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Abstract: SA-PO322

Finerenone Improves Cardiovascular Benefits After Diet Normalization in a Mouse Model of High-Fat Diet-Induced Obesity

Session Information

Category: Hypertension and CVD

  • 1403 Hypertension and CVD: Mechanisms

Authors

  • Jaisser, Frederic, INSERM U1138, Paris, France
  • Pieronne-Deperrois, Marie, INSERM U1096, UFR Santé, University of Normandy, Rouen, France
  • Bonnard, Benjamin, INSERM U1138, Paris, France
  • Nicol, Lionel, INSERM U1096, UFR Santé, University of Normandy, Rouen, France
  • Marouchtchak, Anaëlle, INSERM U1096, UFR Santé, University of Normandy, Rouen, France
  • Kolkhof, Peter, Bayer AG, Wuppertal, Germany
  • Mulder, Paul, INSERM U1096, UFR Santé, University of Normandy, Rouen, France
  • Ouvrard-Pascaud, Antoine, INSERM U1096, UFR Santé, University of Normandy, Rouen, France
Background

Patients with obesity exhibit high prevalence of Heart Failure with preserved Ejection Fraction (HFpEF). We hypothesized that the non-steroidal mineralocorticoid receptor (MR) antagonist Finerenone further improves cardiac function after normalisation of the diet in obese mice.

Methods

B6D2 male mice were fed a High Fat Diet (HFD) (60%) or maintained on normal diet (CTL). After 16 weeks, obese mice were divided in 3 groups for 8 more weeks with either: i) HFD; ii) normal diet (HFD-STOP); iii) normal diet plus Finerenone 1 mg.kg-1.day-1 in the food (HFD-STOP+FINE).

Results

After 16 weeks of HFD, mice showed an increased cardiac filling pressure (LV-End-Diastolic-Pressure, LVEDP: CTL 2.73±0.1, HFD 4.73±0.34 mmHg; P<0.001) and impaired LV compliance (LV-End-Diastolic-Pressure-Volume-Relation, LVEDPVR: CTL 1.19±0.26, HFD 4.77±0.31 mmHg/RVU; P<0.001) (without alteration of the LV Fractional Shortening) and reduced exercise ability in a stress-test on treadmill. These features are typical of HFpEF. Decreased LV Fractional Shortening developed if HFD is continued for 8 weeks more. Switching HFD to normal diet from weeks 16 to 24 improved LV compliance which was further improved by FINE (LVEDPVR: HFD-STOP 3.44±0.39, HFD-STOP+FINE 2.28±0.23 mmHg/RVU; P<0.05) as well as the reduction in LV fibrosis (% fibrosis: CTL 0.21±0.02, HFD 0.47±0.12, HFD-STOP 0.28±0.03, HFD-STOP+FINE 0.23±0.02 mmHg; P<0.05). Only the FINE treatment on top of diet normalisation improved LV filling pressure (LVEDP: CTL 2.73±0.16, HFD 4.73±0.34, HFD-STOP 4.53±0.33, HFD-STOP+FINE 3.18±0.26 mmHg; P<0.05), Fractional Shortening, Cardiac Output, Coronary Reserve (CR: CTL 3.76±0.72, HFD 1.00±0.33, HFD-STOP 1.19±0.25, HFD-STOP+FINE 2.78±0.67 ml.mg-1.min-1; P<0.05) and total runing distance. Renal function is not altered by HFD. Expression of some renal injury markers are increased by HFD and improved by HFD STOP without further additional effects of FINE.

Conclusion

When administered on top of diet normalisation after HFD-induced obesity, Finerenone improved LV compliance, LV filling pressure, Coronary Reserve and exercise performance thereby indicating benefit of Finerenone in HFpEF associated to HFD in mice.

Funding

  • Commercial Support