In his PhD thesis, Jonas Skogestad has delved into the underlying mechanisms of ventricular arrhythmias.
MAIN RESULTS:
- NKA activity is reduced in hypokalemia and Ankyrin B syndrome.
- Disruption of the ankyrin B/NKA/NCX domain could cause ventricular arrhythmias in Ankyrin B syndrome.
- Phosphodiesterase 2 inhibition increases NKA activity and prevents ventricular arrhythmias in heart failure and Ankyrin B syndrome.
THESIS DEFENCE:
Thesis: A search for novel treatments against ventricular arrhythmias
Candidate: Jonas Skogestad
Time: June 25, 2020 at 12:15
Place: Online-based solution, due to the covid-19 situation
Link to university website
SUMMARY:
(1) The activity of the ion pump Na+/K+-ATPase (NKA) is reduced in hypokalemia, increasing the susceptibility for cardiac arrhythmias. In rat cardiomyocytes exposed to hypokalemia, the NKA activity was reduced by 25%, mainly observed in the NKAα2 isoform, leading to increased intracellular Na+ and Ca2+-levels and higher frequency of spontaneous Ca2+-waves.
(3) Skogestad and co-workers showed increased sparks and waves of Ca2+ in cardiomyocytes following disruption of the interaction between NKA and the adaptor protein ankyrin B. Such disruption could be an important pathophysiological mechanism in the rare genetic disease Ankyrin B syndrome. The disruption abolished the correlation between NKA and Na+/Ca2+ exchanger (NCX) currents, increasing intracellular Na+-levels. None of these effects were seen when NKAα2 was inhibited.
(3) Na+ concentrations are higher near NKA than in the rest of the cytocol. Skogestad and co-workers conducted several experiments that suggested differential Na+ pools in the subsarcolemmal space. These findings could be important for cardiac contractility and genesis of cardiac arrhythmia.
(4) Inhibiting the cAMP-degrading enzyme phosphodiesterase 2 (PDE2) increases NKA activity and reverses the increased susceptibility of ventricular arrhythmias in mice models of heart failure and Ankyrin B syndrome.
REFERENCES:
(1) Aronsen, J. M., Skogestad, J., Lewalle, A., Louch, W. E., Hougen, K., Stokke, M. K., Swift, F., Niederer, S., Smith, N. P., Sejersted, O. M., & Sjaastad, I. (2015). Hypokalaemia induces Ca2+ overload and Ca2+ waves in ventricular myocytes by reducing Na+, K+‐ATPase α2 activity. The Journal of physiology, 593(6), 1509-1521.
(2) Skogestad, J., Lines, G. T., Louch, W. E., Sejersted, O. M., Sjaastad, I., & Aronsen, J. M. (2019). Evidence for heterogeneous subsarcolemmal Na+ levels in rat ventricular myocytes. American Journal of Physiology-Heart and Circulatory Physiology, 316(5), H941-H957.
(3) Skogestad, J., Aronsen, J. M., Tovsrud, N., Wanichawan, P., Hougen, K., Stokke, M. K., arlson, C. R., Sjaastad, I., Sejersted, O. M., & Swift, F. (2020). Coupling of the Na+/K+-ATPase to Ankyrin B controls Na+/Ca2+ exchanger activity in cardiomyocytes. Cardiovascular Research, 116(1), 78-90.
