Adjunctive therapy with an oral H 2 S donor provides additional therapeutic benefit beyond SGLT2 inhibition in cardiometabolic heart failure with preserved ejection fraction.

Autor: Doiron JE; Department of Pharmacology and Experimental Therapeutics, LSU Health Sciences Center, New Orleans, Louisiana, USA., Xia H; Department of Pharmacology and Experimental Therapeutics, LSU Health Sciences Center, New Orleans, Louisiana, USA.; Cardiovascular Center of Excellence, LSU Health Sciences Center, New Orleans, Louisiana, USA., Yu X; Department of Cardiac Surgery, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA., Nevins AR; Department of Cardiac Surgery, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA., LaPenna KB; Department of Pharmacology and Experimental Therapeutics, LSU Health Sciences Center, New Orleans, Louisiana, USA., Sharp TE 3rd; Molecular Pharmacology and Physiology, University of South Florida, Tampa, Florida, USA., Goodchild TT; Department of Cardiac Surgery, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA., Allerton TD; Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA., Elgazzaz M; Department of Pharmacology and Experimental Therapeutics, LSU Health Sciences Center, New Orleans, Louisiana, USA.; Cardiovascular Center of Excellence, LSU Health Sciences Center, New Orleans, Louisiana, USA., Lazartigues E; Department of Pharmacology and Experimental Therapeutics, LSU Health Sciences Center, New Orleans, Louisiana, USA.; Cardiovascular Center of Excellence, LSU Health Sciences Center, New Orleans, Louisiana, USA., Shah SJ; Feinberg School of Medicine, Northwestern University Medicine, Chicago, Illinois, USA., Li Z; Department of Cardiac Surgery, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA., Lefer DJ; Department of Cardiac Surgery, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2024 Nov; Vol. 181 (21), pp. 4294-4310. Date of Electronic Publication: 2024 Jul 09.
DOI: 10.1111/bph.16493
Abstrakt: Background and Purpose: Sodium glucose cotransporter 2 inhibitors (SGLT2i) have emerged as a potent therapy for heart failure with preserved ejection fraction (HFpEF). Hydrogen sulphide (H 2 S), a well-studied cardioprotective agent, could be beneficial in HFpEF. SGLT2i monotherapy and combination therapy involving an SGLT2i and H 2 S donor in two preclinical models of cardiometabolic HFpEF was investigated.
Experimental Approach: Nine-week-old C57BL/6N mice received L-NAME and a 60% high fat diet for five weeks. Mice were then randomized to either control, SGLT2i monotherapy or SGLT2i and H 2 S donor, SG1002, for five additional weeks. Ten-week-old ZSF1 obese rats were randomized to control, SGLT2i or SGLT2i and SG1002 for 8 weeks. SG1002 monotherapy was investigated in additional animals. Cardiac function (echocardiography and haemodynamics), exercise capacity, glucose handling and multiorgan pathology were monitored during experimental protocols.
Key Results: SGLT2i treatment improved E/e' ratio and treadmill exercise in both models. Combination therapy afforded increases in cardiovascular sulphur bioavailability that coincided with improved left end-diastolic function (E/e' ratio), exercise capacity, metabolic state, cardiorenal fibrosis, and hepatic steatosis. Follow-up studies with SG1002 monotherapy revealed improvements in diastolic function, exercise capacity and multiorgan histopathology.
Conclusions and Implications: SGLT2i monotherapy remediated pathological complications exhibited by two well-established HFpEF models. Adjunctive H 2 S therapy resulted in further improvements of cardiometabolic perturbations beyond SGLT2i monotherapy. Follow-up SG1002 monotherapy studies inferred an improved phenotype with combination therapy beyond either monotherapy. These data demonstrate the differing effects of SGLT2i and H 2 S therapy while also revealing the superior efficacy of the combination therapy in cardiometabolic HFpEF.
(© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Databáze: MEDLINE
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