New research published in Nature Cardiovascular Research reveals that heart failure and atrial fibrillation share underlying genetic and molecular mechanisms, suggesting that the two cardiovascular conditions may be less distinct than previously thought.
Two serious heart conditions that often coexist
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.
"This intersection between two very common, very important diseases — both of which cause a lot of morbidity and mortality and billions of dollars in annual healthcare costs — has been called an 'epidemic in cardiology,' yet our understanding has remained very limited," said senior author Ivan Moskowitz, MD, PhD , a pediatric cardiologist and pathologist at the University of Chicago Medicine.
Uncovering TBX5 as a key genetic regulator
This new study was guided by previous research Moskowitz and his collaborators published in 2024, which kick-started when a former lab member 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," Moskowitz said. "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," Moskowitz said. "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."
This finding suggested a mechanistic link: reduced TBX5 in the atrium may contribute to the development of atrial fibrillation in the context of heart failure.
Coordinated genetic response across cell types
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.
"Seeing these correlations emerge effectively indicates that from the atrium's perspective, what's happening in the two conditions is the same," Moskowitz said.
Using single-cell analysis, the team identified which human cell types in the atrium were involved in the disease mechanism. Cardiomyocytes (heart muscle cells) and fibroblasts (cells that form connective tissue) both showed disease-related gene changes, suggesting that the pathological response involves multiple cell types communicating with one another.
Rethinking atrial fibrillation as atrial heart failure
Strikingly, the authors 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.
"The coordinated change in transcription factors lead us to conclude that atrial fibrillation is not really a different disease than heart failure; it is just what we might call 'atrial heart failure,' a manifestation of which is atrial fibrillation," Moskowitz said. "Instead of a rhythm disorder in the atria, we can understand it more like an atrial myopathy that is mimicking what's happening in ventricle cells in heart failure."
Unlocking future treatment avenues
This new perspective could have important implications for cardiovascular disease treatment. Currently, therapies for atrial fibrillation focus on controlling the heart's electrical rhythm, often by targeting ion channels that regulate electrical signals. Moskowitz suggests a broader approach: "We may be able to go higher upstream. Rather than trying to drug the channels directly, we could think more about the response of the atrium to pressure, much like we do the ventricles in heart failure. Approaching atrial fibrillation like heart failure may be a different avenue."
In ongoing work, the UChicago Medicine researchers are continuing to analyze these genetic and molecular pathways. They've already identified multiple signaling genes expressed in cardiomyocytes that are disrupted when TBX5 is "turned down," and are working to investigate whether replenishing those signals can prevent atrial fibrillation from occurring. This combination of insight and fundamental biology is the driving force behind translational advancement.
"This intersection is a fertile ground for insight into atrial fibrillation and how it may be treated," Moskowitz said. "We're excited because this study provides many candidates for future investigation. We hope our work can be applied to new thinking and interventions toward a cure."
" A reduced TBX5-dependent gene regulatory network links atrial fibrillation and heart failure " was published in Nature Cardiovascular Research in February 2026. Co-authors are Sonja Lazarevic, Carlos Perez-Cerventes, Zhezhen Wang, Kaitlyn M. Shen, Margaret Gadek, Junhua Xiao, Naoko Yamaguchi, Johnathon M. Hall, Yildiz Koca, Douglas J. Chapski, Manuel Rosa-Garrido, Marcello Rubino, Rangarajan D. Nadadur, Timothy A. McKinsey, Thomas M. Vondriska, Alexander J. Ruthenburg, Sebastian Pott, David S. Park and Ivan P. Moskowitz.
