Åsmund Treu Røe has studied active and passive mechanisms of diastolic dysfunction in human and animal models of heart failure.
Extracellular fibrosis and cardiomyocyte stiffening cause diastolic dysfunction in concentric hypertrophy.
- Impaired calcium handling leads to diastolic dysfunction in systolic heart failure.
Thesis: Heart failure beyond global systolic dysfunction – active, passive and regional mechanisms of diastolic dysfunction
Candidate: Åsmund Treu Røe
Time: March 4, 2020 at 13:15
Place: Oslo University Hospital Ullevål, Øyeavdelingen: Auditoriet
Link to university website
(1) In a model of heart failure with preserved ejection fraction, extracellular fibrosis and titin-based cardiomyocyte stiffening results in elevated passive stiffness. This critically impairs diastolic filling. Rats were subjected to aortic banding, leading to pressure overload, concentric hypertrophy and diastolic dysfunction but preserved systolic function. Compared to sham-operated rats, the hypertrophic hearts had increased passive tension and extracellular collagen levels, in addition to altered titin phosphorylation leading to increased stiffness.
Cardiomyocate diastolic calcium handling, on the other hand, was enhanced in concentric hypertrophy, with augmented SERCA2 activity and reduced calcium in cytosol during rest.
(2) In heart failure with reduced ejection fraction (HFrEF), cardiomyocyte calcium handling leads to slowed relaxation and impaired regional diastolic function. Calcium removal within cardiomyocytes is impaired due to decreased SERCA expression, leading to increased resting cytosolic calcium levels. Furthermore, high mechanical stress downregulates SERCA and slows relaxation.
The study uses a post-infarction rat model of HFrEF. Diastolic function was reduced and wall stress elevated in the region adjacent to the infarct compared to sham-operated rats, but not in other regions of the myocardium. This was also confirmed in humans with post-infarction HFpEF.
(3) Differences in wall stress is one potential cause of divergent remodeling between heart failure with reduced and preserved ejection fraction.
(1) Røe, Å. T., Aronsen, J. M., Skårdal, K., Hamdani, N., Linke, W. A., Danielsen, H. E., Sejersted, O. M., Sjaastad, I., & Louch, W. E. (2017). Increased passive stiffness promotes diastolic dysfunction despite improved Ca2+ handling during left ventricular concentric hypertrophy. Cardiovascular research, 113(10), 1161-1172.
(2) Røe, Å. T., Ruud, M., Espe, E. K., Manfra, O., Longobardi, S., Aronsen, J. M., Nordén, E. S., Husebye, T., Kolstad, T. R. S., Cataliotti, A., Christensen, G., Sejersted, O. M., Niederer, S. A., Andersen, G. Ø., Sjaastad, I, & Louch, W. E. (2019). Regional diastolic dysfunction in post-infarction heart failure: role of local mechanical load and SERCA expression. Cardiovascular research, 115(4), 752-764.