The mineralocorticoid receptor (MR) plays an important role in the development of chronic kidney disease (CKD) and associated cardiovascular complications. Antagonizing the overactivation of the MR with MR antagonists (MRA) is a therapeutic option, but their use in patients with CKD is limited due to the associated risk of hyperkalemia. Finerenone is a non-steroidal MRA associated with an improved benefit-risk profile in comparison to steroidal MRAs. In this study, we decided to test whether finerenone improves renal and cardiac function in male hypertensive and diabetic ZSF1 rats as an established preclinical HFpEF model. Finerenone was administered at 10 mg/kg/day for 12 weeks. Cardiac function/hemodynamics were assessed in vivo. ZSF1 rats showed classical signs of CKD with increased BUN, UACR, hypertrophy, and fibrosis of the kidney together with characteristic signs of HFpEF including cardiac fibrosis, diastolic dysfunction, and decreased cardiac perfusion. Finerenone treatment did not impact kidney function but reduced renal hypertrophy and cardiac fibrosis. Interestingly, finerenone ameliorated diastolic dysfunction and cardiac perfusion in ZSF1 rats. In summary, we show for the first time that non-steroidal MR antagonism by finerenone attenuates cardiac diastolic dysfunction and improves cardiac perfusion in a preclinical HFpEF model. These cardiac benefits were found to be largely independent of renal benefits.
Introduction AMPK is a central energy sensor with cardioprotective effects, and its activation has emerged as a target for the treatment of metabolic syndrome-related cardiac dysfunction. PXL770 is the first direct AMPK activator under clinical development, currently investigated for the treatment of NASH. Since potential cardiac benefits of PXL770 have not been previously assessed we investigated whether short- and long-term PXL770 treatment exerts protective cardiac effects in rats with metabolic syndrome. Methods ZSF-1 rats were treated with PXL770 (150 mg/kg orally BID for 90 days initiated at the age of 12 weeks, or for 7 days initiated at the age of 23 weeks) in order to determine left ventricular (LV) function and remodeling. Results After 90 days, untreated ZSF-1 rats showed signs of LV diastolic dysfunction, illustrated by the increase in LV end-diastolic pressure (LV EDP; 5.58±0.57 and 8.28±1.02 mmHg in lean and ZSF-1 rats, respectively; p<0.05) and in LV end-diastolic pressure volume-relation (LV EDPVR; 1.10±0.23 and 5.44±0.65 mmHg/RVU in lean and ZSF-1 rats, respectively; p<0.05) with preserved LV systolic function, illustrated by the slight decrease in LV fractional shortening (LV FS; 46±1 and 42±1% in lean and ZSF-1 rats, respectively; p<0.05) and similar LV end-systolic pressure (LV ESP; 173±10 and 197±6 mmHg, respectively) or LV end-systolic pressure volume-relation (LV ESPVR; 32.7±4.2 to 28.6±1.4 mmHg/RVU, respectively). LV diastolic dysfunction was associated with a significant increase in LV tissue collagen density (2.62±0.17 and 4.03±0.13%, respectively) without an alteration in LV weight (1.27±0.02 to 1.22±0.03 g; respectively) Short- and long-term treatment with PXL770 improved LV diastolic function in treated ZSF-1, illustrated by the reduced LV EDP (5.34±0.93 and 5.98±0.94 mmHg, short- and long-term PXL770, respectively) and the reduced LV EDPVR (3.31±0.43 and 2.73±0.16 mmHg/RVU, respectively; p<0.05 vs untreated ZSF-1). Simultaneously LV FS was significantly increased (52±1 and 50±1%, respectively; p<0.05 vs untreated ZSF-1), as well as LV ESPVR (34.6±1.4 and 33.0±0.9 mmHg/RVU, respectively; p<0.05 vs untreated ZSF-1). The improvement of diastolic function was associated with a reduction in LV weight (1.19±0.04 and 1.17±0.02 g, respectively; long-term PXL770 p<0.0.5 vs untreated ZSF-1) and a significant reduction in collagen density after long-term PXL770 (3.35±0.12%; p<0.05) but not short-term PXL770 (4.22±0.30%). Conclusion These results suggest that PXL770 exerts protective effects on cardiac function and structure in developing or established cardiomyopathy. Thus, by directly activating AMPK, the PXL770 appears promising for the treatment of cardiac dysfunction associated with metabolic diseases. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Poxel SA
Introduction: PXL770 is a direct AMP kinase activator. In models of T2DM and NASH, PXL770 improves hyperglycemia and dyslipidemia and reduces: steatosis, inflammation, fibrogenesis. Whether these beneficial effects are associated with an improvement in diabetes-related cardiac, vascular and renal dysfunctions is unknown. Methods: Diabetic ZSF-1 rats were treated for 90 days with PXL770 (150 mg/kg BID), then cardiac function (left ventricular (LV) hemodynamics), in vitro flow-mediated dilation (FMD; arteriograph) of mesenteric artery, renal histology and function (transcutaneous GFR) were assessed. Results: Untreated ZSF-1 rats exhibited LV diastolic dysfunction, i.e., increases in LV End-Diastolic Pressure (LVEDP; 8.3±1.0 vs. 5.6±0.6 mm Hg in lean, p<.05) and LV End-Diastolic Pressure Volume Relation (LVEDPVR; 5.4±0.6 vs. 1.1±0.2 mm Hg/RVU in lean, p<.05). Myocardial tissue perfusion was reduced (4.0±0.2 vs. 7.4±0.9 ml/min/g in lean, p<.05). Untreated rats exhibited impaired mesenteric FMD (% of preconstriction; 37±11 vs. 70±7% in lean, p<.05) and renal function and structure as shown by a reduction in GFR (4.4±0.5 vs. 5.6±0.5 ml/min in lean, p<.05) and increase in glomerular score (2.3±0.2 vs. 0.6±0.1 AU in lean, p<.05). Compared to untreated ZSF-1 rats, 90-day PXL770 reduced glycaemia (-31 %, p<.05) and plasma triglycerides (-44 %, p<.05). PXL770 decreased LVEDP (-28 %) and LVEDPVR (2.7±0.2 mm Hg/RVU, p<.05) and increased LV tissue perfusion (+30 %, p<.05). PXL770 improved mesenteric FMD (64±3%, p<.05) and increased GFR (6.0±0.1 ml/min, p<.05) and reduced glomerular score (1.6±0.2, p<.05). Conclusion: In ZSF-1 rats, improvement of metabolic status induced by long-term treatment with the AMP kinase activator PXL770 is associated with an improved LV diastolic, vascular and renal function/structure. PXL770 could have therapeutic utility for the treatment of metabolic diseases and related co-morbid conditions. Disclosure Y. Stephan: None. M. Soulié: None. L. Nicol: None. P. Gluais-dagorn: Employee; Self; Poxel SA. S. Hallakou-bozec: None. P. Mulder: None. Funding Poxel SA
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