Atrial fibrillation (A-fib) is an irregular heart rhythm that increases a person's risk of stroke, heart failure, and even premature death.

While there are many risk factors for atrial fibrillation, one of the most prominent is its growing epidemic worldwide: obesity.

I am a cardiology researcher, and my team and I have discovered key mechanisms that contribute to the deleterious effects of obesity on heart function. Targeting these processes may provide new therapeutic avenues.

How obesity puts stress on the heart

Obesity is more than just a weight problem—it fundamentally changes the body's biochemistry. This in turn changes your metabolism, or the chemical reactions that allow your body to function.

In particular, an increase in fatty acids, a marker of obesity, puts additional stress on heart cells. Fatty acids can directly damage heart cells by triggering increased production of reactive oxygen species, specific molecules that can damage tissue and disrupt normal cell function. These effects can cause a disruption in the heart's electrical signals, leading to irregular beating.

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A major source of reactive oxygen species is NOX2, an enzyme that becomes more active in obese people. NOX2 affects the activity of several key proteins that regulate heart rhythm. It also causes oxidative stress in the atria (the upper chambers of the heart), changing their size, shape and function. This cardiac remodeling is a key driver of cardiac arrhythmias.

Two-pronged approach

My team and I set out to better understand how NOX2 affects the heart and whether targeting NOX2 could reduce the risk of arrhythmias in obese people.

We approach this problem from two directions.

First, we induced obesity similar to humans in mice fed a high-fat diet. One group of mice was able to produce functional NOX2, while the other group was not. We tested drugs that specifically inhibit NOX2 and examined the possibility of irregular electrical rhythms in the upper chambers of the heart.

Meanwhile, we generated human atrial heart cells from stem cells and treated them with fatty acids to mimic the effects of obesity. While our mouse model captures the effects of obesity on the entire body, our cell model will allow us to study how obesity affects the heart at the cellular level.

We observed that increased NOX2 activity in obese mice and treated human heart cells resulted in significant changes in cardiac electrical properties. Obese mice without NOX2 had milder atrial fibrillation than obese mice with NOX2. Similarly, obese mice treated with NOX2 inhibitors also experienced improvements in arrhythmia severity, but to a lesser extent. Blocking NOX2 in heart cells exposed to fatty acids reversed the cellular changes caused by fatty acid treatment.

In mouse and human heart cells, inhibition of NOX2 reduces oxidative stress and normalizes cardiac electrical activity. This finding suggests that NOX2 plays a key role in the development of obesity-induced cardiac arrhythmias.

Notably, we found that NOX2 plays an important role in increasing the activity of the PITX2 gene, which is associated with changes in cardiac electrical function. Our data show that PITX2 activity is enhanced in both obese mice and human heart cells, but reducing NOX2 activity directly reduces PITX2 levels. These findings suggest that oxidative stress and genetic factors play a role in the development of arrhythmias.

Treat atrial fibrillation

Current treatments for atrial fibrillation, especially in obese patients, focus more on controlling symptoms rather than addressing the physiological changes that cause atrial fibrillation.

Although still far from the clinic, our study suggests that targeting NOX2 may provide a new therapeutic strategy to prevent or reduce the severity of arrhythmias. Improved understanding of genetic pathways involved in atrial fibrillation, such as PITX2, may lead to more personalized treatments in the future.

By delving deeper into the molecular mechanisms behind irregular heartbeats, researchers can develop more targeted approaches that address the root causes and improve outcomes in patients with obesity and heart disease.