Load-Dependent Effects of Sodium Glucose Co-Transporter Inhibitors on Work in Human Hypertrophic Cardiomyopathy Living Myocardial Slices
Abstract
ABSTRACT:
Background: Disease modifying therapies for hypertrophic cardiomyopathy (HCM) remain a prevailing unmet need. Human-based experimental platforms capable of controlled manipulation of preload and afterload can distinguish direct myocardial and systemic effects and facilitate development of targeted cardiac therapeutics. Sodium glucose cotransporter inhibitors (SGLTi) may directly affect cardiac contractility, potentially related to increased ketone availability. These effects have not been adequately studied in human HCM myocardium under defined loading conditions.
Aims: We sought to establish human living myocardial slices (LMS) as a platform to interrogate load-dependent myocardial mechanics in HCM and to quantify the acute effects of metabolic and pharmacologic interventions—including SGLTi—on myocardial work under physiologic loading conditions.
Methods: Human myocardial tissue was procured from non-failing donor hearts or individuals with HCM undergoing septal myectomy. Freshly prepared human LMS were mechanically tested to generate biomimetic work loops across a range of physiologic preloads and afterloads in either glucose-only fuel or glucose supplemented with ketone. Following baseline measurements, slices were loaded with drug (isoproterenol, mavacamten, sotagliflozin, or empagliflozin) or vehicle (DMSO) and work loop analysis was repeated, allowing each slice to serve as its own control. Mixed effects linear regression models incorporating random effects…
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