Optogenetic-Based Models of Arrhythmia-Induced Cardiomyopathy in Larval Zebrafish
Date
2025-06-19
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Arrhythmia-induced cardiomyopathy (AiCM) has recently emerged as a distinct subset of cardiomyopathy, resulting from chronic tachycardia or high ectopic burden, which leads to structural and functional changes in the heart. Traditional experimental models of AiCM rely on invasive techniques, such as implantable pacemakers, which are low-throughput and technically challenging. In contrast, optogenetics allows for light-based cardiac pacing, which, in transparent zebrafish larvae, offers a non-invasive, high-throughput platform for studying AiCM and identifying novel pharmacological treatments. In this study, we aimed to develop in vivo optogenetic models of AiCM using larval zebrafish to investigate the effects of arrhythmias on cardiac function, structure, and gene expression. We utilized zebrafish with cardiac-specific expression of cation-nonspecific channelrhodopsin-2 (ChR2) or chloride-specific anion channelrhodopsin-1 (ACR1) and exposed them to three arrhythmia protocols: intermittent tachypacing, a 33% ectopic burden, or a 50% ectopic burden through programmed light pulses at 2-7 days post-fertilization. GFP-expressing zebrafish exposed to the same light patterns served as controls. The mechanical function of the atrium and ventricle was assessed in live zebrafish at 7 dpf through brightfield recordings, while structural changes were evaluated in fixed samples using fluorescent microscopy. Additionally, we examined the expression of genetic biomarkers associated with cardiomyopathy using qRT-PCR. Our findings revealed that both tachypacing and ectopic pacing induced significant changes in cardiac structure, function, and gene expression. Intermittent tachypacing induced the most severe dysfunction, followed by the 50% ectopic burden and 33% ectopic burden. Across all protocols, ChR2-expressing fish showed more pronounced changes than ACR1-expressing fish. Specifically, both tachypacing and ectopic pacing resulted in increased end-diastolic area (EDA), end systolic area (ESA), stroke area (SA), and decreased ejection fraction (EF), with changes in gene expression indicative of chamber wall stretch, hypertrophy, inflammation, and fibrosis. To explore the therapeutic potential of this model, we tested the effects of fimasartan on tachypacing-induced dysfunction. Preliminary results demonstrated that 50µM fimasartan improved cardiac function and attenuated structural remodeling in the zebrafish heart, highlighting the potential of this model as a high-throughput platform for therapeutic drug screening.
Description
Keywords
Cardiomyopathy