Phd Defense: Decoding Heavy Hearts Molecular Insights into Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a prevalent heart disease often caused by a mutation and is characterized by thickening of the heart muscle . This remodeling nearly always takes place in the myocardial wall. While many mutation carriers remain asymptomatic, others suffer severe symptoms, potentially requiring myectomy or heart transplant.  Despite its prevalence, there is no clear understanding of what triggers the remodeling and how to detect this.
In this research, it was attempted to better understand the genes that might regulate this pathology. This was done by dispersing mycectomy tissue from patients into single cells. Subsequentially cardiomyocytes were selected  for single cell sequencing to distinguish between healthy and diseased cells. It was discovered that MYL2 is a marker for more hypertrophic cells and this allowed to make predictions about the genes which may orchestrate the genetic pathways activated in these cells. Afterwards it was studied why the septum is more prone to thickening. With Tomo-sequencing, gene expression patterns in septum and free wall were studied, pinpointing NR2F2 as a potential regulator of remodeling in the septum. Lastly, mouse models carrying two of the most prevalent HCM-causing mutations in the Netherlands were generated. The homozygous mice in this model developed clear cardiac dysfunction and hypertrophic remodeling, while heterozygous mice failed to do so, indicating an extra trigger is required in this model. 

Ultimately, we were able to distinguish between more stressed cardiomyocytes and myocardial areas and make prediction on which genes could be driving this pathological state. We generated a model to study the onset and the progression of HCM. Together, these models can help us to get more insight on the molecular mechanisms of this complex disease.