Abstract
Inherited cardiac arrhythmias contribute substantially to sudden cardiac death in the young. The underlying pathophysiology remains incompletely understood because of the lack of representative study models and the labour-intensive nature of electrophysiological patch clamp experiments. Whereas patch clamp is still considered the gold standard for investigating electrical properties in a cell, optical mapping of voltage and calcium transients has paved the way for high-throughput studies. Moreover, the development of human-induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs) has enabled the study of patient specific cell lines capturing the full genomic background. Nevertheless, hiPSC-CMs do not fully address the complex interactions between various cell types in the heart. Studies using in vivo models, are therefore necessary. Given the analogies between the human and zebrafish cardiovascular system, zebrafish has emerged as a cost-efficient model for arrhythmogenic diseases. In this review, we describe how hiPSC-CM and zebrafish are employed as models to study primary electrical disorders. We provide an overview of the contemporary electrophysiological phenotyping tools and discuss in more depth the different strategies available for optical mapping. We consider the current advantages and disadvantages of both hiPSC-CM and zebrafish as a model and optical mapping as phenotyping tool and propose strategies for further improvement. Overall, the combination of experimental readouts at cellular (hiPSC-CM) and whole organ (zebrafish) level can raise our understanding of the complexity of inherited cardiac arrhythmia disorders to the next level.
Highlights
Inherited cardiac arrhythmias (ICAs) are a heterogeneous group of rare disorders often characterised by a structural normal heart despite the presence of disease-specific electrocardiographic deviations
[35].In parallel with automated patch clamp (APC), micro-electrode arrays (MEAs) provide a faster electrophysiological characterisation compared with conventional patch clamp
In the transparent zebrafish larvae, complementary fluorescence imaging of the whole heart as a method to functionally assess ICAs has been used in Long QT syndrome (LQTS) [53,82,104,105], short QT syndrome (SQTS) [106] and cardiac conduction-system disease (CCSD) (Table 2) [107]
Summary
Inherited cardiac arrhythmias (ICAs) are a heterogeneous group of rare disorders often characterised by a structural normal heart despite the presence of disease-specific electrocardiographic deviations. The basis for these deviations is frequently found in the genes encoding for the cardiac ion channels and their subunits, which contain rare pathogenic variants. The normal physiological functioning of these channels is altered, which disturbs the ionic homeostasis inside the cardiomyocytes (CMs) and affects the cardiac action potential (AP). 2. Human-Induced Pluripotent Stem-Cell-Derived Cardiomyocytes (hiPSC-CMs) as a Model for ICA. Numerous somatic cells from patients and healthy individuals have been successfully reprogrammed and differentiated to generate hiPSC-CMs [13,14]
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