Effects of Diet-induced Metabolic Syndrome on Cardiac Function and Angiogenesis in Response to Sodium-glucose Cotransporter-2 Inhibitor Canagliflozin

Introduction Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are antidiabetic medications that have been shown to decrease cardiovascular events and heart failure-related mortality in clinical studies. We attempt to examine the complex interplay between metabolic syndrome (MS) and the SGLT-2 inhibitor canagliflozin (CAN) in a clinically relevant model of chronic myocardial ischemia (CMI). Methods Twenty-one Yorkshire swine were fed a high-fat diet starting at six weeks of age to induce MS. At 11 weeks, all underwent placement of an ameroid constrictor around the left circumflex coronary artery to induce CMI. After two weeks, swine received either control (CON, n=11) or CAN 300 mg PO daily (n=10) for 5 weeks, whereupon all underwent terminal harvest. Results There was a significant increase in cardiac output and heart rate with a decrease in pulse pressure in the CAN group compared to CON (all p<0.05). The CAN group had a significant increase in capillary density (p=0.02). Interestingly, there was no change in myocardial perfusion or arteriolar density. CAN induced a significant increase in markers of angiogenesis, including p-eNOS, eNOS, VEGFR1, HSP70, and ERK (all p<0.05), plausibly resulting in capillary angiogenesis. Conclusions CAN treatment leads to a significant increase in capillary density and augmented cardiac function in a swine model of CMI in the setting of MS. This work further elucidates the mechanism of SGLT-2 inhibitors in patients with cardiac disease; however, more studies are needed to determine if this increase in capillary density plays a role in the improvements seen in clinical studies.