In vivo recording of adult zebrafish electrocardiogram and assessment of drug-induced QT prolongation

Milan, David J.; Jones, Ian; Ellinor, Patrick T.; MacRae, Calum A.

doi:10.1152/ajpheart.00960.2005

Cited by 209 publications

(235 citation statements)

References 17 publications

(17 reference statements)

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“…To determine whether heterozygous fish, like their human LQT2 counterparts, are especially sensitive to I Kr -blocking drugs, we bathed 48 hpf embryos with terfenadine (24). At increasing concentrations, terfenadine causes bradycardia, a 2:1 atrioventricular block, and ultimately ventricular asystole in embryonic zebrafish hearts (11,16,25). For these experiments, high concentrations of terfenadine were required to observe an effect given that the compound must diffuse through the embryo.…”

Section: Homozygous Kcnh2 Mutant Embryonic Ventricle Does Not Generatementioning

confidence: 99%

“…5b) using a protocol similar to that reported by Milan et al (11). The QT interval is a measure of the duration of ventricular repolarization and is defined as the time from the upstroke of the QRS complex (the onset of depolarization) to the end of the T wave (termination of repolarization).…”

Section: Homozygous Kcnh2 Mutant Embryonic Ventricle Does Not Generatementioning

confidence: 99%

“…Electrocardiograms were performed on adult zebrafish by using a protocol modified from Milan et al (11). The fish were anesthetized by immersion in 0.02% tricaine solution and placed ventral surface up in the recording chamber.…”

Section: Measurement Of Electrocardiogramsmentioning

confidence: 99%

“…For example, embryonic and adult heart rates are similar to those of humans (10,11), and the relationship between QT interval and heart rate parallels that of humans (11). Forward-genetic screens using zebrafish have identified many cardiovascular mutants for analysis (12,13), thereby revealing critical pathways in cardiovascular development that parallel those of higher vertebrates (14).…”

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confidence: 99%

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Zebrafish model for human long QT syndrome

Arnaout

Ferrer

Huisken

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

215

212

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Long QT syndrome (LQTS) is a disorder of ventricular repolarization that predisposes affected individuals to lethal cardiac arrhythmias. To date, an appropriate animal model of inherited LQTS does not exist. The zebrafish is a powerful vertebrate model used to dissect molecular pathways of cardiovascular development and disease. Because fundamental electrical properties of the zebrafish heart are remarkably similar to those of the human heart, the zebrafish may be an appropriate model for studying human inherited arrhythmias. Here we describe the molecular, cellular, and electrophysiological basis of a zebrafish mutant characterized by ventricular asystole. Genetic mapping and direct sequencing identify the affected gene as kcnh2, which encodes the channel responsible for the rapidly activating delayed rectifier K ؉ current (IKr). We show that complete loss of functional IKr in embryonic hearts leads to ventricular cell membrane depolarization, inability to generate action potentials (APs), and disrupted calcium release. A small hyperpolarizing current restores spontaneous APs, implying wildtype function of other ionic currents critical for AP generation. Heterozygous fish manifest overt cellular and electrocardiographic evidence for delayed ventricular repolarization. Our findings provide insight into the pathogenesis of homozygous kcnh2 mutations and expand the use of zebrafish mutants as a model system to study human arrhythmias.cardiac ͉ development ͉ kcnh2 ͉ arrhythmia ͉ electrophysiology A utosomal dominant KCNH2 mutations account for Ϸ45% of mutation-positive long QT syndrome (LQTS) (1, 2). Recessive KCNH2 mutations are rarely reported, implying that most homozygous mutations are embryonic-lethal (3, 4). The cellular mechanisms underlying embryonic lethality are not known. Although LQTS has been extensively characterized in humans, establishing an animal model would be helpful to identify genes that modify phenotypic expressivity or to screen against compounds that cause acquired forms of LQTS. To date, an appropriate animal model of inherited LQTS does not exist. Transgenic strategies and targeted deletion of genes that regulate rapidly activating delayed rectifier K ϩ current (I Kr ) and slow delayed rectifier K ϩ current (I Ks ) in mice fail to produce a significant phenotype (5-7). The mouse heart rate is nearly 10 times faster than that of humans, and thus a distinct cadre of ion channels facilitates ventricular repolarization in mice (5-8).Although the zebrafish heart is two-chambered, its fundamental electrical properties are remarkably similar to those of humans (9). For example, embryonic and adult heart rates are similar to those of humans (10, 11), and the relationship between QT interval and heart rate parallels that of humans (11). Forward-genetic screens using zebrafish have identified many cardiovascular mutants for analysis (12, 13), thereby revealing critical pathways in cardiovascular development that parallel those of higher vertebrates (14). Large clutch size facilitates positional clo...

