BIG DATA to understand BIG HEARTS: Unravelling the molecular mechanisms in hypertrophic cardiomyopathy

HCM is the most common genetic heart disease, affecting between 1:500 to 1:200 people worldwide. HCM is considered a sarcomeropathy, since mutations primarily affect proteins located at the cardiac sarcomeres. Furthermore, HCM is a highly heterogeneous disease, where phenotype can vary from asymptomatic to asymmetric hypertrophy of the left ventricle (LV) and intraventricular septum (IVS), diastolic dysfunction and arrhythmias that can inevitably lead to sudden cardiac death. Disease penetrance does not only show high inter- and intrafamilial variability, but also shows variability between men and women. This can even be observed within an HCM heart, where heterogeneity in hypertrophied cardiomyocytes can be observed throughout the tissue. Strikingly, and yet to be explained, the IVS is involved in the majority of HCM cases, regardless of the genetic background.

At present, no cure is available for HCM largely due to the lack of knowledge of the molecular mechanisms behind its onset and progression. For this reason, in-depth understanding of the pathological mechanism is required to improve diagnostics, prevention, treatment and, most importantly, potentially cure.

In this thesis we aimed to extend our knowledge on gene regulation in HCM. For this, we used human myectomy tissue and explanted HCM hearts with which we were able to further understand transcriptional heterogeneity in HCM. Also, we generated two mouse models harboring human pathogenic HCM mutations to identify the molecular mechanisms underlying HCM.