Nice scientists make a discovery that could revolutionize post-heart attack treatments

It was long thought that after a heart attack, all that was needed was to restore blood circulation for the heart to regain its full capacity. A stent was inserted, the artery unblocked... and the matter seemed settled.

In reality, the process is much more complex: the heart must form new blood vessels, repair damaged heart cells (cardiomyocytes), manage the inflammation caused by the heart attack, and prevent a rigid scar (fibrosis) from taking up too much space.

But how does this repair work? And who ensures it runs smoothly? Remember this acronym: WT1. This is the answer provided by two Nice scientists, Kay-Dietrich Wagner and Nicole Wagner (1).

A major discovery

Researchers at the Valrose Institute of Biology (IBV), these two doctors by training (one a cardiologist, the other a pediatrician) were among the first in the world to discover the decisive role, in oncology, of this factor coding for a tumor suppressor. How did they manage to demonstrate its involvement in another major process?

"The gene for this protein, which is naturally present in our bodies, is altered in certain individuals, particularly those with Wilms syndrome (embryonal kidney cancer); however, these same patients present with early cardiac abnormalities," they report.

Another intriguing observation: "Zebrafish, which have two copies of the WT1 gene, are able to regenerate their hearts within a week after a heart attack. Conversely, mammals (such as mice or humans), with only one copy, have a very low capacity for spontaneous regeneration."

Based on these findings, the Nice researchers hypothesized that WT1 likely played a key role in heart repair. And they were able to prove it after years of research and highly complex experiments.

"We used a coronary ligation model in mice, reproducing a massive infarction. Two groups of animals (one expressing WT1, the other not) were followed: at 48 hours, then at 3 weeks post-infarction. Thanks to high-level medical imaging techniques, histology and cellular analysis (echocardiography, flow cytometry, immunofluorescence), we were able to measure the functionality of the heart, vascular density, the rate of fibrosis (scar tissue), apoptosis (cell death) and cardiomyocyte proliferation and the local immune response."

The results are then unequivocal: "In the absence of WT1 (in genetically modified mouse models), we observe: massive fibrosis of the heart after infarction, an increase in apoptosis of cardiac cells, excessive infiltration of lymphocytes and less vascular regeneration. To summarize: without WT1, the heart does not recover; it is at the very heart of the process of cellular and vascular regeneration."

A promising therapeutic target

While medical treatments for heart attacks have barely evolved in 40 years, this discovery opens up fascinating perspectives. "Molecules capable of stimulating WT1 expression already exist and are approved by the FDA (Food and Drug Administration) for other indications, particularly in oncology. In the near future, we could imagine administering these molecules immediately after a heart attack to boost regeneration and reduce inflammatory damage."

The researchers even anticipate potential adverse effects: "The treatment would only be given during a short post-infarction window (approximately 2 weeks), thus limiting the risks associated with prolonged activation of WT1, which could be carcinogenic in the long term."

"Age, the state of the vascular network, and repair capacities differ among patients. We can therefore imagine, in the long term, evaluating the WT1 production capacity in each patient to predict recovery and adapt treatment."

1- Their work was published last June in the journal Thranostics.