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Section: Homozygous Kcnh2 Mutant Embryonic Ventricle Does Not Generatementioning

confidence: 99%

Section: Homozygous Kcnh2 Mutant Embryonic Ventricle Does Not Generatementioning

confidence: 99%

Section: Measurement Of Electrocardiogramsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Zebrafish model for human long QT syndrome

Arnaout

Ferrer

Huisken

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

215

212

View full text Add to dashboard Cite

show abstract

“…On the other hand, methodologies that require heart explantation techniques have been used for recording the electrophysiological activity from zebrafish heart. However these are invasive and have been performed on adult samples [3,5]. Alternatively, more advanced techniques based on imaging procedures have been implemented through complex image recognition algorithms that assess the time-varying presence of blood cells in the heart chamber during the cardiac cycle [6].…”

Section: Introductionmentioning

confidence: 99%

Functional characterization of developing heart in embryos using Electric Potential Sensors

Rendon-Morales

Prance

et al. 2016

2016 IEEE Sensors Applications Symposium (SAS)

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Abstract-The characterization of the electrocardiographic activity of the living zebrafish heart during early developmental stages is a challenging task. Most of the available techniques are limited to heartbeat rate quantification being this inaccurate. Other invasive methodologies require the insertion of electrodes noise isolated environments and advanced amplification stages making these techniques very expensive. In this paper, we present a novel and non-invasive sensor development to characterize the functional activity of the developing heart of in vivo zebrafish embryos. The design is based on the Electric Potential Sensing technology patented at Sussex which has been developed to achieve reproducibility and continuous detection. We present preliminary functional characterization data of the developing zebrafish heart starting at 3 days-post-fertilization. Results show that using the proposed system for mapping the electrocardiographic activity of the zebrafish heart at early developmental stages is successfully accomplished. This is the first time that such a sensitive sensor has been developed for measuring the electrical changes occurring on micron sized (< 100 µm) living samples such as the zebrafish heart Keywords-Biomedical sensors, cardiology, embryionic heart, Electric Potential Sensors, electrophysiology and electrocardiogram.

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Simultaneously screening multiple UGT1A1 inhibitors from Polygonum multiflorum root using ultrafiltration LC–MS

Jiang

Cai

Zheng

et al. 2022

Biomedical Chromatography

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Liver injury induced by Polygonum multiflorum root (PMR) is an immediate issue requiring global attention. UDP-glucuronosyltransferase 1A1 (UGT1A1) inhibitors are suspected to additively contribute to the hepatotoxicity of PMR. This study was deliberately designed to simultaneously screen UGT1A1 inhibitors from PMR, and their co-contribution to hepatotoxicity was determined. Using ultrafiltration coupled to LC-MS method, four compounds, namely cis-2,3,5,4 0 -tetrahydroxystilbene-2-Oβ-glucoside, trans-2,3,5,4 0 -tetrahydroxystilbene-2-O-β-D-glucoside, emodin-8-O-β-Dglucoside, and emodin, were screened, exhibiting the in vitro inhibitory activities against UGT1A1 with IC 50 values of 76.23, 18.70, 62.18, and 34.02 μM, respectively.The varying activities of the screened UGT1A1 inhibitors were demonstrated by performing a molecular docking simulation. Finally, zebrafish larvae and mice assays demonstrated that the UGT1A1 inhibitors co-contributed to the hepatotoxicity of PMR. These findings are conducive to understand the role of UGT1A1 inhibitors in PMR-induced hepatotoxicity.

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In vivo recording of adult zebrafish electrocardiogram and assessment of drug-induced QT prolongation

Cited by 209 publications

References 17 publications

Zebrafish model for human long QT syndrome

Zebrafish model for human long QT syndrome

Functional characterization of developing heart in embryos using Electric Potential Sensors

Simultaneously screening multiple UGT1A1 inhibitors from Polygonum multiflorum root using ultrafiltration LC–MS

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