Research reveals that failing hearts have minimal capacity for self-repair, but mechanical support can trigger remarkable regeneration of heart muscle cells, opening new therapeutic possibilities.
Scientists have discovered that whilst the human heart’s ability to repair itself is severely diminished during heart failure, supporting the heart with a mechanical pump can stimulate regeneration of heart muscle cells at rates significantly higher than in healthy hearts. This groundbreaking finding, published recently in the journal Circulation [1], suggests there may be untapped regenerative potential in diseased hearts that could be therapeutically
exploited.
Understanding heart repair
The research team, led by scientists at Karolinska Institutet in Sweden, investigated the heart’s capacity to generate new cardiac muscle cells (cardiomyocytes) under different conditions. They studied tissue samples from 52 patients with advanced heart failure, including 28 who received support from a left ventricular assist device (LVAD) – a surgically implanted pump that helps propel blood.
Using an innovative method to determine cell age based on radioactive carbon dating, the researchers found that heart failure patients without mechanical support showed extremely low rates of cardiomyocyte renewal – 18 to 50 times lower compared to healthy hearts.
Mechanical support triggers regeneration
However, the results were strikingly different in patients receiving LVAD support whose hearts showed significant improvement. These “responder” patients demonstrated cardiomyocyte renewal rates more than six times higher than those seen in healthy hearts.
“The results suggest that there might be a hidden key to kick-start the heart’s own repair mechanism”, says Olaf Bergmann, senior researcher at the Department of Cell and Molecular Biology at Karolinska Institutet and one of the authors of the paper.
Complex cellular changes
The study revealed complex cellular changes in failing hearts. The researchers found that heart failure patients showed increased DNA synthesis in cardiac cells, but this was primarily related to cells becoming larger (polyploidization) and developing multiple nuclei (multinucleation) rather than generating new cells.
In non-LVAD patients and those who didn’t respond to LVAD therapy, less than 0.3% of DNA synthesis was attributed to actual cell renewal. However, in LVAD responders, nearly 30% of DNA synthesis was linked to the generation of new cardiomyocytes.
Implications for future treatments
These findings have significant implications for developing new heart failure therapies. The research demonstrates that the adult human heart possesses greater regenerative potential than previously thought, but this capacity appears to be suppressed during heart failure.
The authors note in their paper: “Our data demonstrate that cardiomyocyte renewal is minimal in failing hearts but can elevate well beyond the levels observed in healthy hearts through LVAD-mediated functional cardiac improvement.”
Regenerative mechanism remains unclear
While the discovery is promising, the mechanism behind this regenerative effect remains unknown. As Bergmann notes: “It is difficult to say. In the existing data we cannot find an explanation for the effect, but we will now continue to study this process at a cellular and molecular level.”
The research team acknowledges in their paper that the relationship between functional improvement and cell renewal is complex: “Because of the nature of our study, it is difficult to understand the exact causal relationship between reverse remodelling, functional improvement and cardiomyocyte renewal in the patients studied. However, our results demonstrate that reverse remodelling likely plays an important role in the observed phenotype.”
They also note that most DNA synthesis in failing hearts appears ineffective at generating new cells: “The fact that cardiomyocyte renewal is greatly reduced in heart failure suggests that the increased cardiomyocyte DNA synthesis, as determined by changes in genomic 14C levels in failing hearts, is almost exclusively related to polyploidization and multinucleation.”
The results suggest that there might be a hidden key to kick-start the heart’s own repair mechanism.
Future therapeutic possibilities
The findings point toward potential new treatment approaches. As the authors explain in their discussion: “The discovery of a latent cardiomyocyte regenerative potential in the adult human heart identifies an attractive target for new therapies. This motivates studies to unveil the molecular regulation of this process, which would facilitate the development of pharmaceutical therapies for heart regeneration.”
The research team suggests that mechanical unloading might work through multiple mechanisms: “For instance, mechanical unloading might reverse metabolic cascades that increase reactive oxygen species production. This, in turn, can reduce oxidative DNA damage and activation of the DNA damage response pathway that causes cell cycle arrest in cardiomyocytes.”
This research opens new avenues for developing treatments that could stimulate the heart’s natural repair mechanisms. Such approaches could potentially reduce reliance on heart transplants or long-term mechanical support devices.
The study suggests that understanding how mechanical unloading triggers cardiac regeneration could lead to new therapeutic strategies. These might focus on creating conditions that promote actual cell renewal rather than just cellular enlargement, potentially offering new hope for heart failure patients.
Reference:
- Derks, W., Rode, J., Collin, S., et. al. (2024). A latent cardiomyocyte regeneration potential in human heart disease. Circulation.
doi: https://doi.org/10.1161/CIRCULATIONAHA.123.067156
