The USF Health study, using a rat model for high blood pressure, helps explain the different nerve-induced physiological response to air pollution in patients with preexisting cardiovascular disease

Numerous studies have linked air pollution with cardiovascular disease, including evidence suggesting that chronic exposure accelerates the process of atherosclerosis.

TAMPA, Fla. (June 18, 2019) — Air pollution significantly increases the risk for premature deaths, particularly in people with underlying cardiovascular disease, clinical and epidemiological studies have determined

In healthy people, inhaling ozone or particle pollution triggers a defensive lung-heart reflex (pulmonary-cardiac reflex) that automatically slows heart rate to accommodate oxygen deficiency and help slow distribution of pollutants throughout the body. Yet, when patients with cardiovascular diseases breathe pollutants that same protective mechanism does not kick in.  Instead, their heart rates intermittently speed up, known as tachycardia, and can evoke a potentially deadly irregular heart rhythm, known as premature ventricular contractions.

What accounts for the difference?  University of South Florida Health (USF Health) researchers who study the role of sensory airway nerves in protective behaviors wanted to know.

Their preclinical findings, reported May 11 in The Journal of Physiology, help explain the altered physiological response to air pollution in patients with preexisting cardiovascular disease.

Thomas Taylor-Clark, PhD, of the USF Health Department of Molecular Pharmacology and Physiology, was senior author for the study.| Photo by Eric Younghans

Using a rat model for high blood pressure (hypertension), a common chronic cardiovascular condition, the USF Health team found that preexisting hypertension altered normal reflexes in the lungs to affect autonomic regulation of the heart when an irritant mimicking air pollution was inhaled. In particular, hypertension appeared to shift the reflex response from the parasympathetic nervous system to the sympathetic nervous system.  The sympathetic nervous system mobilizes the body’s defensive “fight-or-flight” response to a threat, including releasing adrenaline that increases heart rate. In contrast, the parasympathetic nervous system controls involuntary responses, including breathing and heart rate, while the body is at rest and maintains a state of calm.

“The speeding up of heart rate and abnormal heart beats (in the hypertensive rats) were due to the switching on of this ‘flight-or-fight’ nervous system not seen in the healthy animals exposed to noxious agents,” said senior author Thomas Taylor-Clark, PhD, associate professor of molecular pharmacology and physiology in the USF Health Morsani College of Medicine. “The heart was responding to an aberrant nerve-generated reflex that may worsen preexisting cardiovascular disease.”

To simulate effects of air pollution inhaled into the lungs — difficult to recreate in a laboratory setting — the USF researchers used allyl isothiocyanate, the pungent ingredient in wasabi and horseradish.  When healthy rats with normal blood pressure inhaled this irritant, their heart rates slowed as expected.  But, in the rats with chronic hypertension, inhaling the same irritant stimulated an increased heart rate accompanied by premature ventricular contractions.

Surprisingly, a rapid heart rate and abnormal heart rhythm did not occur when allyl isothiocyanate was intravenously injected into the hypertensive rats.

USF Health postdoctoral scholar J. Shane Hooper, PhD, was the study lead author.

“It did not evoke the peculiar reflex; instead, we observed a slowing of the heart rate like that seen in the rats with normal blood pressure,” Dr. Taylor-Clark said. “This suggests that the sensory airway nerves accessible by IV are different than those accessible by inhalation… so perhaps the pathways of airway sensory nerves (connecting organs like the heart and lungs with the brainstem,) are more complex than previously understood.”

Chronic hypertension may remodel airway sensory nerves controlling the pulmonary-cardiac reflex that helps defend the body against physical damage from air pollution, the USF study suggests. This remodeling, which may happen in the developmental stages of hypertension, could turn on inappropriate sympathetic nervous system excitation of the heart, Dr. Thomas-Taylor said.

By better understanding how cardiovascular disease changes neuronal interactions between the heart and lungs, the researchers hope to help doctors with treatment choices – and eventually discover new treatments.

“Our goal is to add another piece of information that clinicians could consider when selecting a best treatment for hypertension. In addition to the patient’s age, ethnicity and race, that might include whether the person lives in an area with high pollution levels,” he said. “In the long-term, if we can identify the nervous system mechanisms involved in remodeling the pulmonary-cardiac reflex, we can target those to develop new blood pressure drugs.”

The USF Health study was supported by grants from the American Heart Association, the National Institutes of Health’s National Heart, Lung and Blood Institute, and the NIH Commonfund.

A slice of the brainstem showing central projections of defensive nerves (red) into the medulla, where the nerves transmit signals to brainstem networks to control various involuntary functions like breathing, cough, swallowing, heart rate and blood pressure.

