A possible treatment for arrhythmogenic cardiomyopathy type 5, a rare disease affecting between 0.02 and 0.1% of the general population, for which unfortunately there is no cure, was described by experts from the Spanish National Center for Cardiovascular Research (CNIC) and the Puerta de Hierro Hospital. Scientists have used a mouse model to evaluate the efficacy of medications used in humans with heart failure.
The team of researchers, whose work is published in Circulation, proved in a mouse model that inhibiting a protein, GSK3b kinase, reduces fibrosis and improves cardiac function.
Arrhythmogenic cardiomyopathy can cause sudden death, especially in young men. But it can also cause heart failure over time, explain the study coordinators, Enrique Lara Pezzi, of the CNIC, and Pablo García-Pavia, of the Puerta de Hierro Majadahonda University Hospital. The most aggressive subtype of this disease is called arrhythmogenic cardiomyopathy type 5 and is due to a genetic alteration in the TMEM43 gene.
Although the first patients with type 5 arrhythmogenic cardiomyopathy were identified on the island of Newfoundland (Canada), it has also been detected in other areas of the world, including Spain.
During the initial stages, the hidden phase, patients do not usually have symptoms, although they already have a risk of arrhythmias and sudden death. The right ventricle is the most affected in early stages. As the fibrosis expands, the left ventricle can also be compromised and heart failure symptoms appear, that make patients require a heart transplant.
“However, the mechanisms by which this disease occurs are not known and, as of today, there is no cure,” says Lara Pezzi. This makes the treatment fundamentally palliative and based on the prevention of sudden death.
Therapy in mice
The groups of Lara Pezzi and García-Pavia studied this disease in order to find new treatments that could be applied to patients diagnosed for the first time in Spain. “We found a disease that was very little known and in which multiple people of the same family died very young,” says Garcia-Pavia.
The researchers developed a transgenic mouse model that expressed the human protein TMEM43 so that they had the human disease.
Thus they found that the mutant version of TMEM43 causes the activation of a protein, the GSK3b kinase that causes the progressive death of cardiac cells, which are gradually replaced by fibrosis, one of the most characteristic features of this disease.
“After a few months, the heart does not have enough cells that function properly and pump blood effectively, so the animal dies from heart failure,” explains Laura Padrón-Barthe, first author of the article.
In the search for a therapy, the researchers inhibited GSK3b kinase by two different strategies (a pharmacological inhibitor or the overexpression of a subunit of the calcineurin CnAβ1). “Both approaches reduced cardiac cell death, improved contraction of the heart and prolonged the survival of mice,” says Lara Pezzi.
The research continues
Scientists warn that, although this transgenic mouse model is the only one that reproduces human ARVC5, it does not have certain characteristics of human pathology. For example, no significant differences were found between males and females, in contrast to human patients, in whom the disease is much more aggressive among males.
Once a possible effective way to treat the disease in mice is known, the researchers are working to transfer their findings to patients.
They are using this mouse model to evaluate the efficacy of medications used in humans suffering from heart failure, in order to find out if they would be useful for treating arrhythmogenic cardiomyopathy type 5. In addition, they are analyzing gene therapy strategies that can improve cardiac function and even cure the disease.