Understanding 'heartbreak' - Study finds link between stress and heart failure

Research shows that the stress caused by heart failure is remembered by the body and can lead to relapse of the disease and other related health problems. Scientists have discovered that heart failure leaves a "stress memory" in the form of changes in the DNA of hematopoietic stem cells, which are involved in the production of blood and immune cells called macrophages.

These immune cells play an important role in protecting heart health. However, an important signaling pathway (a chain of molecules that transmit signals within a cell) called transforming growth factor beta (TGF-β) in hematopoietic stem cells was suppressed during heart failure, negatively affecting macrophage production.

Improving TGF-β levels may provide a new treatment for recurrent heart failure, and detecting stress memory accumulation may serve as an early warning before it occurs.

Healthy lifestyles and improved well-being are part of the global UN Sustainable Development Goals. On a positive note, recent research shows that life expectancy worldwide will increase by about 4.5 years by 2050. This is largely due to public health efforts to prevent disease and improve survival from diseases such as cardiovascular disease. However, heart disease is still the leading cause of death in the world, and an estimated 26 million people suffer from heart failure.

Once heart failure occurs, it tends to recur, accompanied by other health problems such as kidney and muscle disease. Researchers in Japan wanted to understand what causes these relapses and deterioration of other organs, and whether it can be prevented.

The study was published in the journal Science Immunology.

"Based on our previous studies, we hypothesized that relapses may be caused by the stress experienced during heart failure, which accumulates in the body, especially in hematopoietic stem cells," explained project professor Katsuito Fuju from the University of Tokyo Graduate School of Medicine. Hematopoietic stem cells are found in the bone marrow and are the source of blood cells and immune cells called macrophages, which help protect heart health.

This illustration shows that during heart failure, stress signals are transmitted to the brain, which then transmits them through nerves to hematopoietic stem cells in the bone marrow, storing them as stress memory. These stress-accumulated stem cells produce immune cells with reduced protective capabilities for organs such as the heart, kidneys and muscles. Source: Science Immunology (2024). DOI: 10.1126/sciimmunol.ade3814

By studying mice with heart failure, the researchers found evidence of stress imprinting on the epigenome, meaning chemical changes had occurred in the DNA of the mice. An important signaling pathway called transforming growth factor beta, which is involved in the regulation of many cellular processes, was suppressed in hematopoietic stem cells of mice with heart failure, resulting in the production of dysfunctional immune cells.

These changes persisted over time, so when the team transplanted bone marrow from mice with heart failure into healthy mice, they found that the stem cells continued to produce dysfunctional immune cells. These mice subsequently developed heart failure and became susceptible to organ damage.

"We called this phenomenon stress memory because the stress of heart failure is remembered for a long period and continues to affect the entire body. Although various other types of stress can also leave this stress memory, we believe that stress caused by heart failure particularly significant," Fuju said.

The good news is that by identifying and understanding these changes in the TGF-β signaling pathway, new opportunities for potential future treatments open up.

"Completely new therapies may be considered to prevent the accumulation of these stress memories during hospitalization for heart failure," Fuju said. "In animals with heart failure, the addition of additional active TGF-β has shown potential as a treatment modality. Correction of the epigenome of hematopoietic stem cells may also be a way to eliminate stress memory."

Now that this has been identified, the team hopes to develop a system that can detect and prevent stress memory accumulation in people, with the long-term goal of not only preventing relapses of heart failure, but also detecting the condition before it fully develops.