Scientists uncover how support cells, once thought harmless, send damaging signals that weaken the heart

Heart failure (HF) is one of the leading causes of death and disability worldwide, affecting millions of people and placing an enormous burden on health care systems. The disease occurs when the heart can no longer pump blood efficiently, leaving patients short of breath, fatigued, and at risk of life-threatening complications.

For decades, scientists have focused on studying cardiomyocytes—the heart’s muscle cells responsible for pumping blood—believing that these were the key drivers of the disease. But new research challenges this long-standing view by showing that another, often-overlooked group of cells plays a central role in HF progression.

A study published in Nature Cardiovascular Research, reveals how a specialized type of cardiac fibroblast—cells that traditionally provide structural support—can actively worsen HF.

A research team led by Professor Shinsuke Yuasa from the Department of Cardiovascular Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Japan, along with Dr. Jin Komuro from The University of Tokyo, Japan, discovered that these fibroblasts use a signaling pathway known as the MYC–CXCL1–CXCR2 axis to promote harmful changes in the heart.

“We were surprised to discover that fibroblasts, which were thought to be support players in the heart, can actually drive the worsening of HF,” said Prof. Yuasa. “They send out signals that disrupt the normal work of muscle cells, ultimately reducing the heart’s ability to pump effectively.”

To uncover this mechanism, the team studied both patient samples and experimental models of HF.

By examining cardiac fibroblasts at a molecular level, researchers identified a fibroblast population unique to “failing hearts” in mice models that expresses the gene Myc. These fibroblasts release a chemokine (signaling molecule), CXCL1, which destroys cardiomyocyte function through its complementary receptor CXCR2, expressed on cardiomyocytes.

In simpler terms, fibroblasts communicate with other cells using chemical signals, but in HF, this communication becomes harmful. The signaling pathway and consequent chemical signals weaken heart muscle cells, leading to disease progression.

Researchers found that blocking this pathway in mice models improved heart function, suggesting that fibroblasts could be a potential target for new therapeutic strategies.

The researchers further examined if these findings were applicable to human HF. They used cardiac biopsy samples from patients with HF and from healthy patients who served as controls. They found that MYC and CXCL1 were expressed in elevated amounts in the cardiac fibroblasts of patients with HF, suggesting that the MYC–CXCL1–CXCR2 axis is responsible for cardiac dysfunction in human hearts.

“This discovery opens new possibilities for treatment,” said Prof. Yuasa. “Severe HF often leaves transplantation as the only option. By targeting fibroblasts and their signaling pathways, we may be able to develop therapies that slow disease progression and give patients more choices,” he explains.

The findings are important as they challenge the belief that HF research should focus mainly on cardiomyocytes. By showing that fibroblasts also contribute to cardiac dysfunction, the study expands opportunities for drug discovery.

“This research is an extension of our long-standing studies on HF,” emphasized Prof. Yuasa. “We hope our research inspires a more multifaceted approach, where therapies address not just the muscle cells but also the support cells that shape the disease.”

This new perspective is especially valuable given the limited options currently available to patients with severe HF. Medications can help manage symptoms, but for many, a transplant remains the only hope.

By identifying fibroblasts as a key causal factor, scientists may be able to develop drugs that target the signaling pathway used to damage the heart—offering a more direct approach to stop disease progression.

The researchers stress that while the findings are promising, more work is needed to translate them into clinical treatments. Future studies will focus on developing safe therapeutics that can block fibroblast signaling in humans and exploring whether these therapies can improve outcomes in patients with the less advanced form of the disease.

Overall, by uncovering the unexplored influence of fibroblasts, this study reshapes our understanding of HF and highlights a promising new avenue for the management of cardiac diseases.

Heart failure (HF) is one of the leading causes of death and disability worldwide, affecting millions of people and placing an enormous burden on health care systems. The disease occurs when the heart can no longer pump blood efficiently, leaving patients short of breath, fatigued, and at risk of life-threatening complications.

For decades, scientists have focused on studying cardiomyocytes—the heart’s muscle cells responsible for pumping blood—believing that these were the key drivers of the disease. But new research challenges this long-standing view by showing that another, often-overlooked group of cells plays a central role in HF progression.

A study published in Nature Cardiovascular Research, reveals how a specialized type of cardiac fibroblast—cells that traditionally provide structural support—can actively worsen HF.

A research team led by Professor Shinsuke Yuasa from the Department of Cardiovascular Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Japan, along with Dr. Jin Komuro from The University of Tokyo, Japan, discovered that these fibroblasts use a signaling pathway known as the MYC–CXCL1–CXCR2 axis to promote harmful changes in the heart.

“We were surprised to discover that fibroblasts, which were thought to be support players in the heart, can actually drive the worsening of HF,” said Prof. Yuasa. “They send out signals that disrupt the normal work of muscle cells, ultimately reducing the heart’s ability to pump effectively.”

To uncover this mechanism, the team studied both patient samples and experimental models of HF.

By examining cardiac fibroblasts at a molecular level, researchers identified a fibroblast population unique to “failing hearts” in mice models that expresses the gene Myc. These fibroblasts release a chemokine (signaling molecule), CXCL1, which destroys cardiomyocyte function through its complementary receptor CXCR2, expressed on cardiomyocytes.

In simpler terms, fibroblasts communicate with other cells using chemical signals, but in HF, this communication becomes harmful. The signaling pathway and consequent chemical signals weaken heart muscle cells, leading to disease progression.

Researchers found that blocking this pathway in mice models improved heart function, suggesting that fibroblasts could be a potential target for new therapeutic strategies.

The researchers further examined if these findings were applicable to human HF. They used cardiac biopsy samples from patients with HF and from healthy patients who served as controls. They found that MYC and CXCL1 were expressed in elevated amounts in the cardiac fibroblasts of patients with HF, suggesting that the MYC–CXCL1–CXCR2 axis is responsible for cardiac dysfunction in human hearts.

“This discovery opens new possibilities for treatment,” said Prof. Yuasa. “Severe HF often leaves transplantation as the only option. By targeting fibroblasts and their signaling pathways, we may be able to develop therapies that slow disease progression and give patients more choices,” he explains.

The findings are important as they challenge the belief that HF research should focus mainly on cardiomyocytes. By showing that fibroblasts also contribute to cardiac dysfunction, the study expands opportunities for drug discovery.

“This research is an extension of our long-standing studies on HF,” emphasized Prof. Yuasa. “We hope our research inspires a more multifaceted approach, where therapies address not just the muscle cells but also the support cells that shape the disease.”

This new perspective is especially valuable given the limited options currently available to patients with severe HF. Medications can help manage symptoms, but for many, a transplant remains the only hope.

By identifying fibroblasts as a key causal factor, scientists may be able to develop drugs that target the signaling pathway used to damage the heart—offering a more direct approach to stop disease progression.

The researchers stress that while the findings are promising, more work is needed to translate them into clinical treatments. Future studies will focus on developing safe therapeutics that can block fibroblast signaling in humans and exploring whether these therapies can improve outcomes in patients with the less advanced form of the disease.

Overall, by uncovering the unexplored influence of fibroblasts, this study reshapes our understanding of HF and highlights a promising new avenue for the management of cardiac diseases.