Atrial fibrillation, or A-fib, is an irregular coronary heart rhythm that will increase an individual’s threat of stroke, coronary heart failure and even untimely loss of life.
Whereas many threat components contribute to A-fib, one stands out for its rising prevalence worldwide: weight problems.
I’m a cardiology researcher, and my workforce and I uncovered key mechanisms contributing to the dangerous results of weight problems on coronary heart operate. Concentrating on these processes might provide new avenues for therapy.
How weight problems stresses the center
Weight problems is excess of a weight concern – it essentially alters the physique’s biochemistry. This in flip adjustments your metabolism, or the chemical reactions that enable the physique to operate.
Specifically, the elevated presence of fatty acids, an indicator of weight problems, places extra pressure on coronary heart cells. Fatty acids can instantly harm coronary heart cells by triggering the elevated manufacturing of reactive oxygen species – particular molecules that may harm tissues and disrupt regular mobile features. These results end in a disruption of the center’s electrical indicators, resulting in irregular beating.
When antioxidants aren’t capable of maintain dangerous reactive oxygen species in test, the imbalance results in extra stress on the physique.
One main supply of reactive oxygen species is NOX2, an enzyme that turns into extra lively in folks with weight problems. NOX2 influences the exercise of a number of key proteins that regulate the center’s rhythm. It additionally contributes to oxidative stress within the atria – the center’s higher chambers – altering their dimension, form and performance. This cardiac reworking is a key driver of irregular coronary heart rhythms.
A 2-pronged method
My workforce and I got down to higher perceive how NOX2 impacts the center, and whether or not focusing on it might scale back the danger of growing irregular coronary heart rhythms amongst folks residing with weight problems.
We approached this drawback from two instructions.
First, we used mice fed a high-fat eating regimen to induce weight problems just like that in folks. One group of those mice have been capable of produce purposeful NOX2 whereas one other group couldn’t. We examined medication that particularly inhibit NOX2 and checked how probably the higher chambers of the center have been to develop irregular electrical rhythms.
In parallel, we generated human atrial coronary heart cells from stem cells and handled them with fatty acids to simulate the results of weight problems. Whereas our mouse mannequin would seize the results of weight problems within the physique as a complete, our cell mannequin would allow us to check the way it impacts the center on the mobile degree.
Electrocardiograms measure the center’s electrical exercise.
Peter Charlton, CC BY-SA
We noticed that elevated NOX2 exercise in each overweight mice and handled human coronary heart cells led to vital adjustments within the coronary heart’s electrical properties. Overweight mice with out NOX2 had much less extreme atrial fibrillation than overweight mice with NOX2. Equally, overweight mice handled with NOX2 inhibitors additionally confirmed enhancements within the severity of their irregular coronary heart rhythms, although to a lesser extent. And blocking NOX2 in coronary heart cells uncovered to fatty acids reversed the mobile adjustments brought on by fatty acid therapy.
In each mice and human coronary heart cells, inhibiting NOX2 lowered oxidative stress and normalized the center’s electrical exercise. This discovering means that NOX2 performs a key function within the growth of obesity-induced irregular coronary heart rhythms.
Notably, we discovered that NOX2 performs a big function in rising the exercise of a gene referred to as PITX2, which is linked to adjustments within the coronary heart’s electrical operate. Our information confirmed that PITX2 exercise was amplified in each overweight mice and human coronary heart cells, however lowering NOX2 exercise instantly lowered PITX2 ranges. These findings counsel that oxidative stress and genetic components play a job within the growth of irregular coronary heart rhythms.
Treating atrial fibrillation
Present therapies for atrial fibrillation, notably for sufferers residing with weight problems, have targeted extra on managing signs than addressing the physiological adjustments that trigger it.
Although removed from reaching the clinic, our analysis means that focusing on NOX2 might provide a brand new therapy technique to stop or scale back the severity of irregular coronary heart rhythms. An extra understanding of the genetic pathways concerned in atrial fibrillation, akin to PITX2, might result in extra customized therapies sooner or later.
By delving into the molecular mechanisms behind irregular coronary heart rhythms, researchers can develop extra focused approaches that deal with the basis causes and enhance outcomes for sufferers fighting each weight problems and coronary heart situations.