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 ���Ǵڳ�’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.

Over the past decade, the laboratory has responded to national emergencies, studying highly infectious diseases such as SARS and others. Today it is being called upon in research efforts focusing on the novel coronavirus, SARS-CoV-2, and the disease it causes, COVID-19. And in that lab, researchers are exploring compounds that hold promise as therapeutic agents against the disease and could be grown quickly in host tobacco plants.

That’s right, tobacco. A strain of the reviled plant that has caused fatal diseases for centuries could be the key to quickly mass-producing a preventive agent, treatment or vaccine for COVID-19.

“A protein in the university’s own proprietary portfolio and other compounds from industry sources may be useful against SARS-CoV-2,” said Kenneth Palmer, PhD, director of ���Ǵڳ�’s (CPM).�� “We are currently conducting laboratory research with these compounds that could eventually lead to a therapeutic agent against COVID-19.”

���Ǵڳ�’s (RBL) is housed in the CPM and is part of a network of 12 regional and two national labs that were established with support from the NIH to conduct research with infectious agents. The national labs are located at Boston University and at the University of Texas Medical Branch at Galveston. Regional labs are located at the University of Chicago, Duke University, Boston University and other universities throughout the U.S. The RBL network stands ready in response to public health emergencies and emerging diseases such as the novel coronavirus.

The UofL RBL includes Biosafety Level 3 facilities built to the most exacting federal safety and security standards. The stringently secure facilities protect researchers and the public from exposure to the pathogens being investigated. As part of the RBL network, the UofL RBL is able to respond to needs of researchers, federal agencies and pharmaceutical companies nationwide to conduct research with infectious agents.

Palmer and his research team received samples of SARS-CoV-2 last month and are researching it only in the highly secure confines of the RBL. Covered head to toe in personal protective equipment to prevent self-infection, the researchers now are testing the therapeutic candidates against the disease in cell cultures.

The UofL compound is known as and is co-owned by the university with the National Cancer Institute and the University of Pittsburgh. It is a potent anti-viral protein that possesses microbicidal capabilities. The other compounds are proprietary to their respective companies.

The research goal is to identify the best potential treatment option that could eventually be tested in humans, first at UofL to gauge its safety and efficacy and then later at the University of Pittsburgh and other clinical trial sites to continue to test its effectiveness. Although there are no guarantees, “we believe we could move into human clinical trials by the end of the year,” Palmer said.

That’s where the tobacco plants come in. A large amount of the ultimate therapeutic will be needed for human trials. Kentucky’s historical cash crop is a perfect host to produce the quantities needed.

“The unique quality about studying these compounds in Kentucky is that we can rapidly scale up production of tobacco plants to produce the large amounts of the agent we will need for human testing,” Palmer said. “As people already know, tobacco grows very well in Kentucky.”

Some of the compounds are already showing promise in the laboratory. While the end of the year seems far off in the current coronavirus climate, it is realistic because “SARS-CoV-2 may be with us for a couple of winter seasons. We’d like to have a product that could be tested if the infection comes back in the cold season like influenza does,” Palmer said.

If it does, Palmer and his team will be ready. “We think we will be able to deliver the drug as a nasal spray and hope we can use it as a preventive, pre-exposure treatment before a vaccine could be developed. This will be important for the public and especially for those who are at risk because of their age or pre-existing health conditions or because they work in health care.”

.��

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.”

Brad Rodu, DDS, professor at the University of Louisville School of Medicine, says smokers can reduce health consequences of smoking tobacco by switching to smoke-free alternatives, including dip and chew products, and e-cigarettes.

“These smoke-free tobacco products provide tobacco pleasure and satisfaction. More importantly, decades of research document that smoke-free tobacco is vastly safer than cigarettes,” Rodu said.

For more than 20 years, Rodu has worked to educate smokers and non-smokers on safer alternatives to smoking tobacco, authoring more than 60 tobacco research articles for medical and scientific journals. He has been in the forefront of policy development in this field, and in 2011, he launched , the first-ever community cessation program based on switching to smoke-free alternatives.

At the next Beer with a Scientist, Rodu will discuss, “Harm Reduction: What You Don’t Know About Tobacco and Health.”

