Adjunctive therapy with an oral H2S donor provides additional therapeutic benefit beyond SGLT2 inhibition in cardiometabolic heart failure with preserved ejection fraction

Jake E. Doiron; Huijing Xia; Xiaoman Yu; Alexandra R. Nevins; Kyle B. LaPenna; Thomas E. Sharp; Traci T. Goodchild; Timothy D. Allerton; Mona Elgazzaz; Eric Lazartigues; Sanjiv J. Shah; Zhen Li; David J. Lefer

doi:10.1111/bph.16493

Adjunctive therapy with an oral H₂S donor provides additional therapeutic benefit beyond SGLT2 inhibition in cardiometabolic heart failure with preserved ejection fraction

Jake E. Doiron, Huijing Xia, Xiaoman Yu, Alexandra R. Nevins, Kyle B. LaPenna, Thomas E. Sharp, Traci T. Goodchild, Timothy D. Allerton, Mona Elgazzaz, Eric Lazartigues, Sanjiv J. Shah, Zhen Li, David J. Lefer^*

^*Corresponding author for this work

Medicine, Cardiology Division

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

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 (H₂S), a well-studied cardioprotective agent, could be beneficial in HFpEF. SGLT2i monotherapy and combination therapy involving an SGLT2i and H₂S 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 H₂S 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 H₂S 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 H₂S therapy while also revealing the superior efficacy of the combination therapy in cardiometabolic HFpEF.

Original language	English (US)
Pages (from-to)	4294-4310
Number of pages	17
Journal	British journal of pharmacology
Volume	181
Issue number	21
DOIs	https://doi.org/10.1111/bph.16493
State	Published - Nov 2024

Funding

The authors thank Sulfagenix, Inc. (Oro Valley, Arizona) for the generous supply of SG1002 for these studies. The authors would like to thank the Cell Biology and Bioimaging Core at Pennington Biomedical Research Center (National Institutes of Health [NIH] 8 P20-GM103538 and NIH 2P30-DK072476) for assistance with the histological investigations in this study. These studies were supported by grants from the National Institutes of Health HL146098, HL146514 and HL151398 to D. J. L., HL159428 to T. T. G., AA029984 to T. E. S., P20GM135002 and U54GM104940 to T. D. A. and by an American Heart Association Postdoctoral fellowship to Z. L. (20POST35200075). J. E. D. is the recipient of a training fellowship from the NIH National CCTS awarded to the University of Alabama at Birmingham as part of a TL1 Training Grant (TL1TR003106). Funding information 2

Keywords

HFpEF
SGLT2 inhibitor
heart failure
hydrogen sulphide
sodium glucose cotransporter 2 inhibitors

ASJC Scopus subject areas

Pharmacology

Access to Document

10.1111/bph.16493

Cite this

Doiron, J. E., Xia, H., Yu, X., Nevins, A. R., LaPenna, K. B., Sharp, T. E., Goodchild, T. T., Allerton, T. D., Elgazzaz, M., Lazartigues, E., Shah, S. J., Li, Z., & Lefer, D. J. (2024). Adjunctive therapy with an oral H₂S donor provides additional therapeutic benefit beyond SGLT2 inhibition in cardiometabolic heart failure with preserved ejection fraction. British journal of pharmacology, 181(21), 4294-4310. https://doi.org/10.1111/bph.16493

@article{381e159090c74b03a8597d7a2122befb,

title = "Adjunctive therapy with an oral H2S donor provides additional therapeutic benefit beyond SGLT2 inhibition in cardiometabolic heart failure with preserved ejection fraction",

abstract = "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 (H2S), a well-studied cardioprotective agent, could be beneficial in HFpEF. SGLT2i monotherapy and combination therapy involving an SGLT2i and H2S 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 H2S 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 H2S 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 H2S therapy while also revealing the superior efficacy of the combination therapy in cardiometabolic HFpEF.",

keywords = "HFpEF, SGLT2 inhibitor, heart failure, hydrogen sulphide, sodium glucose cotransporter 2 inhibitors",

author = "Doiron, {Jake E.} and Huijing Xia and Xiaoman Yu and Nevins, {Alexandra R.} and LaPenna, {Kyle B.} and Sharp, {Thomas E.} and Goodchild, {Traci T.} and Allerton, {Timothy D.} and Mona Elgazzaz and Eric Lazartigues and Shah, {Sanjiv J.} and Zhen Li and Lefer, {David J.}",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.",

year = "2024",

month = nov,

doi = "10.1111/bph.16493",

language = "English (US)",

volume = "181",

pages = "4294--4310",

journal = "British journal of pharmacology",

issn = "0007-1188",

publisher = "John Wiley and Sons Inc.",

number = "21",

}

Doiron, JE, Xia, H, Yu, X, Nevins, AR, LaPenna, KB, Sharp, TE, Goodchild, TT, Allerton, TD, Elgazzaz, M, Lazartigues, E, Shah, SJ, Li, Z & Lefer, DJ 2024, 'Adjunctive therapy with an oral H₂S donor provides additional therapeutic benefit beyond SGLT2 inhibition in cardiometabolic heart failure with preserved ejection fraction', British journal of pharmacology, vol. 181, no. 21, pp. 4294-4310. https://doi.org/10.1111/bph.16493

Adjunctive therapy with an oral H₂S donor provides additional therapeutic benefit beyond SGLT2 inhibition in cardiometabolic heart failure with preserved ejection fraction. / Doiron, Jake E.; Xia, Huijing; Yu, Xiaoman et al.
In: British journal of pharmacology, Vol. 181, No. 21, 11.2024, p. 4294-4310.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Adjunctive therapy with an oral H2S donor provides additional therapeutic benefit beyond SGLT2 inhibition in cardiometabolic heart failure with preserved ejection fraction

AU - Doiron, Jake E.

AU - Xia, Huijing

AU - Yu, Xiaoman

AU - Nevins, Alexandra R.

AU - LaPenna, Kyle B.

AU - Sharp, Thomas E.

AU - Goodchild, Traci T.

AU - Allerton, Timothy D.

AU - Elgazzaz, Mona

AU - Lazartigues, Eric

AU - Shah, Sanjiv J.

AU - Li, Zhen

AU - Lefer, David J.

PY - 2024/11

Y1 - 2024/11

N2 - 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 (H2S), a well-studied cardioprotective agent, could be beneficial in HFpEF. SGLT2i monotherapy and combination therapy involving an SGLT2i and H2S 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 H2S 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 H2S 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 H2S therapy while also revealing the superior efficacy of the combination therapy in cardiometabolic HFpEF.

AB - 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 (H2S), a well-studied cardioprotective agent, could be beneficial in HFpEF. SGLT2i monotherapy and combination therapy involving an SGLT2i and H2S 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 H2S 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 H2S 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 H2S therapy while also revealing the superior efficacy of the combination therapy in cardiometabolic HFpEF.

KW - HFpEF

KW - SGLT2 inhibitor

KW - heart failure

KW - hydrogen sulphide

KW - sodium glucose cotransporter 2 inhibitors

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