More than four in 10 Americans are at risk of disease and premature death due to air pollution, the American Lung Association reports. And, more than one-third of the deaths from lung cancer, heart disease and stroke are associated with air pollution, according to the World Health Organization.

Heart disease and stroke impact so many families across the United States, including our own families here at USF Health.

The American Heart Association is holding its annual Heart Walk to raise funds and awareness for heart disease and stroke, and USF Health faculty, staff and students are gearing up to participate.

The annual event draws thousands from across the Tampa Bay area and is one of nearly 340 events held across the country each year. In total, the national AHA Heart Walk events include more than 1 million walkers.

USF Health faculty, staff and students participate in the local event – details below – by forming teams, making direct donations, sponsoring teams and walking themselves as ways to help raise funds for the American Heart Association and awareness for heart disease and stroke.

While many walk for the cause in general, a large number walk for someone they know battling heart disease or living with stroke. Many are walking in memory of loved ones who have been lost to these diseases. Heart disease and stroke continue to top the list at #1 and #5 for killer diseases in the United States.

USF Health takes active roles in helping AHA’s search for cures, said Phillip J. Marty, PhD, vice president for USF Health Research.

“A foundation of science is what will help find new therapies, treatments and procedures for ending heart disease and stroke,” he said. “We have many promising scientists doing promising research that is laying the groundwork for advances.”

USF Health faculty currently have 11 AHA-funded research awards totaling nearly a million dollars aiming toward the solid science that could lead to cures.

“Much of the work we do at USF falls into the category of translational research, in which basic science researchers work with our clinical researchers to test and translate their work into treatments, cures and preventive measures,” Dr. Marty said. “These collaborative research approaches will ultimately help reduce, and even eradicate, forms of cardiovascular disease and stroke in future generations.”

Click here to register or contribute today!  Participation is not limited to employees and students, so please encourage your family and friends to join a USF team.

And check out a great video for this year’s Heart Walk!

Details:

AHA Heart Walk – Tampa

Saturday, Nov. 7

Raymond James Stadium, 4201 N. Dale Mabry Hwy., Tampa, FL 33607

Festivities Begin at 8:00 a.m. and the walk kicks off at 9:00 a.m.  Plan to arrive early for parking, which is free in the general parking lot south of Raymond James Stadium between Dale Mabry and Himes. The walk route will be 3.2 miles with a one-mile route option.

A national clinical trial was halted when it became evident that more intensive management of high blood pressure for certain people improved survival and incidence of heart attacks, strokes and heart failure.

The Systolic Blood Pressure Intervention Trial, nicknamed SPRINT study, aimed to see if using multiple targeted medications to reduce the systolic blood pressure in certain patients to less than 120 mmHg would be beneficial.

By the fourth year of the 5-year study, it became clear that aiming for less than 120 mmHg was beneficial and the study was halted, said Ramon Lopez, MD, associate professor in the Division of Nephrology and Hypertension in the USF Health Morsani College of Medicine and SPRINT principal investigator at the USF Health clinical site.

Dr. Ramon Lopez (center) is principal investigator for the USF Health SPRINT study, with co-investigators Dr. Jacques Durr, director of the Division of Nephrology and Hypertension, and Dr. Juris Janavs, study coordinator.

USF Health was one of the sites participating in this large study that was sponsored by the National Institutes of Health (NIH). The USF Health team, which studied 54 of the 9,361 participants, earned honorary awards for their performance and compliance in the study.

The SPRINT Data and Safety Monitoring Board decided to stop the study at the end of August 2015, Dr. Lopez said.

“The results showed a clear benefit in survival and cardiovascular events for more aggressive management of hypertension,” Dr. Lopez said. “For this group of  patients, reducing the systolic blood pressure to less than 120 mmHg  reduced their likelihood of cardiovascular events by as much as a third and the risk of any cause death by nearly a quarter compared to the targeted systolic pressure of  less than 140 mmHg.”

Although the study ended early, participants will continue to be monitored for the remaining year of the study to obtain further data on cognitive and kidney function, he said.

“For patients, the early information will not likely change how their own hypertension is being treated currently because the final data is being compiled for peer-reviewed publication, a critical step before any wide-spread guidelines can be adjusted.”

All SPRINT study participants were non diabetic and 50 years old or older, with the average being age 67. The 9,361 study participants were divided into two groups, a standard group that was given and average of two medications, which caused a reduction in systolic blood pressure to 134 mmHg, and an intensive group, which was given an average of three medications that resulted in a larger decrease in systolic blood pressure to 118 mmHg.

Study participant Charles Helsene (center) has a follow up visit at the USF Health Morsani Center with Dr. Janavs and Dr. Lopez.

