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Breakthrough in fundamental heart failure research

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An international team of scientists, among them scientists of the DZHK, discovered an important fundamental process in hearts from patients with advanced heart failure, allowing a better understanding of the origin of this disease. Previously, it was already noted that sporadically genes were activated in the failing heart that used to play a role in the developing embryonic heart. Prof. Dr. Leon de Windt and Dr. Paula da Costa Martins from Maastricht University led an international team of researchers that demonstrated which protein (transcription factor) is responsible for this undesirable process. The finding is published in the leading scientific journal Nature Cell Biology.

Heart failure is a condition characterized by reduced pump function of the heart. This can occur as a result of high blood pressure, a heart attack, or other symptoms. The treatment has not significantly changed or improved in the past decades. "We really understand too little of what exactly goes wrong in a heart in heart failure", says Prof. Leon de Windt, Professor of Molecular Cardiology, who led the research team. "Every year 200,000 new heart failure cases occur in the Netherlands alone, and the only real cure, a heart transplantion procedure, is only reserved for no more than three hundred patients in our country."

The origin
His team therefore set out to examine what exactly goes wrong in the failing heart. The origin of the problem appears to be correlated with the origin of every human life. The heart is the first organ formed in a human embryo. Stem cells receive the instruction of a specific protein, a transcription factor, that they need to differentiate and form a heart. The embryonic heart has barely any pumping power, because the mother's heart supplies the embryonic blood circulation. My theory is that, in fact, heart failure is a disease in which the adult heart more and more resembles its embryonic state. This means obviously that such a heart has a totally inadequate pumping capacity to meet the requirements of an adult body."

The transcription factor responsible for this process is called Hand2. "We observed that Hand2 was reactivated in biopsies we obtained from human hearts, after the owners had undergone a heart transplantation and donated their diseased hearts to science. We could unravel the mechanism how this protein is reactivated in the failing heart. Hand2 in its turn activates some 100 to 200 other genes. "The challenge is now to find out what role each of these genes play in the disease mechanisms of the failing heart. This invention therefore provides a treasure trove of information that scientists could use years ahead."

Patient care
Because this research is fundamental, De Windt currently sees no obvious possibilities to use this discovery for patient care. "But before you can develop new drugs or treatments for heart failure, which is really badly needed, you have to understand the underlying mechanisms that cause the disease. "In mice that were genetically engineered so that the protein Hand2 could be removed at will, we observed that they were resistant to the development of heart failure, proving that Hand2 is at the cause of the disease. "This approach will never be used in humans for the obvious ethical reasons, so we need to continue looking for ways to keep Hand2 from being reactivated. This is difficult, but at least we now understand better what is happening in the diseased heart. For now, that is already a major breakthrough," concludes De Windt.

The full title of the publication in Nature Cell Biology is "NFAT and miR-25 cooperate to reactivate the transcription factor Hand2 in heart failure”. Scientists from the US, UK, Norway, Germany and France participated with the research team from Maastricht University.

Source: Press release Maastricht  Univertity