Canagliflozin Improves Myocardial Perfusion, Fibrosis, and Function in a Swine Model of Chronic Myocardial Ischemia
Background Sodium‐glucose cotransporter‐2 inhibitors are cardioprotective independent of glucose control, as demonstrated in animal models of acute myocardial ischemia and clinical trials. The functional and molecular mechanisms of these benefits in the setting of chronic myocardial ischemia are poo...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-01-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.122.028623 |
| _version_ | 1797905042912575488 |
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| author | Sharif A. Sabe Cynthia M. Xu Mohamed Sabra Dwight Douglas Harris Akshay Malhotra Ahmed Aboulgheit Madigan Stanley M. Ruhul Abid Frank W. Sellke |
| author_facet | Sharif A. Sabe Cynthia M. Xu Mohamed Sabra Dwight Douglas Harris Akshay Malhotra Ahmed Aboulgheit Madigan Stanley M. Ruhul Abid Frank W. Sellke |
| author_sort | Sharif A. Sabe |
| collection | DOAJ |
| description | Background Sodium‐glucose cotransporter‐2 inhibitors are cardioprotective independent of glucose control, as demonstrated in animal models of acute myocardial ischemia and clinical trials. The functional and molecular mechanisms of these benefits in the setting of chronic myocardial ischemia are poorly defined. The purpose of this study is to determine the effects of canagliflozin therapy on myocardial perfusion, fibrosis, and function in a large animal model of chronic myocardial ischemia. Methods and Results Yorkshire swine underwent placement of an ameroid constrictor to the left circumflex artery to induce chronic myocardial ischemia. Two weeks later, pigs received either no drug (n=8) or 300 mg sodium‐glucose cotransporter‐2 inhibitor canagliflozin orally, daily (n=8). Treatment continued for 5 weeks, followed by hemodynamic measurements, harvest, and tissue analysis. Canagliflozin therapy was associated with increased stroke volume and stroke work and decreased left ventricular stiffness compared with controls. The canagliflozin group had improved perfusion to ischemic myocardium compared with controls, without differences in arteriolar or capillary density. Canagliflozin was associated with decreased interstitial and perivascular fibrosis in chronically ischemic tissue, with reduced Jak/STAT (Janus kinase/signal transducer and activator of transcription) signaling compared with controls. In ischemic myocardium of the canagliflozin group, there was increased expression and activation of adenosine monophosphate‐activated protein kinase, decreased activation of endothelial nitric oxide synthase, and unchanged total endothelial nitric oxide synthase. Canagliflozin therapy reduced total protein oxidation and increased expression of mitochondrial antioxidant superoxide dismutase 2 compared with controls. Conclusions In the setting of chronic myocardial ischemia, canagliflozin therapy improves myocardial function and perfusion to ischemic territory, without changes in collateralization. Attenuation of fibrosis via reduced Jak/STAT signaling, activation of adenosine monophosphate‐activated protein kinase, and antioxidant signaling may contribute to these effects. |
| first_indexed | 2024-04-10T09:58:47Z |
| format | Article |
| id | doaj.art-57ce511c7c794b28b88ed7df1410e55d |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-04-10T09:58:47Z |
| publishDate | 2023-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-57ce511c7c794b28b88ed7df1410e55d2023-02-16T10:55:33ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802023-01-0112110.1161/JAHA.122.028623Canagliflozin Improves Myocardial Perfusion, Fibrosis, and Function in a Swine Model of Chronic Myocardial IschemiaSharif A. Sabe0Cynthia M. Xu1Mohamed Sabra2Dwight Douglas Harris3Akshay Malhotra4Ahmed Aboulgheit5Madigan Stanley6M. Ruhul Abid7Frank W. Sellke8Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital Alpert Medical School of Brown University, Rhode Island Hospital Providence RIDivision of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital Alpert Medical School of Brown University, Rhode Island Hospital Providence RIDivision of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital Alpert Medical School of Brown University, Rhode Island Hospital Providence RIDivision of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital Alpert Medical School of Brown University, Rhode Island Hospital Providence RIDivision of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital Alpert Medical School