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 demise.
Whereas many threat elements 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 perform. Focusing on these processes could provide new avenues for remedy.
How weight problems stresses the guts
Weight problems is way over a weight concern – it basically alters the physique’s biochemistry. This in flip modifications your metabolism, or the chemical reactions that permit the physique to perform.
Particularly, the elevated presence of fatty acids, an indicator of weight problems, places further pressure on coronary heart cells.
Fatty acids can straight injury coronary heart cells by triggering the elevated manufacturing of reactive oxygen species – particular molecules that may injury tissues and disrupt regular mobile features.
These results end in a disruption of the guts’s electrical indicators, resulting in irregular beating.
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One major source of reactive oxygen species is NOX2, an enzyme that becomes more active in people with obesity. NOX2 influences the activity of several key proteins that regulate the heart’s rhythm. It also contributes to oxidative stress in the atria – the heart’s upper chambers – altering their size, shape and function. 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 guts, and whether or not focusing on it might cut back the danger of creating irregular coronary heart rhythms amongst folks residing with weight problems.
We approached this downside from two instructions.
First, we used mice fed a high-fat food regimen to induce weight problems just like that in folks. One group of those mice was capable of produce purposeful NOX2 whereas one other group couldn’t. We examined medication that particularly inhibit NOX2 and checked how doubtless the higher chambers of the guts 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 consequences of weight problems. Whereas our mouse mannequin would seize the consequences of weight problems within the physique as an entire, our cell mannequin would allow us to review the way it impacts the guts on the mobile degree.
We noticed that elevated NOX2 exercise in each overweight mice and handled human coronary heart cells led to important modifications 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 modifications attributable to fatty acid remedy.
In each mice and human coronary heart cells, inhibiting NOX2 lowered oxidative stress and normalized the guts’s electrical exercise. This discovering means that NOX2 performs a key function within the improvement of obesity-induced irregular coronary heart rhythms.
Notably, we discovered that NOX2 performs a major function in growing the exercise of a gene referred to as PITX2, which is linked to modifications within the coronary heart’s electrical perform.
Our information confirmed that PITX2 exercise was amplified in each overweight mice and human coronary heart cells, however decreasing NOX2 exercise straight lowered PITX2 ranges. These findings recommend that oxidative stress and genetic elements play a job within the improvement of irregular coronary heart rhythms.
Treating atrial fibrillation
Present therapies for atrial fibrillation, significantly for sufferers residing with weight problems, have targeted extra on managing signs than addressing the physiological modifications that trigger it.
Although removed from reaching the clinic, our analysis means that focusing on NOX2 might provide a brand new remedy technique to forestall or cut back the severity of irregular coronary heart rhythms.
An extra understanding of the genetic pathways concerned in atrial fibrillation, comparable to PITX2, could 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 tackle the foundation causes and enhance outcomes for sufferers scuffling with each weight problems and coronary heart circumstances.
Arvind Sridhar, Postdoctoral Scholar in Cardiology, College of Illinois Chicago
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