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J. Thorac. Cardiovasc. Surg. · Dec 2023
Canagliflozin improves coronary microvascular vasodilation and increases absolute blood flow to the myocardium independent of angiogenesis.
- Debolina Banerjee, Sharif A Sabe, Hang Xing, Cynthia Xu, Mohamed Sabra, Dwight D Harris, Mark Broadwin, M Ruhul Abid, Anny Usheva, Jun Feng, and Frank W Sellke.
- Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI.
- J. Thorac. Cardiovasc. Surg. 2023 Dec 1; 166 (6): e535e550e535-e550.
ObjectivesSodium-glucose cotransporter-2 inhibitor, canagliflozin, improves myocardial perfusion to ischemic territory without accompanying changes in vascular density. We aimed to (1) characterize effects on angiogenic pathways, (2) use multiomics to identify gene expression and metabolite profiles relevant to regulation of myocardial blood flow, and (3) investigate drug effect on coronary microvascular reactivity.MethodsA nondiabetic swine model of chronic myocardial ischemia and nondiabetic rat model were used to study functional and molecular effects of canagliflozin on myocardium and in vitro microvascular reactivity.ResultsCanagliflozin resulted in increased coronary microvascular vasodilation and decreased vasoconstriction (P < .05) without changes in microvascular density (P > .3). Expression of the angiogenic modulator, endostatin, increased (P = .008), along with its precursor, collagen 18 (P < .001), and factors that increase its production, including cathepsin L (P = .004). Endostatin and collagen 18 levels trended toward an inverse correlation with blood flow to ischemic territory at rest. Proangiogenic fibroblast growth factor receptor was increased (P = .03) and matrix metalloproteinase-9 was decreased (P < .001) with canagliflozin treatment. Proangiogenic vascular endothelial growth factor A (P = .13), Tie-2 (P = .10), and Ras (P = .18) were not significantly altered. Gene expression related to the cardiac renin-angiotensin system was significantly decreased.ConclusionsIn chronic myocardial ischemia, canagliflozin increased absolute blood flow to the myocardium without robustly increasing vascular density or proangiogenic signaling. Canagliflozin resulted in altered coronary microvascular reactivity to favor vasodilation, likely through direct effect on vascular smooth muscle. Downregulation of cardiac renin-angiotensin system demonstrated local regulation of perfusion. VIDEO ABSTRACT.Copyright © 2023 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.
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