Abstract
Abstract Fri102: Ryanodine receptor 2 Dysfunction Triggers Cardiac Muscle Loss and Fibrofatty Infiltrations Consistent with Arrhythmogenic Cardiomyopathy in a Rabbit Model
Circulation research, Vol.137(Suppl_1), Fri102
08/01/2025
DOI: 10.1161/res.137.suppl_1.Fri102
Abstract
Background: Ryanodine receptor 2 (RyR2) dysfunction occurs early in Arrhythmogenic Cardiomyopathy (ACM), contributing to ventricular arrhythmia, but its role in subsequent structural remodeling remains unclear. While RyR2 mutations have been linked to ACM, this association has been disputed due to conflicting clinical data and the lack of appropriate animal models. Here, we present a RyR2-V2475F rabbit model that exhibits hallmark ACM features.
Methods: RyR2-V2475F New Zealand white rabbits were generated via CRISPR-Cas9. Cardiac function and structure changes were assessed in vivo and in vitro using histology, telemetry, echocardiography, Ca2+ imaging, and single-nucleus RNA sequencing (snRNA-seq).
Results: Sudden death (SD) occurred in 33% (28/84) of homozygous (Homo) rabbits, whereas no wild-type or heterozygotes littermates were affected. Hearts from SD rabbits exhibited right ventricular (RV)-dominant muscle loss and fibrofatty infiltration, initiating epicardially and progressing transmurally, closely resembling ACM. Ventricular tachycardia and SD occurred even before structural remodeling was evident. Echocardiography revealed early biventricular dilation, followed by RV specific contractile dysfunction. Isolated Homo cardiomyocytes (CMs) exhibited increased Ca2+ leak, reduced Ca2+ transient amplitude, and prolonged time to peak and decay. snRNA-seq identified early CM metabolic defects, including increased fatty acid uptake and impaired mitochondrial function, shifting toward inflammation and advanced disease stages. Fibroblasts (FBs) were initially proliferative but later transitioned to a fibrosis-producing phenotype, particularly in the RV, contributing to increased fibrosis.
Conclusion: The RyR2-V2475F rabbit is the first animal model of RyR2-induced ACM with RV-dominant muscle loss, fibrofatty infiltration, and lethal arrhythmias. RyR2 dysfunction and Ca2+ mishandling drive not only early arrhythmias but also progressive structural remodeling. Metabolic defects in CMs and RV-specific FB activation contribute to disease progression, providing mechanistic insights that may guide therapeutic strategies.
Details
- Title: Subtitle
- Abstract Fri102: Ryanodine receptor 2 Dysfunction Triggers Cardiac Muscle Loss and Fibrofatty Infiltrations Consistent with Arrhythmogenic Cardiomyopathy in a Rabbit Model
- Creators
- Jingjing Zheng - University of Wisconsin–MadisonDaniela PONCE-BALBUENA - University of Wisconsin–MadisonSergio Estrada - University of Wisconsin–MadisonLi Xiao - University of Wisconsin–MadisonClaudia Korcarz - University of Wisconsin–MadisonKristin Hansen - University of Wisconsin–MadisonHolly Dooge - University of Wisconsin–MadisonHector Valdivia - University of Wisconsin–MadisonFrancisco Alvarado - University of Wisconsin–Madison
- Resource Type
- Abstract
- Publication Details
- Circulation research, Vol.137(Suppl_1), Fri102
- DOI
- 10.1161/res.137.suppl_1.Fri102
- ISSN
- 0009-7330
- eISSN
- 1524-4571
- Publisher
- Lippincott Williams & Wilkins
- Language
- English
- Date published
- 08/01/2025
- Academic Unit
- Internal Medicine
- Record Identifier
- 9985178658102771
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