The talk begins at 8 p.m. on Wednesday, June 20, at Against the Grain Brewery, 401 E. Main St. in Louisville. A 30-minute presentation will be followed by an informal Q&A session. Admission is free. Purchase of beer, other beverages or menu items is not required but is encouraged.

Green is a second-year student in the UofL School of Dentistry. UofL News had the chance to talk to her about her motivation and her goals.��

UofL News: What motivated you to invest in health and social justice?

Ashton Green: I’ve always been very aware that the best way to be useful in society is to serve those around you. I have also always had an interest in the field of health care. In my initiative to address local health care disparities, I think my target area would deal primarily with cigarette smokers because in Kentucky smoking is a huge issue. ��Part of my motivation for choosing to focus on smoking also stems from my family. Some of my mother’s side of the family is from Kentucky and we have lost several relatives due to lung cancer and esophageal cancer. Smoking and diseases that stem from it are very personal to me and I want to come up with a resource that I feel the greater community can easily use and learn from. Hopefully this knowledge can contribute to cultural change. The impact might be small at first, but I feel that if you target one area you have the ability to focus on it and expand it to make greater change later.

UofL News: Explain one experience that drives you to make a difference.

Green: Upon first moving here I wasn’t quite aware of how intense the problem of smoking is. One time while walking home from school I passed by the hospital. As I walked by, I saw patients in hospital gowns and some carrying IV poles standing outside smoking cigarettes. As you can imagine, this was such a confusing sight, but in that moment I realized people must not be aware of how detrimental smoking actually is. I was definitely shocked that day. I remember calling my mom about it and saying, ‘You won’t believe what I just saw.’ That was pretty eye-opening.

UofL News: What would you like to accomplish as a Health and Social Justice Scholar?

Green:��I want to create something that is sustainable long after I graduate. I have a few ideas I would like to speak with my mentor about and get the ball rolling. I definitely want to address smoking cessation and create a resource that will last long after I’m gone, because the point is to make permanent, positive change if you can. I have some ideas that I am really excited about.

Editor’s note: UofL News also had the opportunity to talk to Health and Social Justice Scholar��Mallika Sabharwal. .��

About the Health and Social Justice Scholars program

Introduced in the spring of 2016, the Health and Social Justice Scholars Program engages professional students with local communities and faculty mentors to bring about changes to benefit underserved populations in the Louisville area.��For more information, visit .

Samet will deliver the University of Louisville’s School of Public Health and Information Sciences inaugural on Sept. 19 at 6:30 p.m. The event will be held at the Kosair Charities Clinical and Translational Research (CTR) Building, 505 S. Hancock St., with a reception at 5:30 p.m. in the same location.

The timely topic is a reminder of Kentucky’s dismal health statistics related to tobacco, such as facing the highest rate for cancer in the United States, especially lung cancer. From 2009 through 2013, 118 men and 80 women out of every 100,000 individuals were diagnosed with lung cancer compared to 75 men and 53 women per 100,000 nationally. The death rate for lung cancer is 70 per 100,000 in Kentucky compared to 46 per 100,000 nationally. Kentucky’s death rates for other tobacco-related health problems, such as heart disease, stroke and non-cancer chronic lung disease, also are higher than national averages.

Samet’s research is focused on smoking, pollution, and cancer causes and outcomes, to name a few. Throughout his career, he has maintained a commitment to using research findings to support policies that protect population health. Samet has been part of numerous committees related to the use of scientific evidence in characterizing risks and policy-making, including chairing the Clean Air Scientific Advisory Committee of the U.S. Environmental Protection Agency and the Food and Drug Administration’s Tobacco Products Scientific Advisory Committee (TPSAC). For three decades he has authored and edited reports of the Surgeon General related to smoking and health, including serving as Senior Scientific Editor for the 50th Anniversary report in 2014.��

A member of the National Academy of Medicine, Samet has been the recipient of many honors. In 2004, he received the Prince Mahidol Award for Global Health awarded by the King of Thailand, and the Surgeon General’s Medallion in 1990 and 2006.

