Marianne Ruud has investigated mechanical wall stress and how it influences t-tubule structure, calcium handling and heart function in rats and humans with heart failure with reduced ejection fraction.
MAIN RESULTS:
- Elevated ventricular wall stress triggers remodelling of t-tubule structure and function.
- Regional changes in myocardial relaxation contribute to regional diastolic dysfunction in rats with heart failure with reduced ejection fraction.
- Regional diastolic dysfunction is also present in human patients with HFrEF.
THESIS DEFENCE:
Thesis: Regulation of cardiomyocyte structure and function by workload
Candidate: Marianne Ruud
Time: November 27, 2020 at 12:15
Place: Online-based solution, due to the covid-19 situation
Link to university website
SUMMARY:
(1) Mechanical wall stress is increased in rats with heart failure with reduced ejection fraction. High mechanical wall stress causes lower levels of junctophilin-2 and disruption of t-tubule structure and calcium handling in cardiac muscle tissue, ultimately leading to reduced contractility.
Moreover, regional differences in wall stress contribute to regional differences in t-tubule density, calcium handling and junctophilin-2 levels. The largest disruptions were seen in the thin-walled region proximal to the infarct.
(2) Diastolic strain rate is reduced close to the infarcted area in rats with post-infarction heart failure with reduced ejection fraction. This is not seen in the remote regions of the heart. The regionally impaired diastolic function relates to impaired SERCA2 function, causing disrupted calcium handling. Wall stress is elevated in the region adjacent to the infarct, and high mechanical stress is directly linked to SERCA downregulation and slowing of relaxation.
Similar regional diastolic dysfunction is also present in human patients with heart failure with reduced ejection fraction. Patients were compared with healthy controls.
(3) Moderately elevated wall stress leads to increased t-tubule density, improved calcium handling and better heart function. This was shown by employing experimental surgery methods, patient biopsies, and ex vivo experiments.
REFERENCES:
(1) Frisk, M., Ruud, M., Espe, E. K., Aronsen, J. M., Røe, Å. T., Zhang, L., Norseng, P. A., Sejersted, O. M., Christensen, G. A., Sjaastad, I., & Louch, W. E. (2016). Elevated ventricular wall stress disrupts cardiomyocyte t-tubule structure and calcium homeostasis. Cardiovascular Research, 112(1), 443-451.
(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.
