Canagliflozin Improves Myocardial Perfusion, Fibrosis, and Function in a Swine Model of Chronic Myocardial Ischemia

Abstract

Background Sodium‐glucose cotransporter‐2 inhibitors are cardioprotective independent of glucose control, as demonstrated in animal models of acute myocardial ischemia and clinical trials. The functional and molecular mechanisms of these benefits in the setting of chronic myocardial ischemia are poorly defined. The purpose of this study is to determine the effects of canagliflozin therapy on myocardial perfusion, fibrosis, and function in a large animal model of chronic myocardial ischemia. Methods and Results Yorkshire swine underwent placement of an ameroid constrictor to the left circumflex artery to induce chronic myocardial ischemia. Two weeks later, pigs received either no drug (n=8) or 300 mg sodium‐glucose cotransporter‐2 inhibitor canagliflozin orally, daily (n=8). Treatment continued for 5 weeks, followed by hemodynamic measurements, harvest, and tissue analysis. Canagliflozin therapy was associated with increased stroke volume and stroke work and decreased left ventricular stiffness compared with controls. The canagliflozin group had improved perfusion to ischemic myocardium compared with controls, without differences in arteriolar or capillary density. Canagliflozin was associated with decreased interstitial and perivascular fibrosis in chronically ischemic tissue, with reduced Jak/STAT (Janus kinase/signal transducer and activator of transcription) signaling compared with controls. In ischemic myocardium of the canagliflozin group, there was increased expression and activation of adenosine monophosphate‐activated protein kinase, decreased activation of endothelial nitric oxide synthase, and unchanged total endothelial nitric oxide synthase. Canagliflozin therapy reduced total protein oxidation and increased expression of mitochondrial antioxidant superoxide dismutase 2 compared with controls. Conclusions In the setting of chronic myocardial ischemia, canagliflozin therapy improves myocardial function and perfusion to ischemic territory, without changes in collateralization. Attenuation of fibrosis via reduced Jak/STAT signaling, activation of adenosine monophosphate‐activated protein kinase, and antioxidant signaling may contribute to these effects.

Proteomic Profiling of SGLT-2 Inhibitor Canagliflozin in a Swine Model of Chronic Myocardial Ischemia

“…This study is a continuation of our previously published swine cohort that received a regular diet [ 19 ]. Sixteen 11-week-old Yorkshire swine (Cummings School of Veterinary Medicine of Tufts University Farm, North Grafton, MA, USA) arrived at our facility at 9 weeks of age.…”

“…To increase our knowledge of how SGLT-2 inhibition improves cardiac function, our lab chose to extensively study SGLT2 inhibitors in chronic myocardial ischemia using a swine model of chronic myocardial ischemia [ 19 ]. We previously demonstrated several remarkable changes with this model, including increased myocardial function, improved coronary perfusion, and decreased myocardial fibrosis [ 19 ].…”

“…To increase our knowledge of how SGLT-2 inhibition improves cardiac function, our lab chose to extensively study SGLT2 inhibitors in chronic myocardial ischemia using a swine model of chronic myocardial ischemia [ 19 ]. We previously demonstrated several remarkable changes with this model, including increased myocardial function, improved coronary perfusion, and decreased myocardial fibrosis [ 19 ]. We also began to elucidate the molecular underpinnings of these functional benefits, having already demonstrated modulations in angiogenic signaling, insulin signaling, and myocardial inflammation following treatment with the SGLT-2 inhibitor canagliflozin (CAN) [ 20 , 21 ].…”

One Billion hiPSC-Cardiomyocytes: Upscaling Engineered Cardiac Tissues to Create High Cell Density Therapies for Clinical Translation in Heart Regeneration

“…Two Yorkshire swine (male and female; Tufts University, Medford, MA, USA), aged 8 to 10 weeks and weighing between 22 and 25 kg at the time of the initial procedure, were used. This pilot study was designed to assess technical feasibility using an established model of chronic myocardial ischemia developed by Dr. Sellke as previously described [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44]. To induce chronic ischemia, a small left thoracotomy was performed, the pericardium was opened, and an ameroid constrictor composed of hygroscopic casein material cased in titanium (Research Instruments SW, Escondido, CA, USA) was sized and placed around the proximal left circumflex (LCX) coronary artery (Figure 2B).…”

Post-myocardial infarction fibrosis: Pathophysiology, examination, and intervention

“…In experimental studies and clinical trials, it has been demonstrated that SGLT2is are cardioprotective independently from controlling glucose, for instance, canagliflozin attenuates fibrosis via reducing JAK/STAT signaling, activating adenosine monophosphate-activated protein kinase, and antioxidant signaling ( Sabe et al, 2023 ). In clinical practice, empagliflozin can significantly reduce mortality and hospitalization of HF patients ( Kang et al, 2020 ).…”