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Adjudication committee
- First opponent: Professor Martina Krüger, Heinrich-Heine Universität, Düsseldorf, Germany
- Second opponent: Associate Professor Helge Skulstad, Institute of Clinical Medicine, University of Oslo
- Third member and chair of the evaluation committee: Associate Professor Tor Erik Rusten, Institute of Clinical Medicine, University of Oslo
Chair of defence
Associate Professor Maja Elstad, Institute of Basic Medical Sciences, University of Oslo
Principal Supervisor
Professor II William Edward Louch, Institute of Clinical Medicine, University of Oslo
Summary
Heart failure is heterogeneous clinical syndrome, resulting from reduced cardiac pump function. Pumping function depends on ventricular contraction (systolic function), and filling in between each contraction (diastolic function). Traditionally, heart failure has been considered a consequence of systolic dysfunction, but impaired filling (diastolic dysfunction) is increasingly recognised as another key mechanism. Diastolic dysfunction may result from impaired active relaxation, or elevated passive stiffness of the ventricle. The underlying mechanisms remain however incompletely mapped, and it is unclear whether mechanisms differ between different types of heart failure. The aims of the thesis were therefore to examine active and passive mechanisms of diastolic dysfunction at the molecular, cellular, tissue, and in vivo level, in human and animal models of heart failure. We show that mechanisms of diastolic dysfunction are complex, and active and passive properties influence all phases of diastolic filling. In heart failure with reduced ejection fraction, impairments in cardiomyocyte Ca2+ homeostasis, leading to slowed relaxation, are an important mechanism of diastolic dysfunction. In contrast, elevated passive stiffness resulting from extracellular fibrosis and cardiomyocyte stiffening, critically impairs filling in concentric hypertrophy and heart failure with preserved ejection fraction. Here, we found Ca2+ homeostasis to be compensated. The thesis identified differences in wall stress as one potential cause of divergent remodelling between heart failure with reduced and preserved ejection fraction. Together, these findings highlight heart failure as a pathophysiologically heterogeneous syndrome, and suggest a need for more targeted treatments.
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