Scientists identify key enzyme connecting obesity and atrial fibrillation offering new hope for treatment

Scientists from the University of Illinois Chicago (UIC) have uncovered a cellular mechanism that links obesity to atrial fibrillation (AF), a condition affecting over 33 million people worldwide. This breakthrough not only enhances our understanding of the relationship between excess body fat and AF but also presents a promising new target for the development of therapeutic treatments.

Atrial fibrillation is a common yet serious heart disorder characterised by an irregular heartbeat, which can lead to complications such as heart failure and stroke. Obesity is widely recognised as a significant contributor to this condition. However, the precise cellular mechanisms by which excess body fat triggers atrial fibrillation have remained elusive.

In a newly published study in The Journal of Clinical Investigation, researchers at UIC have identified a crucial cellular pathway that plays an essential role in the onset of obesity-related atrial fibrillation. The study reveals that inhibiting a specific enzyme known as NOX2 can prevent and potentially reverse the adverse changes in the heart caused by obesity.

According to Dr Dawood Darbar, senior author of the study, chief of cardiology, and professor of medicine and pharmacology at UIC, this discovery paves the way for developing new treatments aimed at both preventing and managing AF in people with obesity.

“A drug that blocks this enzyme may have two uses,” explained Dr Darbar. “We could use this drug to prevent the development of atrial fibrillation in individuals who have obesity but who haven’t yet developed atrial fibrillation. For those who already have obesity and atrial fibrillation, we can use it to treat them and prevent the progression of the disease.”

Investigating the Role of Oxidative Stress

The research team, led by UIC postdoctoral scholar Arvind Sridhar, focused on oxidative stress, a cellular process that has long been suspected of connecting obesity and atrial fibrillation. Oxidative stress occurs when harmful molecules called reactive oxygen species (ROS) accumulate in cells, causing damage. This can result from various conditions, including obesity and diabetes.

Antioxidants, such as vitamins and minerals found in fruits and vegetables, are known to neutralise ROS and protect against oxidative stress. However, antioxidant therapies for treating atrial fibrillation have so far produced inconsistent results. Some clinical studies have shown positive effects, while others have been inconclusive or ineffective.

“Some of these studies were positive, some were negative, some were neutral, and we didn’t understand why,” said Dr Darbar. “Now it seems the reason why antioxidants didn’t work in atrial fibrillation is because they didn’t target the specific pathway that caused the oxidative stress.”

Through their investigation, the UIC team uncovered this specific pathway by analysing heart tissue samples obtained from individuals during surgery. They discovered that the enzyme NOX2, which is responsible for generating reactive oxygen species, was significantly more active in patients with higher body mass indexes (BMIs) compared to those with lower BMIs.

“As the BMI of the individual increased, we saw an increased severity of atrial fibrillation,” explained Sridhar. “We also saw a similar increase in the expression of NOX2 as the BMI increased, which tells us that the two are intrinsically related.”

Experimental Evidence in Mice and Human Cells

Building on this insight, the researchers conducted a series of experiments using mice and cells derived from people with atrial fibrillation. In one set of experiments, they studied mice that had been genetically engineered to lack the NOX2 gene. While normal mice fed a high-fat diet developed atrial fibrillation, the mice without the NOX2 gene did not.

Additionally, the researchers found that administering a drug to normal mice to block NOX2 activity prevented the development of atrial fibrillation, even when the mice were fed a high-fat diet.

In another key experiment, the team used heart stem cells taken from individuals with atrial fibrillation. This innovative technique, developed by Dr Darbar in collaboration with Salman Khetani from UIC’s College of Engineering, enabled the researchers to mimic the cellular environment of people with atrial fibrillation. When these cells were treated with a NOX2 inhibitor, the levels of reactive oxygen species dropped, and the abnormal electrical activity that characterises atrial fibrillation was eliminated.

Moving Towards New Therapeutic Approaches

Although the drug used in the laboratory experiments has not yet received approval from the U.S. Food and Drug Administration (FDA), the researchers are optimistic about the potential to identify and test other compounds that inhibit NOX2. These alternative compounds could eventually lead to clinical trials and the development of new therapies for atrial fibrillation in individuals with obesity.

“Because obesity is becoming so common, I think this finding will have a tremendous impact,” stated Dr Darbar. “If we can find a way to safely and effectively block NOX2 in humans, we could not only prevent atrial fibrillation from developing in people with obesity, but also stop it from getting worse in those who already have the condition.”

The study’s implications extend beyond obesity and atrial fibrillation, as oxidative stress plays a role in many other diseases as well. Identifying NOX2 as a key player in this process could therefore open the door to a range of new therapeutic strategies for various conditions linked to oxidative stress.

A Collaborative Effort

This significant discovery was the result of collaborative work among various experts at UIC. In addition to Dr Darbar and Arvind Sridhar, other co-authors of the paper include Jaime DeSantiago, Hanna Chen, Mahmud Arif Pavel, Olivia Ly, Asia Owais, Miles Barney, Jordan Jousma, Sarath Babu Nukala, Dr Khaled Abdelhady, Dr Malek Massad, Lona Ernst Rizkallah, Sang Ging Ong, and Dr Jalees Rehman.

The researchers are hopeful that their findings will accelerate the development of new, targeted treatments that can significantly improve the lives of individuals living with both obesity and atrial fibrillation.