of Brown University, Rhode Island Hospital Providence RIDivision of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital Alpert Medical School of Brown University, Rhode Island Hospital Providence RIDivision of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital Alpert Medical School of Brown University, Rhode Island Hospital Providence RIDivision of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital Alpert Medical School of Brown University, Rhode Island Hospital Providence RIDivision of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital Alpert Medical School of Brown University, Rhode Island Hospital Providence RIBackground Sodium‐glucose cotransporter‐2 inhibitors are cardioprotective independent of glucose control, as demonstrated in animal models of acute myocardial ischemia and clinical trials. The functional and molecular mechanisms of these benefits in the setting of chronic myocardial ischemia are poorly defined. The purpose of this study is to determine the effects of canagliflozin therapy on myocardial perfusion, fibrosis, and function in a large animal model of chronic myocardial ischemia. Methods and Results Yorkshire swine underwent placement of an ameroid constrictor to the left circumflex artery to induce chronic myocardial ischemia. Two weeks later, pigs received either no drug (n=8) or 300 mg sodium‐glucose cotransporter‐2 inhibitor canagliflozin orally, daily (n=8). Treatment continued for 5 weeks, followed by hemodynamic measurements, harvest, and tissue analysis. Canagliflozin therapy was associated with increased stroke volume and stroke work and decreased left ventricular stiffness compared with controls. The canagliflozin group had improved perfusion to ischemic myocardium compared with controls, without differences in arteriolar or capillary density. Canagliflozin was associated with decreased interstitial and perivascular fibrosis in chronically ischemic tissue, with reduced Jak/STAT (Janus kinase/signal transducer and activator of transcription) signaling compared with controls. In ischemic myocardium of the canagliflozin group, there was increased expression and activation of adenosine monophosphate‐activated protein kinase, decreased activation of endothelial nitric oxide synthase, and unchanged total endothelial nitric oxide synthase. Canagliflozin therapy reduced total protein oxidation and increased expression of mitochondrial antioxidant superoxide dismutase 2 compared with controls. Conclusions In the setting of chronic myocardial ischemia, canagliflozin therapy improves myocardial function and perfusion to ischemic territory, without changes in collateralization. Attenuation of fibrosis via reduced Jak/STAT signaling, activation of adenosine monophosphate‐activated protein kinase, and antioxidant signaling may contribute to these effects.https://www.ahajournals.org/doi/10.1161/JAHA.122.028623canagliflozinchronic myocardial ischemiacoronary diseasecoronary microcirculationsodium glucose cotransporter 2 inhibitor |
| spellingShingle | Sharif A. Sabe Cynthia M. Xu Mohamed Sabra Dwight Douglas Harris Akshay Malhotra Ahmed Aboulgheit Madigan Stanley M. Ruhul Abid Frank W. Sellke Canagliflozin Improves Myocardial Perfusion, Fibrosis, and Function in a Swine Model of Chronic Myocardial Ischemia Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease canagliflozin chronic myocardial ischemia coronary disease coronary microcirculation sodium glucose cotransporter 2 inhibitor |
| title | Canagliflozin Improves Myocardial Perfusion, Fibrosis, and Function in a Swine Model of Chronic Myocardial Ischemia |
| title_full | Canagliflozin Improves Myocardial Perfusion, Fibrosis, and Function in a Swine Model of Chronic Myocardial Ischemia |
| title_fullStr | Canagliflozin Improves Myocardial Perfusion, Fibrosis, and Function in a Swine Model of Chronic Myocardial Ischemia |
| title_full_unstemmed | Canagliflozin Improves Myocardial Perfusion, Fibrosis, and Function in a Swine Model of Chronic Myocardial Ischemia |
| title_short | Canagliflozin Improves Myocardial Perfusion, Fibrosis, and Function in a Swine Model of Chronic Myocardial Ischemia |
| title_sort | canagliflozin improves myocardial perfusion fibrosis and function in a swine model of chronic myocardial ischemia |
| topic | canagliflozin chronic myocardial ischemia coronary disease coronary microcirculation sodium glucose cotransporter 2 inhibitor |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.122.028623 |
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