Abstract: SA-PO278
Effects of Global SGLT2 Knockout on Heart Failure with Preserved Ejection Fraction
Session Information
- Diabetic Kidney Disease: Basic - 2
October 26, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
Authors
- Fain, Margaret E., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
- Misener, Sol, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
- Zhou, Yalu, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
- Rousselle, Thomas, University of Maryland School of Medicine, Baltimore, Maryland, United States
- Mas, Valeria R., University of Maryland School of Medicine, Baltimore, Maryland, United States
- Quaggin, Susan E., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
Background
Until recently, there were no effective regimens for heart failure with preserved ejection fraction (HFpEF); however, clinical data from the EMPEROR-Preserved trial has shown that sodium glucose cotransporter 2 inhibitors (SGLT2is) reduce hospitalization and mortality in HFpEF patients. However, the mechanism(s) responsible for cardioprotection following inhibition of a kidney-restricted SGLT2 cotransporter is incompletely known. However, off- versus on- target drug effects remain unclear, and a clear explanation would allow for more directed drug therapy development.
Methods
To investigate the effect of SGLT2i on-target drug action, we used the SweetPee (SP) Slc5a2 loss-of-function model on a high fat diet (HFD) L-NAME model of HFpEF to model the effects of on-target Sglt2 inhibition in new onset HFpEF. 8-10-week-old SP or wild type (WT) mice were maintained on either 60% HFD+L-NAME (0.5 g/L) or normal diet (ND) for 8 weeks. The animals were monitored every two weeks with echocardiography, blood pressure measurements, and weight surveillance, and were also tested for cardiovascular function using an exercise tolerance test before sacrifice and harvesting. The lung wet-to-dry weight ratio was also recorded in these animals as evidence of pulmonary edema.
Results
Echocardiography data showed no significant difference in ejection fraction, as is expected in HFpEF condition; however, the WT HFD+L-NAME group showed a trend towards an increase in E/e’ relative to the SP HFD+L-NAME group, indicating an increase in left ventricular filling pressure which is a hallmark of heart failure. Furthermore, WT HFD-LNAME trended towards a higher systolic and diastolic blood pressure and lung wet-to-dry weight ratio and a decrease in running distance as measured via treadmill. These changes show that the SP genotype was protective against incipient HFpEF as induced by an HFD-L-NAME model.
Conclusion
These results show promise that cardioprotection observed in patients stems from on-target drug inhibition of the SGLT2 cotransporter. Future directions will identify potential molecular pathways underlying protection, as well as distinguish on-target from off-target effects.
Funding
- NIDDK Support