Proteomic Analysis Reveals Sex Specific Changes in Chronically Ischemic Swine Myocardium Treated with Sodium-glucose Cotransporter-2 Inhibitor Canagliflozin
Dwight D. Harris*, Sharif A. Sabe, Mark Broadwin, Cynthia Xu, Mohamed Sabra, M. Ruhul Abid, Frank Sellke
Division of Cardiothoracic Surgery, Department of Surgery, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI
Objective:
Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a relatively new class of antidiabetic medications that have been shown to decrease cardiovascular events and heart failure readmissions independent of diabetes mellitus. We have previously demonstrated increased cardiac function and coronary perfusion with SGLT2 inhibitor canagliflozin (CAN) treatment in a swine model for chronic myocardial ischemia. CAD is known to have many sex specific differences; However, little is known about the sex specific changes seen with SGLT-2 inhibitor therapy. The objective of this study is to investigate the sex specific changes with CAN treatment using a swine model of chronic myocardial ischemia.
Design:
Non-randomized control trial, large animal model using Yorkshire swine
Setting:
Academic medical center animal facility
Patients:
Sixteen 11-week-old Yorkshire swine
Interventions:
Sixteen 11-week-old Yorkshire swine underwent placement of an ameroid constrictor on the left circumflex artery to model chronic myocardial ischemia. After two weeks of recovery, swine were assigned to received either control (CON, F=3, M=5, n=8) or 300mg of canagliflozin daily (F=4, M=4, n=8). After five weeks, swine were sedated for functional measurements and euthanized. Ischemic myocardium from the left circumflex territory was sent for total proteomic analysis.
Main Outcome Measure:
Total proteomic analysis of ischemic myocardium
Secondary outcome:
Cardiac function and coronary perfusion
Results: Proteomic analysis of ischemic myocardium quantified 3,256 proteins. There were 97 down-regulated proteins and six total up-regulated in the female CAN group compared to the female CON group (all p<0.05). Pathway analysis showed decreases in proteins involved in nuclear transport, and tricarboxylic acid cycle. The male CAN group had 172 down-regulated and 639 up-regulated proteins when compared to the male control (all p<0.05). Pathway analysis showed increases in pathways contributing to glycolysis, complex carbohydrate metabolism, and amino acid metabolism, and decreases in pathways contributing to dilated cardiomyopathy and hypertrophic cardiomyopathy. Functional measurements showed males treated with CAN had increase in cardiac output, stroke volume, ejection fraction, and ischemic flow rest compared to CON males (all p<0.05). Females treated with CAN had no change in cardiac output, stroke volume, ejection fraction, and ischemic flow rest compared to CON females (all p>0.05, Figure 1).
Conclusions: Males treated with CAN had significant improvements in cardiac function that was not demonstrated in females. CAN treatment was associated with significantly more changes in protein expression in ischemic male myocardium compared to female, including decreased protein expression in pathways contributing to cardiomyopathy. The increased proteomic changes seen with male CAN likely contribute to the more robust changes in cardiac function seen in males treated with CAN.
Figure 1: Functional Data. Males treated with canagliflozin had increase in cardiac output, stroke volume, ejection fraction, and ischemic flow rest compared to control. Females treated with canagliflozin had no change in cardiac output, stroke volume, ejection fraction, and ischemic flow rest compared to control. CAN-F, canagliflozin female; CAN-M, canagliflozin male; CON-F, control female; CON-M, control male. *p<0.05, **p<0.01, ***p<0.001
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