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Sex-Specific Improvements in Myocardial Function and Angiogenesis with SGLT-2 Inhibitor Canagliflozin in a Swine
Dwight D Harris1, Mark Broadwin1, Christopher Stone1
1Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Alpert Medical School of Brown University, Brown University Health, 2 Dudley Street, MOC 360, Providence, RI 02905, USA.
Abstract:
There is a significant body of literature to suggest that coronary artery disease (CAD) is a highly sex-specific disease. The study of sex-specific therapeutics and sex-specific responses to treatment for CAD remains underreported in the literature. Sodium-glucose transporter 2 (SGLT2) inhibitors are of growing interest in the treatment of ischemic heart disease and heart failure; however, the sex-specific response to SGLT2 inhibitors is unknown. We studied an SGLT2 inhibitor, canagliflozin, in a swine model of metabolic syndrome (MS) and chronic myocardial ischemia with emphasis on the sex-specific outcomes. Yorkshire swine (n = 21) were obtained at 6 weeks of age and fed a high-fat diet to induce MS. Left thoracotomy was performed on all swine at 11 weeks of age for the placement of an ameroid constrictor to model chronic myocardial ischemia. Swine recovered for two weeks, then were assigned to either the drug group, CAN 300 mg daily group (M = 5, F = 5), or the control group (CON, M = 5, F = 6). Both groups received 5 weeks of therapy. After completion of therapy, swine underwent functional assessment and terminal harvest. The male animals treated with CAN (CAN-M) had significant increases in stroke volume and cardiac output (p = 0.047, p < 0.001) compared to control males (CON-M), which were not seen in females treated with CAN (CAN-F) compared to control females (CON-F). Effective arterial elastance was decreased in CAN-M compared to CON-M. The CAN-F group had a significant increase in ischemic myocardial capillary density compared to CON-F (p = 0.04). There was no difference in capillary density between the CAN-M and CON-M groups. CAN treatment resulted in sex-specific changes in angiogenesis and myocardial function. The CAN-M group had significant improvements in cardiac function based on afterload reduction, stroke volume, and increased cardiac output not seen in the CAN-F group. The CAN-F group had increased ischemic myocardial capillary density. These findings provide a foundation for further investigation of the sex-specific effects of SGLT-2 inhibitors in humans.
Insights
Sodium-glucose transporter 2 (SGLT2) inhibitors like canagliflozin show sex-specific effects in treating heart conditions. Male pigs improved cardiac function, while females showed increased blood vessel growth in the heart.
Area of Science:
- Cardiology
- Pharmacology
- Sex-Specific Medicine
Background:
- Coronary artery disease (CAD) exhibits significant sex-specific characteristics.
- Research on sex-specific treatments and responses for CAD is limited.
- Sodium-glucose transporter 2 (SGLT2) inhibitors are emerging treatments for ischemic heart disease and heart failure, but their sex-specific effects are unknown.
Purpose of the Study:
- To investigate the sex-specific outcomes of the SGLT2 inhibitor canagliflozin in a swine model of metabolic syndrome and chronic myocardial ischemia.
- To determine if canagliflozin impacts cardiac function and myocardial angiogenesis differently between male and female subjects.
Main Methods:
- A swine model was established by inducing metabolic syndrome with a high-fat diet and chronic myocardial ischemia via ameroid constrictor placement.
- Swine were treated with canagliflozin (CAN) or a control (CON) for five weeks.
- Functional assessments and terminal harvests were performed to evaluate sex-specific outcomes.
Main Results:
- Male pigs treated with canagliflozin (CAN-M) showed significant increases in stroke volume and cardiac output compared to control males (CON-M).
- Effective arterial elastance decreased in CAN-M compared to CON-M, indicating improved cardiac function.
- Female pigs treated with canagliflozin (CAN-F) exhibited a significant increase in ischemic myocardial capillary density compared to control females (CON-F), unlike males.
Conclusions:
- Canagliflozin treatment induced distinct sex-specific changes in angiogenesis and myocardial function.
- Male subjects experienced enhanced cardiac function through afterload reduction and increased cardiac output.
- Female subjects demonstrated increased myocardial capillary density, suggesting a different therapeutic mechanism.
