Treatment of Heart Failure with preserved Ejection Fraction (HFpEF)
1. Purpose
We will examine whether different pharmacological therapies will attenuate development of HFpEF, attenuate/prevent or reverse fibrosis and/or improve diastolic function in HFpEF animals. Currently, there exists no effective treatment for this patient group. We will examine whether cyclic nucleotide enhancing therapy or antifibrotic treatment will attenuate development of HFpEF and/or improve diastolic function in HFpEF animals.
2. Distress
- DSS-LepR (DahlS.Z-Leprfa/Leprfa) rats develop metabolic syndrome with hypertension, diabetes mellitus and obesity from 12-15 weeks of age and can eventually reach the humane end point around age 20-25 weeks.
- Mice fed a combination of high fat diet (HFD) and L-NAME will develop metabolic syndrome and HFpEF within 5-10 weeks.
- Administration of therapy by either intraperitoneal injections, intravenous injections or subcutaneous insertion of osmotic pumps allows for minimal invasiveness for drug delivery in rats and mice.
3. Expected benefit
There is no medication or group of medications currently known to improve morbidity or survival of HFpEF patients. Therefore, any success of these therapeutic approaches will be beneficial for the society.
4. Number of animals, and what kind
- For these studies, we will need 780 DSSLepR fat rats, 646 DSSLepR lean rats, 120 Wistar rats, 514 C57BL/6N mice fed normal diet and 600 C57BL/6N mice fed HFD + L-NAME.
5. How to adhere to 3R
We will accomplish the requirement of 3R by:
-Performing parts of our investigation in cells (cell lines and primary cells)
-Performing some preliminary experiments in Wistar rats and mice to optimize the system and avoid repetitive experimentation
-Performing several measurements in each animal whenever possible and accepted for the well being of the animal. This will help to reduce the total number of animals for the study.
-The animals will be kept in the required cages by the KPM personnel.
-Based on the above points, we are seeking permission to conduct detailed studies including physiological in vivo experiments in rats and mice and ex vivo and in vitro experiments utilizing organs, tissues and cells from rats and mice.
We will examine whether different pharmacological therapies will attenuate development of HFpEF, attenuate/prevent or reverse fibrosis and/or improve diastolic function in HFpEF animals. Currently, there exists no effective treatment for this patient group. We will examine whether cyclic nucleotide enhancing therapy or antifibrotic treatment will attenuate development of HFpEF and/or improve diastolic function in HFpEF animals.
2. Distress
- DSS-LepR (DahlS.Z-Leprfa/Leprfa) rats develop metabolic syndrome with hypertension, diabetes mellitus and obesity from 12-15 weeks of age and can eventually reach the humane end point around age 20-25 weeks.
- Mice fed a combination of high fat diet (HFD) and L-NAME will develop metabolic syndrome and HFpEF within 5-10 weeks.
- Administration of therapy by either intraperitoneal injections, intravenous injections or subcutaneous insertion of osmotic pumps allows for minimal invasiveness for drug delivery in rats and mice.
3. Expected benefit
There is no medication or group of medications currently known to improve morbidity or survival of HFpEF patients. Therefore, any success of these therapeutic approaches will be beneficial for the society.
4. Number of animals, and what kind
- For these studies, we will need 780 DSSLepR fat rats, 646 DSSLepR lean rats, 120 Wistar rats, 514 C57BL/6N mice fed normal diet and 600 C57BL/6N mice fed HFD + L-NAME.
5. How to adhere to 3R
We will accomplish the requirement of 3R by:
-Performing parts of our investigation in cells (cell lines and primary cells)
-Performing some preliminary experiments in Wistar rats and mice to optimize the system and avoid repetitive experimentation
-Performing several measurements in each animal whenever possible and accepted for the well being of the animal. This will help to reduce the total number of animals for the study.
-The animals will be kept in the required cages by the KPM personnel.
-Based on the above points, we are seeking permission to conduct detailed studies including physiological in vivo experiments in rats and mice and ex vivo and in vitro experiments utilizing organs, tissues and cells from rats and mice.