Sex-Specific Improvements in Myocardial Function and Angiogenesis in a Swine Model of Metabolic Syndrome and Chronic Myocardial Ischemia with SGLT-2 Inhibitor Canagliflozin
*Dwight D. Harris , *Mark Broadwin MD, *Christopher Stone MD, *Sharif A. Sabe MD, *Meghamsh Kanuparthy MD, *Ju-woo Nho , *Jiayu Hu , *M. Ruhul Abid MD PhD, Frank Sellke MD
Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI
Background: Although coronary artery disease (CAD) is known to be a highly sex-specific disease, the study of sex-specific therapeutic responses remains underrepresented in the literature. Sodium-glucose transporter 2 (SGLT2) inhibitors are antidiabetic medications that have shown promise in the treatment of CAD in both clinical and pre-clinical models; however, little is known about the sex-specific response to these drugs. Accordingly, we assessed the sex-differential response to the SGLT-2 inhibitor canagliflozin (CAN) in a swine model of chronic myocardial ischemia and metabolic syndrome (MS).
Study Design:Twenty-one Yorkshire swine were fed a high-fat diet starting at the age of 6 weeks to induce metabolic syndrome (MS). All swine then underwent left thoracotomy for placement of an ameroid constrictor at 11 weeks to model chronic myocardial ischemia. After two weeks, swine were assigned to either the control group (CON, F=6, M=5) or CAN 300 mg daily (F=5, M=5). After 5 weeks of therapy, swine underwent terminal harvest with functional measurements. Immunofluorescent staining was used to determine capillary and arteriolar density. Protein expression was quantified with immunoblotting.
Results:There were significant increases in cardiac output and stroke volume (p<0.001, p=0.047) treated with CAN that were not seen in females. Effective arterial elastance a marker for afterload was decreased in CAN males compared to control males. CAN males exhibited a strong trend towards increased stroke work and ejection fraction (p=0.07, p=0.06) that was also not observed in CAN females. CAN females exhibited a significant increase in capillary density in the ischemic myocardium compared to CON females (p=0.01); this was not seen in CAN males. Immunoblotting demonstrated a significant increase in ERK in the CAN male ischemic myocardium (p=0.01) not seen in CAN females. There was a trend toward increased p-eNOS and a significant increase in the ratio of p-eNOS to total eNOS in the CAN male ischemic myocardium (p=0.17, p=0.04) that was not replicated in CAN females. There was no significant change in myocardial perfusion, interstitial fibrosis, perivascular fibrosis, PI3K, NOX 1, SOD 2, and arteriolar density by sex (all p>0.10).
Conclusions:Males treated with CAN showed improved cardiac function based on increased cardiac output, stroke volume, and afterload reduction, with trends towards increased stroke work and ejection fraction. These changes were accompanied by favorable alterations in nitric oxide signaling and ERK signaling in the ischemic myocardium. Females treated with CAN exhibited increased capillary density in the ischemic myocardium. These changes demonstrate that CAN treatment produces sex-specific changes in myocardial function and angiogenesis. This provides targets for further investigation in animal models and humans treated with SGLT-2 inhibitors, and may help guide research into sex-specific treatment modalities for ischemic heart disease.
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