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364 Beneficial Actions of SGLT2 Inhibition and H2S Therapy in Heart Failure with Preserved Ejection Fraction

OBJECTIVES/GOALS: SGLT2i therapy is currently a cornerstone in heart failure with preserved ejection fraction (HFpEF) therapy. Similarly, H2S has been shown to be beneficial in preclinical models of heart failure. With this in mind, we sought to investigate the effects of the SGLT2i and H2S donor th...

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Autores principales: Doiron, Jake, Li, Zhen, Xia, Huijing, Lapenna, Kyle B., Allerton, Timothy D., Kapusta, Daniel R., Lefer, David J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cambridge University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10129481/
http://dx.doi.org/10.1017/cts.2023.404
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author Doiron, Jake
Li, Zhen
Xia, Huijing
Lapenna, Kyle B.
Allerton, Timothy D.
Kapusta, Daniel R.
Lefer, David J.
author_facet Doiron, Jake
Li, Zhen
Xia, Huijing
Lapenna, Kyle B.
Allerton, Timothy D.
Kapusta, Daniel R.
Lefer, David J.
author_sort Doiron, Jake
collection PubMed
description OBJECTIVES/GOALS: SGLT2i therapy is currently a cornerstone in heart failure with preserved ejection fraction (HFpEF) therapy. Similarly, H2S has been shown to be beneficial in preclinical models of heart failure. With this in mind, we sought to investigate the effects of the SGLT2i and H2S donor therapy alone or in combination in a rodent model of cardiometabolic HFpEF. METHODS/STUDY POPULATION: Male C57BL/6N mice (9 weeks of age) were fed a high fat, Western diet (HFD) and received L-NG-Nitro arginine methyl ester (L-NAME) in the drinking water (0.5 g/L) to induce HFpEF. At 5 weeks, animals were randomized to either control, H2S donor (SG-1002, 90 mg/kg/d, P.O), Empagliflozin (155 mg/L, P.O), or the combination of SG-1002 and Empagliflozin for an additional 5 weeks while being maintained on HFD and L-NAME. Echocardiography, left ventricular invasive LV and systemic hemodynamics, and exercise capacity testing were performed to assess cardiovascular disease severity. Fasted glucose, circulating triglyceride and cholesterol content were similarly measured to quantify key clinical metabolic parameters. H2S and its metabolite, sulfane sulfur, were quantified to assure adequate H2S donation. RESULTS/ANTICIPATED RESULTS: Administration of SG-1002 restored H2S and sulfane sulfur to normal circulating levels. All treatment groups exhibited similar improvements in LV diastolic dysfunction as measured by E/E’and LVEDP. Combination therapy significantly improved exercise capacity whereas the monotherapy groups did not. Treatment with SG-1002 decreased fasting glucose and circulating cholesterol while all treatment groups displayed decreased circulating triglycerides and body weight compared to HFpEF control. DISCUSSION/SIGNIFICANCE: These data indicate that restoring H2S or treatment with an SGLT2i in this preclinical HFpEF model attenuates pathology. Combination of both drugs exhibited greater benefit than either monotherapy in important HFpEF parameters such as exercise capacity. Further studies are underway to characterize the benefits observed from combination therapy.
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spelling pubmed-101294812023-04-26 364 Beneficial Actions of SGLT2 Inhibition and H2S Therapy in Heart Failure with Preserved Ejection Fraction Doiron, Jake Li, Zhen Xia, Huijing Lapenna, Kyle B. Allerton, Timothy D. Kapusta, Daniel R. Lefer, David J. J Clin Transl Sci Precision Medicine/Health OBJECTIVES/GOALS: SGLT2i therapy is currently a cornerstone in heart failure with preserved ejection fraction (HFpEF) therapy. Similarly, H2S has been shown to be beneficial in preclinical models of heart failure. With this in mind, we sought to investigate the effects of the SGLT2i and H2S donor therapy alone or in combination in a rodent model of cardiometabolic HFpEF. METHODS/STUDY POPULATION: Male C57BL/6N mice (9 weeks of age) were fed a high fat, Western diet (HFD) and received L-NG-Nitro arginine methyl ester (L-NAME) in the drinking water (0.5 g/L) to induce HFpEF. At 5 weeks, animals were randomized to either control, H2S donor (SG-1002, 90 mg/kg/d, P.O), Empagliflozin (155 mg/L, P.O), or the combination of SG-1002 and Empagliflozin for an additional 5 weeks while being maintained on HFD and L-NAME. Echocardiography, left ventricular invasive LV and systemic hemodynamics, and exercise capacity testing were performed to assess cardiovascular disease severity. Fasted glucose, circulating triglyceride and cholesterol content were similarly measured to quantify key clinical metabolic parameters. H2S and its metabolite, sulfane sulfur, were quantified to assure adequate H2S donation. RESULTS/ANTICIPATED RESULTS: Administration of SG-1002 restored H2S and sulfane sulfur to normal circulating levels. All treatment groups exhibited similar improvements in LV diastolic dysfunction as measured by E/E’and LVEDP. Combination therapy significantly improved exercise capacity whereas the monotherapy groups did not. Treatment with SG-1002 decreased fasting glucose and circulating cholesterol while all treatment groups displayed decreased circulating triglycerides and body weight compared to HFpEF control. DISCUSSION/SIGNIFICANCE: These data indicate that restoring H2S or treatment with an SGLT2i in this preclinical HFpEF model attenuates pathology. Combination of both drugs exhibited greater benefit than either monotherapy in important HFpEF parameters such as exercise capacity. Further studies are underway to characterize the benefits observed from combination therapy. Cambridge University Press 2023-04-24 /pmc/articles/PMC10129481/ http://dx.doi.org/10.1017/cts.2023.404 Text en © The Association for Clinical and Translational Science 2023 https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article, distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is unaltered and is properly cited. The written permission of Cambridge University Press must be obtained for commercial re-use or in order to create a derivative work.
spellingShingle Precision Medicine/Health
Doiron, Jake
Li, Zhen
Xia, Huijing
Lapenna, Kyle B.
Allerton, Timothy D.
Kapusta, Daniel R.
Lefer, David J.
364 Beneficial Actions of SGLT2 Inhibition and H2S Therapy in Heart Failure with Preserved Ejection Fraction
title 364 Beneficial Actions of SGLT2 Inhibition and H2S Therapy in Heart Failure with Preserved Ejection Fraction
title_full 364 Beneficial Actions of SGLT2 Inhibition and H2S Therapy in Heart Failure with Preserved Ejection Fraction
title_fullStr 364 Beneficial Actions of SGLT2 Inhibition and H2S Therapy in Heart Failure with Preserved Ejection Fraction
title_full_unstemmed 364 Beneficial Actions of SGLT2 Inhibition and H2S Therapy in Heart Failure with Preserved Ejection Fraction
title_short 364 Beneficial Actions of SGLT2 Inhibition and H2S Therapy in Heart Failure with Preserved Ejection Fraction
title_sort 364 beneficial actions of sglt2 inhibition and h2s therapy in heart failure with preserved ejection fraction
topic Precision Medicine/Health
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10129481/
http://dx.doi.org/10.1017/cts.2023.404
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