Air Force

Scientists have known for decades that air pollution can be hazardous to your health. Lung cancer, emphysema, asthma and a host of other pulmonary diseases have been linked definitively to unhealthy air.

Curiously, the relationship between pollution and heart disease -- which kills more people annually than all pulmonary disorders combined -- has largely been ignored, despite a growing body of evidence suggesting that poor air quality causes a variety of cardiovascular maladies ranging from the chronic (atherosclerosis) to the acute (fatal heart attacks).

"There are 300,000 cases of sudden cardiac death every year in the United States," explains Aruni Bhatnagar, Ph.D., a professor of medicine in the Division of Cardiology at the University of Louisville.

"Out of that, the Environmental Protection Agency has attributed 60,000 to 80,000 of those deaths to air pollution.

"But heart disease is typically not thought of as a consequence of pollution. We talk about cancer-causing pollutants or asthma-causing chemicals. No one ever talks about heart disease-causing chemicals. It's not in our vocabulary."

Now, Bhatnagar and a group of more than 25 UofL scientists are working to change that with the help of a $7 million, five-year grant from the National Institutes of Health.

The grant is allowing researchers to explore the relationship between a specific component of pollution -- aldehydes -- and the progression of heart disease.

Aldehydes are commonly found in smoke, vehicle exhaust, fried foods and contaminated water. They also occur naturally in the body as the result of normal metabolism.

Bhatnagar and his team of researchers decided to focus on aldehydes because they are highly reactive molecules that bind to proteins at the molecular level and interfere with a broad range of physiologic processes, including heartbeat regulation. They also play a key role in the development of artery-clogging plaques, Bhatnagar says.

The UofL research is designed to explore four key areas:

• How do cardiovascular tissues metabolize aldehydes, and how does the cardiovascular system handle the challenge of foreign chemicals?
• How, and how quickly, do aldehydes accelerate the progression of heart disease?
• How do aldehydes interact with blood cells to cause cardiac and vascular inflammation?
• How do high levels of aldehydes raise the risk of heart attack and worsen heart failure?

Researchers also will examine the role of aldehydes in blood clotting and atherosclerosis, as well as the means by which aldehydes make heart tissue more susceptible to damage when the heart muscle's flow of blood is reduced or cut off during a heart attack.

"Our goal is to establish cause and effect," Bhatnagar says. "We know there is a link between air pollution and heart disease, but that's just an epidemiological statistic. We want to show that pollution does specific things in a controlled setting."

The project's principal investigators are Bhatnagar, physiologist Stanley D'Souza, Ph.D., cardiologist Sumanth Prabhu, M.D., and biochemist Russell Prough, Ph.D.

The effort also will benefit from the expertise of William Pierce, Ph.D., director of UofL's bioanalytical core laboratory, whose mass spectrometer will play a critical role in performing molecular structural analyses, Bhatnagar says. Additional support will be provided by the University of Alabama at Birmingham and Jewish Hospital.

A new area of research

The team's research is so novel that it's being recognized as the opening salvo in a new war on heart disease, and it comes with a fittingly new name: environmental cardiology.

"To be selected as the scientific 'birthplace' for environmental cardiology -- an entirely new discipline -- demonstrates the level of research excellence and national recognition that UofL has achieved," says university president James R. Ramsey, Ph.D.

"Dr. Bhatnagar and the entire team of scientists recognized by this award are scientific and academic leaders in every sense of the word."

Bhatnagar first developed an interest in the relationship between pollution, aldehydes and heart disease while conducting research at the University of Texas in the late 1990s. With funding from two NIH grants, he began to investigate the effects of endogenous aldehydes -- those generated internally by the body's own metabolism -- on cardiovascular disease.

Endogenous aldehydes are formed continually when fats in the body deteriorate as the result of constant exposure to oxygen, Bhatnagar explains. Although oxygen is necessary to sustain life, it also causes toxicity because it stimulates the creation of tissue-damaging free radicals -- a process known as oxidative stress.

