Sodium-Glucose Cotransporter-2 Inhibition Normalizes Metabolic Derangements in the Ischemic Myocardium

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have shown efficacy in the context of heart failure but have not been well-studied in ischemic heart disease. We employed a large animal model of chronic coronary artery disease and metabolic syndrome (MS) to investigate the hemodynamic and metabolic consequences of SGLT2i administration.

Thirty-eight Yorkshire swine were divided into two groups, with half (n = 21) receiving a high fat diet to induce MS, and the other half fed a standard diet (n = 17). All animals underwent thoracotomy for ameroid constrictor placement over the left circumflex coronary artery. Treatment with SGLT2i was then initiated, generating four groups: regular diet placebo (CON, n = 9), regular diet canagliflozin (n = 8), high-fat control (n = 11), and high-fat canagliflozin (n = 10). After 5 wks, all animals underwent terminal myocardial harvest with pressure-volume loop acquisition, perfusion studies, and tissue resection for molecular analysis.

SGLT2i improved multiple measures of myocardial performance, including a nearly 1.5-fold increase in both cardiac output and ejection fraction; these changes were associated with augmented capillary density and a twofold increase perfusion to the ischemic myocardium. These augmentations were blunted; however, in the presence of MS, and associated with modulated myocardial expression of multiple major metabolic enzymes.

SGLT2i significantly improved cardiac function in our large animal model of coronary artery disease, with metabolic modulation of the myocardial tissue serving as a candidate account of these changes. The blunting seen with MS underscores the dependence of clinical translatability on faithful representation of the biochemical environment of human disease.