Abstract 14641: Diastolic Dysfunction “In a Dish“- A Novel Organoid Model of Heart Failure With Preserved Ejection Fraction
IntroductionHeart 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 usin...
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| Published in: | Circulation (New York, N.Y.) Vol. 146; no. Suppl_1; p. A14641 |
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| Main Authors: | , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
Lippincott Williams & Wilkins
08-11-2022
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| Online Access: | Get full text |
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| Summary: | IntroductionHeart 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. MethodsHuman 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 HFpEFhigh 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. ResultsExposure 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. DiscussionCardiac 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. |
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| ISSN: | 0009-7322 1524-4539 |
| DOI: | 10.1161/circ.146.suppl_1.14641 |