Zebrafish Heart Failure Models

Heart failure is a complex pathophysiological syndrome of pumping failure caused by injury, infection, or toxin-induced myocardial damage, as well as genetic influences. Heart failure causes significant morbidity and mortality worldwide, and there is a need to develop new animal models and rapid assays for heart failure research and drug screening. Extrapolating these results to the whole organism is often challenging due to the lack of cardiac structure or drug absorption, distribution, metabolism, and excretion, currently of limited value in in vitro heart failure assays. Traditional in vivo mammalian models of heart failure are often laborious, expensive and time-consuming, limiting their use in early screening.

In recent years, zebrafish have been increasingly used to study development, anatomy and physiology. The zebrafish heart is highly comparable to the human heart in structure, function, signaling pathways and ion channels, both muscles designed to pump oxygen-carrying blood throughout the body. Like all vertebrates, the heart is the first functional organ in zebrafish, it develops rapidly and is fully formed by 2 days after fertilization (dpf). Currently, zebrafish has become an excellent model for the study of human cardiovascular diseases (eg, congenital heart defects, cardiomyopathy) and the preclinical development of drugs targeting these diseases.

Fig.1 Cardiac dilatation and reduced venous congestion in heart failure zebrafish treated with human therapeutic drugs for 4.5 hours.

Our Zebrafish Heart Failure Models

Creative Biogene has established several zebrafish models of cardiac hypertrophy, hyperplasia, dysfunction and remodeling through genetic manipulation or drug induction. Cardiac phenotypes can appear as early as the embryonic stage of 48 hpf, and these changes include a distortion of heart shape and a reduction in heart size and a gradual decrease in heart rate. For each model, we accurately characterized cardiac structure and function, including quantifying cardiac size, while discriminating between cardiac hypertrophy and hyperplasia. We are committed to providing multiple zebrafish heart failure models for rapid in vivo screening and efficacy evaluation of heart failure therapeutics and improving your understanding of the pathogenesis of heart failure.

Table 1 Genetic models of heart failure.

Gene	Embryo/Adult	Knock-out (KO)/Morpholino/Other	Main Phenotype
bag3	Both	Morpholino and KO	Cardiac dysfunction
band3	Adult	KO	hypertrophy and hyperplasia
cmlc1	Adult	KO	Arrhythmia
dcos226	Embryo	KO	Conduction defect
erbb2	Both	KO	Hypertrophy, cardiac dysfunction
gtpbp3	Both	KO	Hypertrophy
heg1	Embryo	KO	Cardiac dysfunction
hhatla	Embryo	Morpholino	Hypertrophy, cardiac dysfunction
ilk	Embryo	KO	Cardiac dysfunction
jag2b	Both	Genetic ablation	Hypertrophy
lamp2	Adult	KO	Hypertrophy, cardiac dysfunction
lmcd1, tns1	Embryo	Morpholino	Valvular heart defect
lrrc10	Embryo	Morpholino	Hypertrophy
lztr1	Adult	KO	Hypertrophy
mcu	Both	KO	Cardiac dysfunction, arrhythmia
mybpc3	Embryo	Morpholino	Hypertrophy
myh6	Adult	KO	Hyperplasia
ndufa7	Embryo	Morpholino	Hypertrophy, cardiac dysfunction
pkd2	Embryo	Morpholino	Cardiac dysfunction, AV-block
ptpn11	Embryo	mRNA injections	left-right asymmetry
rbfox1	Embryo	Morpholino	Cardiac dysfunction
sept7b	Embryo	Morpholino	Cardiac dysfunction
tnnt2	Embryo	KO and morpholino	Cardiac dysfunction
trim55	Embryo	KO	Cardiac dysfunction
ttn	Embryo	KO	Cardiac dysfunction
vclb	Adult	KO	Hyperplasia
vegfaa	Adult	Overexpression	Hyperplasia
vezf1	Embryo	Morpholino	Attenuation of cardiac growth
z-usmg5	Embryo	Morpholino	Cardiac dysfunction
kif20a	Embryo	Morpholino	Restrictive cardiomyopathy
Plakoglobin	Until 3 months of age	2057del2 mutant	Arhythmogenic right ventricular cardiomyopathy
nnt	Embryo	Morpholino	Left ventricular non-compaction cardiomyopathy

Table 2 Drug-induced models of heart failure.

Drug	Embryo/Adult	Main Phenotype
Aristolochic acid (AA)	Embryo	Cardiac dysfunction
Benzo(a)pyrene (Bap)	Both	Hypertrophy
Doxorubicin	Embryo	Cardiac dysfunction
Isoproterenol (ISO)	Both	Cardiac dysfunction
Phenyl hydrazine hydrochloride (PHZ)	Adult	Hypertrophy and hyperplasia
Phenylephrine (PE)	Adult	Hypertrophy and hyperplasia
Streptozocin	Adult	Diabetic cardiomyopathy
Terfenadine	Embryo	Cardiac dysfunction, AV-block
Tolterodine	Embryo	Arrhythmia
Verapamil	Embryo	Cardiac dysfunction

Advantages

Non-invasive visualization of in vivo organs and biological processes at high resolution
Visualization of Pathogenesis
Examine multiple functions of genes in different mutants
High-throughput genetic and drug screening

References

Zhu XY, et al. A Zebrafish Heart Failure Model for Assessing Therapeutic Agents. Zebrafish. 2018, 15(3):243-253.
Narumanchi S, et al. Zebrafish Heart Failure Models. Front Cell Dev Biol. 2021, 9:662583.
Shi X, et al. Zebrafish heart failure models: opportunities and challenges. Amino Acids. 2018, 50(7):787-798.

For research use only. Not intended for any clinical use.

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