A healthier lifestyle is one of the United Nations’ global sustainable development goals. On a positive note, a recent study shows that global life expectancy is expected to increase by about 4.5 years by 2050. This is largely due to public health efforts to prevent and treat chronic diseases , including cardiovascular disorders. However, heart disease remains the leading cause of death worldwide, with 26 million people affected by heart failure.
Once heart failure occurs, it tends to recur simultaneously with other health problems, such as kidney and muscle disorders. The Japanese team therefore sought to understand the causes of these recurrences and damage to other organs, and to see if it was possible to avoid them.
Lead author Dr. Katsuhito Fujiu, a researcher at the University of Tokyo, recalls his team’s previous research, which suggested “the hypothesis that recurrence could be caused by stress experienced during heart failure, a stress that could affect hematopoietic stem cells”.
Hematopoietic stem cells are found in bone marrow and are the Source of blood cells and a type of immune cell called macrophages, which help protect heart health. The researchers here document this “stress memory” materialized in the form of modifications of the DNA of hematopoietic stem cells. Macrophage immune cells play an important role in protecting heart health. However, a key signaling pathway called transforming growth factor beta (TGF-β), in hematopoietic stem cells, is suppressed during heart failure, negatively affecting macrophage production.
The study consisted of transplanting bone marrow from mice suffering from heart failure into healthy mice. Experience reveals, by echocardiogram, that:
- this transplantation leads to cardiac dysfunction characteristic of heart failure, with therefore a disruption of movements and an increased size of the heart;
- scientists observe in mouse models of heart failure, evidence of an imprint of stress on the epigenome, that is to say that chemical modifications have occurred in the DNA of these mice;
- this important signaling pathway, TGF-β, involved in the regulation of many cellular processes, is suppressed in the hematopoietic stem cells of these mice suffering from heart failure, which leads to the production of dysfunctional immune cells;
- this change lasts for a prolonged period: once heart failure sets in, stem cells continue to produce dysfunctional immune cells. These mice suffer from organic damage.
“We called this phenomenon ‘stress memory’ because the stress caused by heart failure is remembered for an extended period of time and continues to affect the entire body. Although various other types of stress can also imprint this stress memory, we believe that heart failure-induced stress is particularly powerful.”
What implications? Taken together, these observations suggest that improving TGF-β levels may provide a new treatment option for recurrent heart failure. Detecting “stress memory” could constitute an early warning system for the risk of cardiac events. The researchers provide here a first proof of concept: “in animals suffering from heart failure, it has been demonstrated that supplementation with additional active TGF-β constitutes a promising treatment, which corrects the epigenome of hematopoietic stem cells and could exhaust this stress memory.”
The team is now working to develop a system capable of detecting and preventing the accumulation of stress memories in humans, with the long-term goal of not only being able to prevent recurrence of heart failure, but also detect the condition as soon as it appears.
