Researchers here present an interesting view of heart failure and atrial fibrillation, providing evidence for both to be manifestations of reduced TBX5 expression. TBX5 is a transcription factor, and thus influences expression of a very large number of genes; transcription factors are thus often central points of regulation for cell and tissue behavior. The evidence suggests that the present quite distinct treatments for atrial fibrillation and heart failure could potentially be replaced in the future by forms of therapy that increase TBX5 expression, a point of intervention that is upstream of present targets.
Heart failure occurs when the heart muscle is damaged and unable to pump enough nutrient-rich blood to meet the body's needs for oxygen. Heart failure is usually evaluated in the heart's lower chambers, called ventricles, which provide most of the pumping power. Atrial fibrillation is an arrhythmia - an irregular heart rhythm - that originates in the heart's upper chambers, known as the atria. During atrial fibrillation, the heart beats too fast, resulting in a lower blood flow to the body and a higher risk for clots or stroke. Epidemiologists have observed that these two conditions aren't independent of one another: People with heart failure are much more likely to have atrial fibrillation, and vice versa. Patients' outcomes also tend to be worse when they have both conditions.
New research was guided by a past study in which scientists created a mouse model by "turning up" a gene linked to human heart failure in the mouse heart. "We expected to get a heart failure mouse model, but instead we got an atrial fibrillation model. That observation put us on the right path." This focused attention on a gene called TBX5. TBX5 is a transcriptional regulator - a protein in the cell nucleus that controls which genes are turned on or off at a given time. When TBX5 levels are decreased in the atrium, it disrupts the normal gene expression needed to maintain a stable heart rhythm.
Zeroing in on transcriptional responses, the researchers compared different mouse models of heart failure and atrial fibrillation, finding that an atrial fibrillation model created by removing TBX5 from the atria actually creates gene expression changes almost identical to those seen in heart failure. "That made us think that diminished TBX5 may be important in heart failure. So, we looked at human gene expression data, and lo and behold, TBX5 was very downregulated in the atria of patients with heart failure, but not the ventricles."
Further analysis revealed that over 100 other transcription factors - proteins that regulate gene expression - were altered in both the heart failure and TBX5-deficient atrial fibrillation models. Almost all the key transcription factors changed in the same direction in both conditions. Researchers argue that the results should prompt a fundamental shift in how atrial fibrillation is understood. The rhythm disorder seen in atrial fibrillation may be a symptom of underlying atrial muscle dysfunction similar to the ventricular dysfunction in heart failure.
View the full article at FightAging
