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PhD Defence: Mani Sadredini

Cand.med. Mani Sadredini has defended the thesis “The role of CaMKII in RyR2-dependent CPVT” for the degree of PhD (Philosophiae Doctor).

February 16, 2023

Adjudication committee

  • First opponent: Associate Professor Morten Bækgaard Thomsen, University of Copenhagen, Denmark
  • Second opponent: Professor Emeritus Øyvind Ellingsen, NTNU – Norwegian University of Science and Technology,
  • Third member and chair of the evaluation committee: Professor II Theresa Mariero Olasveengen, University of Oslo

Chair of the Defence

Professor II Henrik Schirmer, University of Oslo

Principal Supervisor

Professor Mathis Korseberg Stokke, University of Oslo

Summary

Ventricular arrhythmias can lead to sudden cardiac death in both inherited and acquired diseases. In catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1), genetic variants of cardiac ryanodine receptors (RyR2) cause ventricular arrhythmias in response to physical or emotional stress. Ca2+/calmodulin-dependent protein kinase II (CaMKII) regulates RyR2 and has been suggested as a therapeutic target for CPVT1. The aim of this thesis was to investigate the antiarrhythmic effects of exercise training, CaMKII inhibition and reduced CaMKII oxidation in mice with the CPVT1-causative human RyR2 variant RyR2-R2474S. For this purpose, treadmill interval exercise running, pharmacological inhibitors, genetically engineered resistance to CaMKII oxidation, telemetric ECG surveillance, live cell Ca2+ imaging and protein analysis were used.

Exercise training reduced the frequency of ventricular arrhythmias in CPVT1 mice in a CaMKII-dependent manner. However, genetically engineered resistance to CaMKII oxidation did not protect CPVT1 mice from arrhythmias. Inhibition of CaMKII protected against the cellular mechanisms of arrhythmias that are associated with CPVT1. But inhibition of CaMKII also induced distinct cellular proarrhythmic features. Yet, these proarrhythmic features were within acceptable levels.

This thesis supports inhibition of CaMKII as an efficient and safe strategy to prevent arrhythmias in CPVT1. However, inhibition of CaMKII oxidation does not protect against arrhythmias in this condition.

Mani Sadredini

Postdoctoral fellow

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Institute for Experimental Medical Research

Oslo University Hospital, Ullevål

PB 4956 Nydalen

NO-0424 Oslo

Norway

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