• Dwight D Harris, Sharif A Sabe, Mark Broadwin, Christopher Stone, Akshay Malhotra, Cynthia M Xu, Mohamed Sabra, M Ruhul Abid, and Frank W Sellke.
• From the Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI.
• J. Am. Coll. Surg. 2024 Jan 30.

BackgroundAlthough sodium-glucose cotransporter-2 (SGLT-2) inhibitors have been shown to improve cardiovascular outcomes in general, little is presently known about any sex-specific changes that may result from this therapy. We sought to investigate and quantify potential sex-specific changes seen with the SGLT-2 inhibitor canagliflozin (CAN) in a swine model of chronic myocardial ischemia.Study DesignEighteen Yorkshire swine underwent left thoracotomy with placement of an ameroid constrictor. Two weeks post-op, swine were assigned to receive either control (F=5, M=5), or CAN 300 mg daily (F=4, M=4). Following five weeks of therapy, swine underwent myocardial functional measurements and myocardial tissue was sent for proteomic analysis.ResultsFunctional measurements showed increased cardiac output, stroke volume, ejection fraction, and ischemic myocardial flow at rest in CAN males compared to control males (all p<0.05). The CAN females had no change in cardiac function when compared to control. Proteomic analysis demonstrated six total up-regulated and 97 down-regulated proteins in the CAN female group compared to the female control. Pathway analysis showed decreases in proteins in the tricarboxylic acidic cycle. The CAN male group had 639 up-regulated and 172 down-regulated proteins compared to male control. Pathway analysis showed increases in pathways related to cellular metabolism and decreases in pathways relevant to the development of cardiomyopathy and to oxidative phosphorylation.ConclusionsMales treated with CAN had significant improvements in cardiac function that were not observed in females. Moreover, CAN treatment in males was associated with significantly more changes in protein expression than in females. The increased proteomic changes seen in the male CAN group likely contributed to the more robust changes in cardiac function seen in males treated with CAN.Copyright © 2024 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.

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