Effects of Sodium Glucose Co-Transporter Inhibitors on Work in Human Hypertrophic Cardiomyopathy Living Myocardial Slices

BackgroundDisease modifying therapies for heart diseases, including hypertrophic cardiomyopathy (HCM) are a prevailing unmet need. Human-based drug testing platforms capable of distinguishing direct myocardial and systemic effects are needed to enable targeted cardiac therapeutics. Sodium glucose cotransporter inhibitors (SGLTi) may have direct effects on cardiac contractility but have not been adequately studied in human tissues in the context of HCM. MethodsHuman myocardial tissues were procured from non-failing donor hearts or patients with HCM undergoing septal myectomy. Human living myocardial slices (LMS) were freshly prepared and mechanically tested to generate biomimetic work loops across a range of physiologic preloads and afterloads, before and after loading with drug (isoproterenol, mavacamten, sotagliflozin, or empagliflozin) or vehicle (DMSO). Mixed effects linear regression modeling accounting for clinical characteristics of patient tissue samples were generated across prespecified preloads and afterloads for baseline work loops and following drug exposure, permitting correlation between myocardial work and clinical characteristics, underlying disease, fuel source, and drug treatment. By repeating work loop analysis following drug administration, each slice acted as its own control. ResultsA total of 120 hLMS from 32 patients (16 non-failing and 16 HCM) were analyzed. Younger age, presence of hypertension, and ejection fraction was positively associated with hLMS work. Ketone supplementation augmented work and work-strain slope particularly in HCM hLMS at high afterloads. We validated our drug testing methodology by demonstrating known positive inotropy of isoproterenol, negative contractile effects of mavacamten particularly in the context of HCM, and null effect of DMSO vehicle. Finally, we tested sotagliflozin or empagliflozin and showed that SGLTis acutely and directly reduce myocardial work, with increased potency of sotagliflozin at high afterloads. ConclusionsOur findings validate a human tissue-based platform to test pharmacologic agents at predefined and physiologic preloads and afterloads, providing insight into the direct effects of SGLTi on human HCM myocardium. We demonstrate that SGLTi and ketones have distinct and discordant effects on human myocardial contractility.