In Germany, about four million people suffer from heart failure. Those affected also have an increased risk of developing dementia. Cognitive impairment is a major burden for patients with heart disease and is poorly understood. Therapies are not available. Therefore, international organisations such as the European Society of Cardiology (ESC) have recommended that cardiology and dementia research experts join forces to develop therapeutic intervention options. A prerequisite for this is an understanding of the underlying molecular mechanisms.
A team led by Professors Karl Toischer and Andre Fischer from the DZHK, DZNE and the University Medical Center Göttingen was able to show in two different mouse models of heart failure that these animals develop massive memory problems. The researchers also found that the learning impairment is causally mediated by a de-regulation of epigenetic gene expression in neurons. In genome-wide analyses, it was observed that specifically, the methylation of histone 3 was disturbed. It was triggered by the pathological activation of signalling pathways leading to cellular stress.
Vorinostat is an epigenetic drug that inhibits the activity of histone deacetylases. Orally administered, it partially restored gene expression in neurons and significantly improved the animals' learning ability. It also induced a compensatory response of the microRNAome. Vorinostat is an approved drug for other indications, and its therapeutic benefit is currently being tested in patients with early Alzheimer's disease.
In summary, this work shows new possibilities for the targeted treatment of cognitive impairment in patients with heart failure.
April 2021