Table 6.

Examples of animal models of inherited cardiac diseases and animal-free innovations

Species	Pathological features	Applications	Animal-free alternatives
Mouse, zebrafish, Drosophila	Targeted deletion or transgenic overexpression of genes identified in human genetic studies, including GWAS Refinement	Study relevance of a specific gene Prove causality Gain novel mechanistic insight	Targeted deletion or overexpression in hiPSC-CMs Replacement and reduction
Mouse, zebrafish, rabbit, pig	Transgenic animals overexpressing mutant proteins identified in patients with inherited cardiomyopathies and channelopathies Refinement	Study relevance of a specific gene mutation Study disease progression Prove causality Gain novel mechanistic insight Therapeutic studies	Introduce mutation in heterologous expression systems, hiPSC-CMs Replacement and reduction
Mouse, zebrafish, pig	CRISPR/Cas9-induced gene mutation Further refinement compared to transgenic models	Mimicking heterozygous and homozygous mutations as present in cardiomyopathy patients	CRISPR/Cas9-induced gene mutations in hiPSC-CMs, and patient-derived iPSC-CMs Replacement and reduction
Rat, cat, dog	Spontaneous cardiomyopathy Refinement and reduction	Study disease progression Gain novel mechanistic insight Therapeutic studies	Introduce mutation in heterologous expression systems, hiPSC-CMs Replacement and reduction

All animal models enable in vivo/ex vivo/in vitro analysis of (electro)physiology, histology, and molecular biology. Abbreviations: GWAS, genome-wide association studies; hiPSC-CMs, human induced pluripotent stem cell-derived cardiomyocytes.