Abstract 14641: Diastolic Dysfunction “In a Dish“- A Novel Organoid Model of Heart Failure With Preserved Ejection Fraction

Abstract

Introduction: Heart failure with preserved ejection fraction (HFpEF) is a major cause of mortality. No therapies have shown a survival benefit in HFpEF. A potential reason may be the lack of an in-vitro model for identifying novel therapeutic targets. Here, we aimed at generating a model of HFpEF using engineered cardiac organoids. Methods: Human cardiomyocytes generated from human-induced pluripotent stem cells were used to form 3D cardiac organoids. The organoids were exposed to conditions mimicking the comorbid conditions (Diabetes, hypertension, obesity, inflammation) leading to HFpEF: high glucose media with insulin deprivation; pro-fibrotic and hypertrophic stimuli such as Angiotensin II and Endothelin-1; free fatty acids, and pro-inflammatory factors ( e.g., IL-1 ). The passive stiffness, active contractile forces, and tau (relaxation constant) were evaluated using a force-transducer and a length controller. Structural and molecular phenotyping were conducted as well. Results: Exposure to HFpEF-inducing media resulted in single cells hypertrophy with an increase of average cell size (6670.87±1363.86 um^2) in comparison to control media (2840.56±520.70 um^2). The generated organoids exposed to HFpEF media developed a significant increase in passive force of 7.35±2.47 N/m vs. 2.04±0.85 N/m for control. Relaxation was prolonged in the HFpEF media and resulted in an increased ratio of 1.87±0.21 of relaxation constant, tau, in comparison to baseline and no modulation of tau in the control (1.08± 0.08 ). Structural and molecular evaluation showed characteristic HFpEF phenotype. Discussion: Cardiac organoids can recapitulate HFpEF phenotypes such as the increase in passive force, elongation of diastole, hypertrophy, and no change in the active force. An HFpEF in-vitro model may provide an unprecedented insight into the early pathogenetic mechanisms involved in HFpEF and may serve as a high-throughput platform for drug discovery.