Key words: heart failure, cardiac hypertrophy, substrate metabolism, protein synthesis, insulin resistance, human stem cells

“Metabolic phenotyping of the pressure-overloaded Heart – Focus on model development”

The general focus of this thesis was to develop experimental models for a type of chronic heart failure in which the left ventricle of the heart must generate higher pressure to pump blood into the aorta (such as aortic valve stenosis and high blood pressure induced heart failure). These established cell and animal models make it possible in the future to (i) further investigate underlying mechanisms that cause the onset of heart failure, and to (ii) test metabolic interventions aimed at the prevention / treatment of structural (heart muscle thickening) and functional changes (contractile force) of the heart. The results imply that changes in fuel consumption precede heart muscle thickening and a decrease in contractile force of the heart muscle. These results confirm the hypothesis that metabolic interventions can be useful in combating and / or treating heart muscle thickening. The first metabolic interventions (aimed at reducing sugar intake) forced heart muscle cells to make more use of fats as fuel, resulting in an improved contractile force. These findings complement the current knowledge regarding the pathophysiology that underlies the onset of heart failure, and can therefore contribute to finding new potential targets.