Combination of an oral H2S donor to dapagliflozin provides additional therapeutic benefit in a cardiorenal model of heart failure with preserved ejection fraction (HFpEF)

Background Heart failure with preserved ejection fraction (HFpEF) remains a challenging condition with limited therapeutic options. While conventional heart failure treatments have largely failed to show benefits in HFpEF, sodium-glucose cotransporter 2 inhibitors (SGLT2i)1,2 have emerged as a breakthrough therapy, improving clinical outcomes in a heterogeneous patient population. Despite therapeutic advances, HFpEF patients still have significant disease burden and limitations in quality of life, underscoring the need for additional therapeutic strategies. Several findings have highlighted the critical role of the gasotransmitter hydrogen sulfide (H2S), a physiological signaling molecule with antioxidant, anti-inflammatory, and cardioprotective properties, in the regulation of cardiac and vascular biology3. Given the overlapping mechanisms of SGLT2 inhibition and H2S donation in targeting key pathophysiological features of HFpEF4, their combined use may offer synergistic benefits Therefore, in this study, we investigated the effects of SGLT2i dapagliflozin alone or in combination with H2S donor (NaHS) in a non-diabetic model of HFpEF. Material and Methods Seven-week-old male Dahl salt-sensitive rats were fed with laboratory chow containing 8% NaCl (high-salt diet, HS) or 0.3% NaCl (low-salt diet, LS). After 5 weeks, the animals on HS diet were randomized to dapagliflozin (0.1mg/Kg/day, DAPA) or combination (DAPA+NaHS) for the following 6 weeks. Echocardiography was used to assess systolic and diastolic function. Hearts were collected for molecular and histological analysis. Results and Conclusions After six weeks of treatments, echocardiography showed that DAPA alone or in combination with NaHS significantly improved cardiac function and hypertrophy. Functional changes were coupled with a reduced mRNA expression of pro-inflammatory (NF-KB and IL-6) and pro-fibrotic genes (TGF-beta and collagen I). Reduced the activity of MMP1, MMP2 and MMP9, confirm the improvement of cardiac fibrosis, a major hallmark of HFpEF. The fibrotic process is closely related to oxidative stress. The mRNA expression of NOX 2 and NOX 4 as well as their protein expression are significantly downregulated in each treated group. Our data suggest beneficial effects of DAPA and DAPA+NaHS, by modulating oxidative profile and inflammatory response, are able to improve diastolic function and cardiac remodeling in a model of HFpEF. Although DAPA treatment was effective, adjunctive H2S therapy resulted in further improvements of cardio-renal perturbations, beyond SGLT2i monotherapy.