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: Professor Christoph Maack, Deutsches Zentrum für Herzinsuffizienz, Universitätsklinikum Würzburg, Germany
- Second opponent: CR1 INSERM Researcher Gregoire Vandecasteele, University Paris-Sud 11, Faculty of Pharmacy, France
- Third member and chair of the evaluation committee: Professor Emeritus Knut Gjesdal, Faculty of Medicine, University of Oslo
Chair of the Defence
Professor II Håvard Attramadal, Faculty of Medicine, University of Oslo
Principal Supervisor
Associate Professor Jan Magnus Aronsen, Faculty of Medicine, University of Oslo
Summary
Ventricular arrhythmias are a major cause of sudden cardiac death among patients with chronic heart disease. Current treatments are ineffective and associated with several side effects, and new treatments targeting the underlying arrhythmias mechanisms are needed.
In the dissertation A search for novel treatments against ventricular arrhythmias, Jonas Skogestad and colleagues aimed to develop novel strategies for preventing ventricular arrhythmias, by identifying and directly target underlying proarrhythmic mechanisms. Their experimental approach encompassed electrophysiological and molecular studies in single cardiac cells and arrhythmia trials in preclinical animal models.
The researchers first identified reduced activity of the Na+/K+-ATPase (NKA), a membrane ion pump, as an upstream mechanism of arrhythmias in hypokalemia and Ankyrin B syndrome, a rare genetic arrhythmia syndrome. Reduced NKA activity shifted the intracellular ion balance towards more Na+ and Ca2+ in strategic intracellular locations, thus promoting Ca2+ overload and cellular arrhythmias. Further studies showed that the changes in intracellular Na+ and Ca2+ occurred in specific domains in the cell, suggesting that targeting of NKA might offer the possibility to prevent arrhythmias with little effects on other cellular functions, which could reduce undesired and unspecific effects.
Next, the researchers found that inhibition of the cAMP-degrading enzyme phosphodiesterase 2 (PDE2) increased the NKA activity and reversed the arrhythmia-provoking effects on a cellular level. Preclinical trials in mice models of heart failure and Ankyrin B showed that PDE2 inhibition, and subsequent NKA activation, strongly prevented ventricular arrhythmias.
This dissertation identifies NKA as an important mechanism for arrhythmias and suggest that PDE2 inhibition could be a novel treatment against ventricular arrhythmias in patients with cardiac disease.
Additional information
Contact the research support staff.