Our blood pressure measurements are given as two numbers, such as 110 over 70 (written as 110/70). The top number is the systolic reading, representing the maximum pressure exerted when your heart contracts. And the bottom number is the diastolic reading, representing the minimum pressure in your arteries when your heart is at rest.

Published data is expected later this fall, Dr. Lopez said.

“While waiting for the study results to be published and guidelines to be revised, we can take steps with our lifestyles that may be beneficial in reducing high blood pressure, including loosing excess weight with diet and exercise and decreasing the amount of salt we consume. Your provider can provide blood pressure screening, diet and exercise advice and monitor changes in your blood pressure,” he said.

At USF Health, 54 patients participated in the national study through the Division of Nephrology and Hypertension in the USF Health Morsani College of Medicine. In addition to Dr. Lopez as Principal Investigator, USF Health faculty involved in the study include: Elias Doumit, MD, Assistant Professor; Jacques Durr, MD, Professor and Director of the Division of Nephrology and Hypertension; Juris Janavs, MD, study coordinator; Christopher McFarren, MD, Associate Professor, Stephen Rifkin, MD, Associate Professor, and Kevin Sneed PharmD, and Dean USF College of Pharmacy.

Story by Sarah Worth, photos by Eric Younghans, USF Health Office of Communications.

Animal-model research examines molecular mechanisms for blood-pressure lowering effect of ancient Chinese therapy

An increase in antioxidant enzymes triggered by acupuncture appeared to play a role in reducing high blood pressure in hypertensive rats treated with the ancient Chinese therapy, a study by researchers at the University of South Florida College of Pharmacy and Guangzhou University of Chinese Medicine found.

The study findings were reported online last month in the biomedical journal PLoS ONE.

“The data clearly show that acupuncture can modulate the expression of enzymes involved in processes that may protect against free radical damage to blood vessel walls,” said Shufeng Zhou, MD, PhD, associate vice president of Global Medical Development at USF Health and professor and associate dean of International Research at the USF College of Pharmacy.  “We need to know the molecular mechanisms for acupuncture to determine the best ways to use it.”

Dr. Shufeng Zhou led the USF-China acupuncture study.

Acupuncture has been an integral part of Chinese medicine for at least 2,500 years.  Although still somewhat controversial in mainstream Western medicine, it has become one of the most widely practiced forms of alternative medicine in the United States.  More than 2 million Americans report recent use of acupuncture for conditions ranging from chronic pain to osteoarthritis and migraines.

Acupuncture involves inserting very thin needles to stimulate various “acupoints” on the body associated with specific energy pathways or meridians. It’s based on the theory that illness can result when the body’s free flow of energy, called ‘Qi’ (pronounced ‘chee’), becomes disrupted or blocked.  Acupuncture is thought to restore health by restoring the body’s energy balance.

In the USF-Guangzhou study, hypertensive rats that had been acclimated to gentle handling and blood pressure measurements were randomized to receive either acupuncture (performed by a Chinese doctor trained in acupuncture), a sham procedure, or no treatment at all.

For seven days the rats receiving acupuncture were administered a daily 5-minute treatment, which stimulated the “Taichong” acupoint located between the first and second metatarsal bones at top of the foot.  The sham procedure followed the same protocol, including needle insertion, but the insertion point was not one of the precise sites prescribed by traditional Chinese medicine for treating blood pressure.

At the end of the study, the group of Taichong-treated rats had significantly lower blood pressures than either the group receiving sham acupuncture or the untreated group. The reduction was not enough to bring the blood pressure down to normal levels.

The researchers also examined the part of the brain involved in regulating blood pressure. They found that decreased expression of seven proteins in the acupuncture-treated rats’ brains was accompanied by an increase in six antioxidant enzymes.

The researchers suggest that the blood pressure-lowering effect of acupuncture may be partially explained by an overall decrease in cellular oxidative stress prompted by a boost in enzymes that help clear toxins called free radicals from the body.  However, they emphasize more studies are needed to further investigate the effects of oxidative stress regulation by acupuncture in the long-term treatment of blood pressure.

The study was supported by the National 973 program of China, the Natural Science Foundation of China, and USF College of Pharmacy startup fund.

Article citation:
“Proteomic Response to Acupuncture Treatment in Spontaneously Hypertensive Rats,” Xinsheng Lai, Jiayou Wang, Neel R. Nabar, Sanqiang Pan, Chunzhi Tang, Yong Huang, Mufeng Hao, Zhonghua Yang, Chunmei Ma, Jin Zhang, Helen Chew, Zhenquan He, Junjun Yang, Baogui Su, Jian Zhang, Jun Liang, Kevin B. Sneed, and Shu-Feng Zhou, PLoS ONE  7(9): e44216. doi:10.1371/journal.pone.0044216.