University of Louisville environmental medicine researchers are working to better understand how natural, social and personal environments affect health, particularly the cardiovascular system. In recent months, the National Institutes of Health have awarded four grants totaling $11.6 million to researchers affiliated with UofL’s to study factors affecting heart health. Through these projects, they hope to better understand how environmental exposures and tobacco products can affect the cardiovascular system, as well as how remodeling takes place in the heart after a heart attack.

“The unique and synergistic research collaborative we have built at the Envirome Institute already has resulted in new discoveries about the biological and the environmental factors that contribute to heart disease,” said Aruni Bhatnagar, chief of the UofL Division of Environmental Medicine and director of the Envirome Institute. “Our studies funded by these new grants will lead to better understanding of the causes and progression of cardiovascular disease and new ways to protect and improve cardiovascular health.”

The new projects address the cardiovascular effects of newly introduced ingredients in electronic cigarette liquids, exposure to benzene, prenatal and infant exposure to combinations of substances and their impact on sleep in adolescence and the metabolic processes occurring after a heart attack that result in scarring in the heart.

One grant provides $3.3 million to investigate how exposure to benzene affects blood vessels. Sanjay Srivastava, professor of medicine who leads the project, said preliminary research shows that benzene worsens atherosclerosis, an underlying cause of cardiovascular disease and stroke. Atherosclerosis, a buildup of fatty deposits in arteries, reduces blood flow and flexibility of the arteries. Benzene is one of the top 20 pollutants from industrial sources in the United States, primarily from gasoline refineries. Outside industrial locations, exposure is higher near gas stations and from automobile exhaust and cigarette smoke. Benzene is known to cause cancer, but this is the first study to evaluate the effects of the chemical on heart disease, especially at levels typically experienced in the environment.

Cardiac fibrosis is essential for upholding the structure of the heart after heart attack, but also tends to produce excessive scar tissue and stiffening of the heart. Bradford Hill is examining the processes behind stiffening and scarring in the heart following myocardial infarction. A $2.3 million grant is funding the professor of medicine’s work to investigate the metabolic processes underlying this process. Hill hopes the work will lead to a therapy that supports the repair process but also reduces excessive scarring, allowing heart attack patients to fare better down the road.

Clara Sears, assistant professor of environmental medicine, received a $2.1 million grant for a project to discover how exposure to mixtures of common chemicals and pollutants before birth and in infancy affects sleep health in adolescence. Ultimately, she hopes to understand whether exposures to phthalates (common components of plastics), metals and per-/polyfluoroalkyl substances (PFAS – known as “forever chemicals”) may be linked to cardiovascular issues later in life.

The largest of the grants, $3.9 million, will fund research into potential toxicity of new synthetic cooling compounds that are being used in electronic cigarette liquids. Daniel J. Conklin leads the project to learn whether these compounds are harmful to the cardiovascular and pulmonary systems when heated and inhaled. The compounds mimic the cooling effect of menthol, which can be irritating in high doses, but they have not been tested for safety or toxicity as inhaled substances. For this new project, Conklin, a professor of medicine who has studied the cardiovascular effects of e-cigarette and cigarette components for more than two decades, is testing the effects of the new constituents as well as documenting the impact of dual use – smoking conventional cigarettes along with vaping. The Food and Drug Administration’s Center for Tobacco Products will use the results of these studies to determine potential recommendations to regulate the products’ use.

“We are going to address the issue of dual use, where there are both cigarettes and e-cigarettes in use, because this is a very common phenomenon and the signals are coming that it’s actually worse than either one alone,” Conklin said.

UofL researchers will use the microscopes to continue their close working relationship with the Clinical Research Foundation (CRF) at the Robley Rex VA Medical Center to understand how environmental exposures cause health effects in military veterans.

The multiphoton confocal microscopes, valued at nearly $2 million, will help the researchers discover the mechanisms behind health effects that have been documented by veterans and their health providers and finding ways to prevent or reduce their impact. The new instruments provide 3-D images of thicker tissue samples than were previously accessible, allowing the researchers to better see changes in biological tissues and metabolic functions in response to specific substances such as benzene and aldehydes.

