CVM’s Chiu Creates Cardiac Model for Testing Drugs’ Effect on Long QT Syndrome

Dr. ChiuIn a well plate, roughly the size of an iPhone, 5,000 heart cells beat in synchrony.

These cells have an important role—their response to different medical drugs is helping researchers like Texas A&M’s Dr. Weihsueh Chiu predict how those drugs and environmental chemicals could cause or exacerbate a heart rhythm condition called long QT syndrome.

Long QT syndrome occurs when the heart takes too long to recharge for the next beat. When the heart pumps blood, electrical signals tell it when to contract and relax. The timing and voltage of the heart’s electrical signals can be seen on a graph called an electrocardiogram (EKG), which is divided into different intervals.

The time between when the heart’s lower chambers start contracting to when they finish relaxing is called the QT interval.

“If the QT interval gets too long, the heart’s not ready to beat again,” Chiu said. “It gets stuck, just kind of thinking, or not thinking—it hasn’t reset for the next beat yet.”

A professor in the College of Veterinary Medicine and Biomedical Sciences’ (CVM) Department of Veterinary Integrative Biosciences (VIBS), as part of the Chancellor’s Research Initiative, Chiu wanted to create a model that could predict what drugs or chemicals affect long QT syndrome, which can cause fainting, seizures, and death.

The project, funded by the United States Environmental Protection Agency, is part of a larger Cardiotoxicity Research Center led by VIBS professor Ivan Rusyn that includes collaborators in the Texas A&M College of Medicine and at North Carolina State University, and the resulting research article is available online at https://doi.org/10.1002/cpt.1259.

Chiu’s interest in cardiotoxicity is not entirely academic. His daughter had cancer as a toddler and had to have routine heart monitoring following her treatment. She’s 15 and cancer-free now, but 5 years ago, her doctors found that she had long QT. Long QT syndrome can be either inherited or caused by certain medications.

“My daughter’s experience is how I was introduced to long QT syndrome, and it just so happened that I could apply my research to it as well,” Chiu said. “The doctors aren’t sure whether her long QT syndrome is due to chemotherapy, genetic susceptibility, or a combination.”

Some drugs can also exacerbate long QT syndrome, which makes Chiu very careful at the pharmacy.

“If my daughter is sick, I always check whether the prescribed drug or what’s on the shelf at Walgreens is on my list of QT-prolonging drugs. She has to be very careful,” Chiu said.

Chiu’s daughter’s experience made him want to see if environmental chemicals could have an impact as well. Because most environmental chemicals aren’t tested for their effect on the heart, Chiu said, there’s little data on their cardiac impacts.

Chiu started by making a model of the impact of drugs on the heart. That way, he could validate the model using data from past clinical trials of drugs whose impact is already known. Later, he could use that same model to predict the impact of environmental chemicals.

“We used the drugs in the model because we know a lot about whether particular drugs are cardiotoxic or not. So, we can use the drug results to make sure our model works,” Chiu said.

Chiu compares the data from past clinical trials to data from heart cells in the lab.

“When you put the heart cells in a petri dish, they all beat together,” Chiu said.

Because the heart cells respond to the drugs just like heart cells in living human hearts would, those in the petri dish experience the same erratic heartbeats from long QT syndrome.

“By using this cellular system plus the computational model, we can predict what concentration of the drug or chemical will lead to how much of a prolongation in QT,” Chiu said.

The average length of a normal QT interval is 400 milliseconds. The U.S. Food and Drug Administration requires that drugs cause no more than a 10 millisecond increase in the QT interval.

Chiu wants to figure out the concentration at which a drug or chemical starts making the QT interval longer.

“For drugs, we want to identify what dose starts to cause problems compared with the dose needed for therapeutic effects,” Chiu said.

Knowing the concentration that causes long QT syndrome is especially important for environmental chemicals, Chiu said.

“For environmental chemicals, it’s not like you can just not be exposed, right? If the chemical is in the air, you want to regulate it so it’s low enough that it’s not going to cause problems,” Chiu said. “Plus, the effects of environmental chemicals tend to be additive. A lot of small things can add up to a bigger effect.”

Having a model that can predict the concentration at which drugs and environmental chemicals cause long QT syndrome can save both lives and money. Clinical drug trials can take a long time and cost millions of dollars.

“In our first round, we tested around 140 chemicals, including 10 drugs known to prolong QT,” Chiu said. “We can essentially make the same predictions as the clinical trial, but for much cheaper.”

Soon, the model should give a better idea of the QT-prolonging effects of environmental chemicals as well. Though the results aren’t in yet, Chiu and Rusyn have already begun testing and analyzing data on food additives, pesticides, and PAHs, a group of chemicals that are released from burning things like coal, gasoline, wood, and tobacco.

Given that Chiu’s model began with a grant to study environmental chemicals, it has had unexpected benefits.

“Originally, we were just using the drugs to make sure that the model worked,” Chiu said. “But we’ve actually developed a model that is helpful for pharmaceuticals as well.”

The experience making this model fits within Chiu’s own approach to doing research.

“When doing research, you have to be focused on what you originally were going to investigate, but also be open to unexpected discoveries along the way,” Chiu said.

By looking into the effects of environmental chemicals and drugs on long QT syndrome, Chiu has made unexpected discoveries on multiple levels. With this model and an iPhone-sized plate of beating heart cells, Chiu has been able to both satisfy his research interests and help his daughter and others like her.