Meghamsh Kanuparthy, Dwight D Harris, Mark Broadwin, Christopher Stone, Jad Hamze, Keertana Yalamanchili, Sharif Sabe, Frank W Sellke
{"title":"Canagliflozin, a sodium-glucose cotransporter-2 inhibitor, reduces lung fibrosis in left heart dysfunction.","authors":"Meghamsh Kanuparthy, Dwight D Harris, Mark Broadwin, Christopher Stone, Jad Hamze, Keertana Yalamanchili, Sharif Sabe, Frank W Sellke","doi":"10.1177/02184923251352222","DOIUrl":null,"url":null,"abstract":"<p><p>BackgroundLeft heart failure is the most common cause of pulmonary hypertension and increases morbidity and mortality. We investigate the use of canagliflozin, an antidiabetic Sodium-glucose Cotransporter-2 Inhibitor, which is first-line therapy in congestive heart failure, on pulmonary fibrosis in a porcine model of chronic myocardial ischemia.MethodologySixteen Yorkshire swine, eight in a normal diet control arm (NDC) and eight in the canagliflozin arm (CAN), underwent left thoracotomy and ameroid constrictor placement on the left circumflex artery. Seven weeks after placement, the swine underwent harvest procedure. During harvest, left ventricular contractility was quantified by direct left ventricular pressure-volume loops. Protein expression was quantified by immunoblotting and Masson's trichrome staining was utilized to assess perivascular collagen deposition.ResultsAnalysis of left ventricular ejection fraction demonstrated no significant difference between CAN and NDC. Western blot analysis demonstrated increases in TGFβ signaling pathways with decreased free TGFβ and TGFβ monomers in CAN pigs (<i>p</i> < 0.01). Downstream mediators of TGFβ were also increased in NDC with an increase in phospho-SMAD2/3 activity (<i>p</i> = 0.005). Masson's Trichrome analysis of lung tissue demonstrated a trend toward reduced perivascular collagen deposition in CAN swine lungs (<i>p</i> = 0.086).ConclusionsCanagliflozin ameliorates chronic fibrotic changes related to pulmonary hypertension in left ventricular failure. While there was a strong trend toward significance in histologic analysis, this may be limited by the duration of our model. Western blot analysis, however, demonstrates that CAN's modulation of TGFβ signaling pathways may play a role in the management of secondary pulmonary hypertension.</p>","PeriodicalId":35950,"journal":{"name":"ASIAN CARDIOVASCULAR & THORACIC ANNALS","volume":" ","pages":"188-195"},"PeriodicalIF":0.7000,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ASIAN CARDIOVASCULAR & THORACIC ANNALS","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1177/02184923251352222","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/7/3 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"Medicine","Score":null,"Total":0}
引用次数: 0
Abstract
BackgroundLeft heart failure is the most common cause of pulmonary hypertension and increases morbidity and mortality. We investigate the use of canagliflozin, an antidiabetic Sodium-glucose Cotransporter-2 Inhibitor, which is first-line therapy in congestive heart failure, on pulmonary fibrosis in a porcine model of chronic myocardial ischemia.MethodologySixteen Yorkshire swine, eight in a normal diet control arm (NDC) and eight in the canagliflozin arm (CAN), underwent left thoracotomy and ameroid constrictor placement on the left circumflex artery. Seven weeks after placement, the swine underwent harvest procedure. During harvest, left ventricular contractility was quantified by direct left ventricular pressure-volume loops. Protein expression was quantified by immunoblotting and Masson's trichrome staining was utilized to assess perivascular collagen deposition.ResultsAnalysis of left ventricular ejection fraction demonstrated no significant difference between CAN and NDC. Western blot analysis demonstrated increases in TGFβ signaling pathways with decreased free TGFβ and TGFβ monomers in CAN pigs (p < 0.01). Downstream mediators of TGFβ were also increased in NDC with an increase in phospho-SMAD2/3 activity (p = 0.005). Masson's Trichrome analysis of lung tissue demonstrated a trend toward reduced perivascular collagen deposition in CAN swine lungs (p = 0.086).ConclusionsCanagliflozin ameliorates chronic fibrotic changes related to pulmonary hypertension in left ventricular failure. While there was a strong trend toward significance in histologic analysis, this may be limited by the duration of our model. Western blot analysis, however, demonstrates that CAN's modulation of TGFβ signaling pathways may play a role in the management of secondary pulmonary hypertension.
期刊介绍:
The Asian Cardiovascular and Thoracic Annals is an international peer-reviewed journal pertaining to cardiovascular and thoracic medicine. Besides original clinical manuscripts, we welcome research reports, product reviews, reports of new techniques, and findings of special significance to Asia and the Pacific Rim. Case studies that have significant novel original observations, are instructive, include adequate methodological details and provide conclusions. Workshop proceedings, meetings and book reviews, letters to the editor, and meeting announcements are encouraged along with relevant articles from authors.