• Remarkably, adult zebra fish can regenerate their hearts after sustaining injury.
• Scientists recently discovered a critical gene in zebra fish that regulates the regeneration and healing of damaged heart tissue.
• The Krüppel-like factor 1 (KLF1) gene works by reprogramming genetic pathways in uninjured heart muscle cells in zebra fish upon injury.
• Understanding how this gene works may lead to innovative treatments in humans that could reduce or reverse damage from a heart attack.

The heart is a muscle responsible for pumping blood throughout the circulatory system. To function, it needs enough oxygen and nutrients, which the coronary arteries supply.

If these arteries are blocked for a prolonged period, heart tissue can die — resulting in a heart attack, or myocardial infarction.

Heart disease causes about 25% of deaths in the United States. And despite advances in treatments, death rates among people aged 65 or older who survive a heart attack remain remarkably high, at:

• 24% after 1 year
• 51% after 5 years
• 65% after 8 years

A heart attack causes the death of heart muscle cells called cardiomyocytes in the left ventricle. Fibrotic scar tissue, which cannot contract, replaces injured cardiomyocytes. This reduces the heart’s ability to pump, potentially leading to congestive heart failure.

Heart failure can significantly reduce the quality of life. A heart transplant is the only cure, but the limited availability of donor organs makes this unfeasible for most people.

After a heart attack, the adult human heart has a low regenerative capacity. The body replaces cardiomyocytes at a rate of 1% per year at age 25 and 0.45% per year at age 75.

Regenerative capabilities

Unlike humans, adult zebra fish regenerate their hearts and other organs after injury. Yet zebra fish share more than 70% of their genes with humans. This and other qualities make these fish an ideal model for the study of organ regeneration with an eye toward treating human diseases.

But until recently, the exact way that zebra fish repair injured heart muscle was a mystery.

Now, researchers at the Victor Chang Cardiac Research Institute, in Darlinghurst, Australia, and other institutions have found that a protein called KLF1 plays a central role in this process. Their findings appear in the journal Science.

Scientists already knew that KLF1 was essential in red blood cell production. The new research found that KLF1 also plays a critical role in the regeneration and healing of damaged heart muscle in zebra fish.

When the researchers inhibited the gene for KLF1, it severely diminished zebra fish’s ability to regenerate heart tissue but did not alter their heart development.

Activation of KLF1 in uninjured zebra fish hearts caused a significant increase in the replication of cardiomyocytes. Researchers discovered that upon injury of the cardiomyocytes, KLF1 rewires mitochondrial metabolic pathways.

These metabolic changes are associated with redirection of the remaining uninjured heart muscle cells, causing them to revert to a more immature state. This allows them to multiply and repair the damage, a process known as myocardial plasticity.

Game-changing revelation

Dr. Kazu Kikuchi, the senior researcher, comments on the findings: “Our research has identified a secret switch that allows heart muscle cells to divide and multiply after the heart is injured. It kicks in when needed and turns off when the heart is fully healed.”

“In humans, where damaged and scarred heart muscle cannot replace itself, this could be a game-changer. With these tiny little fish sharing over 70% of human genes, this really has the potential to save many, many lives and lead to new drug developments.”

– Dr. Kazu Kikuchi

However, clarifying the role of KLF1 in human hearts will require further research.

Prof. Robert Graham, head of the Cardiac Receptor Biology Laboratory, at the Victor Chang Cardiac Research Institute, comments on the implications of the research, in which he was not involved:

“The gene may also act as a switch in human hearts. We are now hoping further research into its function may provide us with a clue to turn on regeneration in human hearts [in order] to improve their ability to pump blood around the body.”

If future studies show how myocardial plasticity is blocked and reactivated in humans, this may lead to innovative treatments that could potentially reduce or reverse damage due to a heart attack. This discovery has the potential to revolutionize the treatment of heart disease.

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