Optogenetic Tachypacing-induced Heart Failure in Larval Zebrafish
Date
2023-07-25
Authors
Purvis, Katherine
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Abstract
Chronic tachypacing is commonly used in mammals to model heart failure (HF). Alternative methods of chronic tachypacing involving the use of light-activated ion channels (‘optogenetics’) have been explored in cultured heart tissue. However, this model lacks the complexity of native myocardium. Recent efforts have explored zebrafish as a model for human cardiac dysfunction based on their electrophysiological similarities. Larval zebrafish offer a particularly attractive tool as they are translucent, allowing for in vivo measurement of cardiac activity. A study by Kossack et al. (2017) investigated the use of larval zebrafish as a model for HF using chronic sympathetic stimulation with isoproterenol. Differences in the genetic response were found in comparison to mammalian models, which suggested different mechanisms of isoproterenol-induced cardiac dysfunction. This study aims to establish a model of chronic tachypacing-induced HF in larval zebrafish using optogenetics to potentially overcome these limitations. The effects of chronic optogenetic tachypacing of larval zebrafish hearts between 2 to 6 and 3 to 7 days post fertilization (dpf) with two opsins (channelrhodopsin-2, ChR2, and anion channelrhodopsin-1, ACR1) were compared. Furthermore, we investigated the effects of continuous and interval chronic tachypacing. To determine the effects of chronic optical tachypacing, we assessed changes in cardiac morphology, function, and gene expression. Cardiac morphology and function were measured from in vivo brightfield microscopic recordings, and morphology was further assessed using fluorescent microscopy. Changes in gene expression were quantified using qRT-PCR. It has been shown that chronic continuous tachypacing results in cardiac development defects, while interval pacing with ChR2-expressing larvae results in morphological changes reminiscent of HR. Furthermore, interval pacing led to an increase in mRNA levels of several markers for heart failure, including levels of ANP, BNP, and TGF-ß1, as well as the marker for hypertrophy, Myh6.
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Keywords
Optogenetics, Zebrafish, Heart failure, Tachypacing