Bhatnagar already knew that aldehydes were partly responsible for modifying LDL cholesterol so that it bonds with blood vessel walls to form plaques. Those first two NIH-funded research projects, which he brought to Louisville when he joined UofL in 1998, were designed to learn more about the effects of oxidative stress-generated aldehydes and the enzymes that are responsible for removing them from the body.

"If we can understand that, we can enhance the removal process and protect tissue from damage," Bhatnagar says.

Taking it outside

While Bhatnagar was studying the role of endogenous aldehydes -- a process that continues today -- evidence continued to mount showing a link between environmental pollution and heart disease.

The first compelling evidence came in 1993 when a group from Harvard University released a study showing that people who live in polluted areas have a lower total life expectancy -- in some cases by as much as 15 years. Other studies have since shown a spike in cardiopulmonary-related deaths 24 hours after a corresponding spike in air pollution.

The most dramatic data, however, came following the temporary closure of a steel mill in Salt Lake City, Utah. Epidemiologists reported a significant decline in the city's death rate for the week the mill was closed, Bhatnagar says. But when the mill reopened, the death rate climbed back up.

"That really startled everybody," he says. "Since then, more than 110 epidemiological studies have shown an association between increased pollution and increased death, which is not surprising. What is surprising is that these people were dying of heart disease, not lung disease. And nobody could figure out why."

That is where UofL's research comes into play. Bhatnagar's examination of endogenous aldehydes got him thinking about exogenous aldehydes. If the body's own pollutants could lead to heart disease, could common air pollution -- laced with the same kinds of aldehydes -- do the same thing?

"Fossil fuels once were living things," Bhatnagar notes. "And when you burn them, they go through the same chemical process as the body's fats do when they're subject to oxidative stress.

"So the burning of fossil fuels generates the same compounds -- aldehydes -- as oxidative stress, only the source is external. When you smell acrid smoke from a wood-burning fireplace, for example, you actually are smelling an aldehyde called, appropriately enough, acrolein.

"So we started to think, maybe exposure to environmental aldehydes could cause the same damage as aldehydes that are generated internally."

In 2002, Bhatnagar organized a national workshop that brought together the handful of researchers working in the nascent field of environmental cardiology. With so little research being done, workshop participants raised more questions than answers.

But the attendees, including representatives from the NIH's National Institute for Environmental Health Sciences, agreed that more work needed to be done, and Bhatnagar seemed the most likely candidate.

"The NIH asked me to look into it because it was an extension of the work I had already done," he notes. "They said, 'We have all this evidence linking pollutants to heart disease, and we can't find anybody in the country who wants to pursue the research.' "

The result was Bhatnagar's two-pronged investigation, building on his earlier work into endogenous aldehydes while expanding it at UofL to include the exogenous variety.

Now, thanks to the those ground-breaking efforts and the $7 million NIH grant, the University of Louisville is in a position of national leadership, says Roberto Bolli, M.D., chief of the Division of Cardiology at UofL and a professor of medicine, physiology and biophysics.

"The field of environmental cardiology is a new and exciting area of research," he says. "Dr. Bhatnagar must be credited with having spearheaded this field and for positioning himself as a leader nationwide."

Bolli notes that "the implications of environmental cardiology are potentially huge, as environmental pollutants and toxins are ubiquitous and have a major impact on cardiovascular disease."

Bhatnagar estimates that Americans could add four to six years to their average life expectancies if air pollution were reduced by half. The number could be even higher in the Ohio Valley, which has some of the worst air pollution in the nation.

"Our rates of heart disease are 2.2 times the national average," Bhatnagar notes. "There are a lot of reasons for that, but pollution certainly contributes."

One unavoidable issue, however, is cost. Pollution reduction will cost billions of dollars, Bhatnagar says, and Americans won't be willing to pay that expense without hard evidence that airborne chemicals cause heart disease.

Bhatnagar hopes his team's research can provide such data.

"If we can help prevent heart disease, we would be able to make the single biggest impact on health care today," he says, noting that cardiovascular disease is America's No. 1 killer.

"We've got outstanding facilities, one of the best labs in the country and some very good, talented people. We're going to see how far we can go with it."