Abstract 4144253: Sotagliflozin Reduces Contractile Work In Human Living Myocardial Slices

Introduction: Sodium glucose co-transporter inhibitors (SGLTi) are a class of medication with clinical benefit in heart failure regardless of subgroup. It has been postulated that SGLTi may have direct effects on the heart in addition to known systemic effects. One potential cardioprotective mechanism of SGLTi is through direct modulation of cardiac tissue mechanics, which few studies have investigated. New tissue slice platforms offer the potential to test impact of compounds on contractility but have not been fully validated. We sought first to establish the ability for human living myocardial slices (LMS) to recapitulate known disease-related and drug-related effects on biomimetic work loop parameters. We then assessed whether SGLTi directly and acutely affect LMS contractility. Methods: Vibratome-generated 300µm-thick slices of left ventricular tissue from non-failing donor hearts (N=10), failing hearts (N=4), and hypertrophic cardiomyopathy (HCM) septal myectomy tissue (N=7) were adhered to 8x8mm anchors and mounted onto the IonOptix Cardiac Slice System. We generated force-length work loops at varying preloads (4-16% strain) and afterloads (25-75% active force). Drug (sotagliflozin 10µM, isoproterenol 5µM, mavacamten 1µM) or vehicle (DMSO) was washed in and work loops were repeated. Results: HCM slices performed more work at baseline compared to nonfailing slices. Across groups, slices demonstrated an increase in total work in response to isoproterenol (known positive inotrope) and a decrease in total work in response to mavacamten (known negative inotrope). Sotagliflozin significantly reduced total work done by slices at a given load. Conclusions: We developed a rigorous and reproducible methodology for phenotyping contractile behavior, including biomimetic work loops, in freshly prepared human LMS at multiple preloads and afterloads. SGLTi acutely and directly reduced the total work performed in human myocardial tissue. Future work is focused on the mechanisms by which SGLTi directly impact contractility.