of e-cigarette smoking: EVALI, exacerbation of asthma and COPD. There is data that daily users of e-cigarettes have more than double the odds of chronic lung disease, including chronic bronchitis, emphysema or COPD.

UofL News: How do you help your patients quit smoking or vaping?

Cavallazzi: I remind my patients that smoking combustible cigarettes or e-cigarettes is not a failure of character. It is never too late to quit smoking. Most people who quit for good tried a number of times before they were successful. Nicotine is highly addictive and is often listed as one of the most addictive substances out there.

Since nicotine is so addictive, I often offer pharmacological aids such as nicotine replacement – patches, gum and lozenges. The nicotine exposure obtained through these medications is sustained, low dose,��designed to be of short term (weeks), not inhaled and not combined with other potentially toxic chemical substances.

There are also other medications that are sometimes offered, including an antidepressant called bupropion, which is often combined with nicotine replacement. And there is a medication called varenicline, which acts on the nicotine receptors.

UofL News: Cigarette smoking has been declining since 1965, which is great news. But e-cigarettes are a relatively new product. What is the most concerning trend in the use of e-cigarettes?

Cavallazzi: Unfortunately, the rates of e-cigarette use are moving in the opposite direction. From 2014 to 2022, current e-cigarette users increased from 3.7% to 6.0% of adults. From 2011 to 2022, the rates went from 0.6% to 4.6% among middle school students and from 1.5% to 10.0% among high school students. This is concerning. These pre-adolescents and adolescents are more vulnerable, and some of the vape companies have marketed their products in ways that attract young users.

Carll: The e-cigarette market is constantly evolving to dodge regulations and enhance appeal, nicotine delivery and the potential for addiction. New untested products and chemical combinations are routinely deployed to users with minimal safety testing. While the long-term risks of current vaping products remain unclear, this real-world uncontrolled experiment continues with little regulation. Our research remains critical to inform users, practitioners and regulators about the overall risks of e-cigarettes and the specific device types, settings and ingredients that pose the greatest harms.

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.

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.