The public defence will be held as a video conference over Zoom.
The defence will follow regular procedure as far as possible, hence it will be open to the public and the audience can ask ex auditorio questions when invited to do so.
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Digital Trial Lecture - time and place
Adjudication committee
- First opponent: Senior Lecturer Katharine Dibb, The University of Manchester, United Kingdom
- Second opponent: Associate Professor Johanna Lanner, Karolinska Institute, Stockholm, Sweden
- Third member and chair of the evaluation committee: Professor Finn Olav Levy, Institute of Clinical Medicine, University of Oslo
Chair of defence
Associate Professor Kjetil Wessel Andressen, Institute of Clinical Medicine, University of Oslo
Principal Supervisor
Professor William E. Louch, Institute of Clinical Medcine, University of Oslo
Summary
Traditionally, heart failure with reduced ejection fraction (HFrEF) has been thought to be caused by systolic dysfunction, but today diastolic dysfunction is recognized as a contributing factor in these patients. These functional deficits have been linked to impaired contraction and relaxation of cardiomyocytes, resulting from disruption of subcellular structures called t-tubules and accompanying changes in Ca2+ homeostasis. However, the triggers of such remodeling have remained unclear. This thesis explores how mechanical wall stress affects t-tubule structure, Ca2+ handling and heart function. We reveal that regional differences in Ca2+ handling, t-tubule density and stress arise post-infarction in a rat model of HFrEF. By subjecting cardiac muscle tissue to elevated load ex vivo, we found a causal relationship between high mechanical stress and t-tubule disruption. Employing these same models combined with ultrasound recordings from human patients, we found that HFrEF patients experience regional differences in diastolic function too, and that this is a direct result from load-induced downregulation of the Ca2+ handling protein SERCA. Thus, the thesis demonstrates that pathologically elevated mechanical stress drives remodeling that results in impaired systolic and diastolic function in HFrEF. We further investigated whether alterations in mechanical stress can contribute to earlier, compensatory stages of remodeling. Indeed, employing experimental surgery methods, patient biopsies, and ex vivo experiments, we found that moderately elevated stress leads to increased t-tubule density, improved Ca2+ handling, and augmented cardiac function. Future research should therefore focus on unraveling how mechanosignaling leads to both adaptive as well as maladaptive cellular remodeling. Ultimately, future heart failure therapies should be aimed at blocking excessive mechanosignaling, and thereby protecting cardiomyocyte structure/function for the benefit of patients.
Additional information
contact the Research Support staff