Samet is the first national public health leader to lecture in Louisville through the Woodson Lectureship Endowment established through an anonymous gift in 2014. The school plans to bring in speakers annually as part of the Woodson Lecture series.

“Our ability to bring high profile speakers to our campus helps build the reputation of the school and speaks to the caliber of our programs,” said Craig Blakely, PhD, MPH, dean of the UofL School of Public Health and Information Sciences.

The public is welcome to attend Samet’s lecture, but must reserve a seat via��email��or by calling 502-852-6655.

The college and the Liberal Studies Project offer the Meet the Professor series each semester to highlight the college’s research and cultural offerings. Here is the fall 2016 schedule:

Sept. 1 – “Recognizing Quality and Value in Handmade Glass,” Che Rhodes, head of studio glass, fine arts. He will discuss the practical aspects of determining quality as well as the personal sensibilities that combine with quality to assign value to crafted glass artwork.

Oct. 6 – “Can Species Conservation and Urban Development Co-exist?” Margaret Carreiro, biology professor. She will dispute the common misperception that true urban nature can only be sustained in parks and reserves and discuss how people in cities and suburbs can create species-friendly habitats where they live and work.

Nov. 3 – “Smokin’ Hot Issues and Smoldering Concerns: Appalachian Youth and Tobacco,” Joy Hart and Kandi Walker, communication professors. They will discuss youth perceptions of tobacco use and products and will report on research from Appalachian regions of Kentucky, North Carolina and New York.

Dec. 1 – “Capital Sentencing in Kentucky,” Gennaro Vito, criminal justice chair. He will talk about research into the state’s capital sentences from 1976 to 2010, how capital punishment operates and why influencing factors at the jury and prosecutorial levels have changed over time.

The Thursday luncheon talks begin at noon in the University Club. Reservations are required, with $15 payment in cash or check. To reserve a spot, contact Janna Tajibaeva at 502-852-2247 or janna@louisville.edu no later than the Monday before each event.

��

University of Louisville School of Dentistry researcher David A. Scott, PhD, explores how cigarettes lead to colonization of bacteria in the body. Scott and his research team have identified how tobacco smoke, composed of thousands of chemical components, is an environmental stressor and promotes bacteria colonization and immune invasion.

Scott says since this initial finding several years ago, a recent literature review published in revealed that cigarette smoke and its components also promote biofilm formation by several other pathogens including Staphylococcus aureus, Streptococcus mutans, Klebsiella pneumonia and Pseudomonas aeruginosa.

Biofilms are composed of numerous microbial communities often made up of complex, interacting and co-existing multispecies structures. Bacteria can form biofilms on most surfaces including teeth, heart valves and the respiratory tract.

“Once a pathogen establishes itself within a biofilm, it can be difficult to eradicate as biofilms provide a physical barrier against the host immune response, can be impermeable to antibiotics and act as a reservoir for persistent infection,” Scott said. “Furthermore, biofilms allow for the transfer of genetic material among the bacterial community and this can lead to antibiotic resistance and the propagation of other virulence factors that promote infection.”

One of the most prevalent biofilms is dental plaque, which can lead to gingivitis – a gum disease found in almost half the world’s population – and to more severe oral diseases, such as chronic periodontitis. Bacterial biofilms also can form on heart valves resulting in heart-related infections, and they can cause a host of other problems as well.

“We are continuing research to understand the interactions of the elaborate communities within biofilms and how they relate to disease. Many studies have investigated biofilms using single species, but more relevant multispecies models are emerging. Novel treatments for biofilm-induced diseases also are being investigated, but we have a long way to go,” Scott said.��

Scott elaborates on this research in a short question and answer style blog published today on the .

Attention to Scott’s work comes as the observes World No Tobacco Day on May 31 to encourage a global 24-hour abstinence from all forms of tobacco consumption. The effort points to the annual 6 million worldwide deaths linked to the negative health effects of tobacco use.

In the United States, , according the Centers for Disease Control and Prevention (CDC). Only West Virginia has more smokers. Kentucky also brings up the rear among youth in grades 9-12 who use tobacco: according to , about 24 percent of high school students smoke cigarettes in the state.