Metabolic perturbations as trigger and driver of disease in hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a frequently occurring disease of the heart muscle, characterized by asymmetrical left ventricular hypertrophy and diastolic dysfunction. In approximately half of all patients the disease is caused by mutations in genes encoding sarcomere proteins. These patients are referred to as genotype-positive (G-positive). In the other half of patients the disease is not caused by genetic mutations (genotype-negative patients; G-negative). Despite the fact that mutations in sarcomere proteins cause HCM in G-positive patients there is remarkable variation in the extent to which mutation carriers develop HCM. One mutation carrier may develop severe hypertrophy and heart failure at young age, while another remains asymptomatic until old age. Thus, the presence of a mutation itself is not sufficient to cause disease. Clinical studies suggest that traditional cardiovascular risk factors such as obesity and diabetes mellitus type II may contribute substantially to disease penetrance and severity of HCM. These factors have a considerable negative impact on cardiac metabolism. In part 1 of this thesis we explore how metabolic perturbations at the systemic level are involved in triggering G-positive HCM. Hereto we provide an overview of clinical literature and design a theoretical framework outlining cellular mechanisms via which obesity-associated metabolic perturbations may trigger HCM. Subsequently we tested this framework in mouse models of G-positive HCM. Our studies showed that in certain mouse models it is possible to indeed trigger HCM by feeding an unhealthy diet, which was accompanied by marked metabolic alterations in the diseased heart. In part 2 of this thesis we study how metabolic perturbations are related cardiac remodeling in HCM. To this end we used myectomy tissue samples of patients with HCM. Structural and functional analyses showed that mitochondrial dysfunction was linked to disruption of cardiomyocyte architecture. Additionally, only in G-negative patients there was a link between septal hypertrophy and mitochondrial dysfunction. In line with this observation, multi-omic analyses revealed contrasting patterns of metabolic alterations in relation to cardiac remodeling in G-positive and G-negative patients with HCM. This suggests that divergent disease mechanisms drive disease in these two patient groups. Lastly, in part 3 we discuss several methodological aspects and considerations in the field of (animal-free) basic cardiac science.