The new microscopes are housed in spaces allocated by the UofL School of Medicine to the VA hospital, one in the (formerly the Diabetes and Obesity Center), part of the , where it will be used to study heart and vascular functions, as well as immune responses in animal models. The other is in the and will be used to understand the effects of environmental toxins on the liver.

“We are exceptionally grateful to the VA for providing this new technology, which will allow our researchers to have a greater understanding of the impacts and effects of wartime exposure on the health of our veterans,” said Toni Ganzel, dean of the UofL School of Medicine. “And we are pleased that the UofL School of Medicine is partnering with the VA and Clinical Research Foundation to improve care for our veterans as well as citizens of Kentucky and beyond.”

Most imaging methods enable scientists to see only small, thin sections of tissue at a time. The images from the larger, thicker samples captured by the new multiphoton microscopes allow scientists to study the metabolic processes taking place.

“The multiphoton microscope uses lasers that can penetrate more deeply into a much thicker section of tissue rather than a very thin slice,” said Steven P. Jones, director of the Center for Cardiometabolic Science and professor of medicine. “Using the system, we can look in real time at what is happening in immune cells that may be trafficking to the liver, skeletal muscle, adipose depots and the heart.”

Matthew Nystoriak, associate professor of medicine, investigates the effects of inhaled substances on the cardiovascular system.

“We can look at the molecular processes behind different disease development that affect a broad section of the population,” Nystoriak said. “One of the things we want to look at is vascular inflammation. With this instrument, we can track immune cells leaving the bloodstream and infiltrating the walls of blood vessels.”

The liver research, led by Matthew Cave and Craig McClain, both professors of medicine at UofL and physicians and researchers affiliated with Robley Rex VA Medical Center, will include evaluating the effects of environmental exposures on liver diseases and the metabolic syndrome, studying interactions of environmental exposures with nutrition and with alcohol intake, and investigating clinically-relevant exposures such as those related to Camp Lejeune and to burn pits.

The VA has increased this research as a result of the PACT Act, recently signed into law to help veterans suffering negative health effects from war and peacetime exposures related to burn pits and other service-related activities. The act improves access to medical care for conditions resulting from these exposures through VA Medical Centers and helps the VA improve research, staff education and treatment related to those exposures.

“The VA enjoys a close relationship with UofL researchers, and this state-of-the-art equipment will be utilized to advance the research agenda of the VA , including allowing VA-affiliated researchers to apply the latest scientific methods to the investigation of respiratory, gastrointestinal, liver and metabolic diseases that commonly affect veterans,” said Gerald Dryden, professor of medicine at the UofL School of Medicine and associate chief of staff for research and development at Robley Rex VA Medical Center. “This will be especially important as we begin to look into the causes and effects of chronic burn pit and other environmental exposures on veterans’ health.”

The CRF is a nonprofit corporation that provides the administrative infrastructure dedicated to Robley Rex VA Medical Center researchers under the U.S. Department of Veterans Affairs (VA). The CRF also works with UofL to provide groundbreaking research opportunities to veterans and active military in the Louisville area.

Nonprofit corporations (NPCs) such as CRF were established to provide a more efficient mechanism for VA researchers to participate in research and educational programs funded by private and non-VA public sources. There are more than 80 NPCs nationally, each affiliated with a VA medical center, who collectively have a resource and voice through the National Association of Veteran Research and ����ֱ�� Foundation.

Michael Book, executive editor of the CRF, underscored what this investment means for the partnership in the future.

“These microscopes further advance the research capabilities of the incredible investigators in our region,” said Michael J. Book, executive director of the CRF. “The equipment will aid in attracting other investigators to the groundbreaking work being done at Robley Rex VA Medical Center and the University of Louisville. Beyond the technological advancement, the investment also signifies the importance of the strong relationship between VAMC, the University of Louisville and the Clinical Research Foundation. We are excited to be a part of the innovation that lies ahead.”