Constructing Einthoven's Triangle to Define Adult Zebrafish Cardiac Electrical Vectors and Evaluate Digitalis Effect vs Cardiotoxicity

Abstract

Zebrafish heart has emerged as a popular high-throughput vertebrate model to study human cardiac electrophysiology, arrhythmias, and myopathies. One reason for this popularity is the purported striking similarities between zebrafish and human electrocardiograms (ECGs) despite their vast cardiac anatomical differences. Yet, the zebrafish heart electrical axis has not been determined and underlying electrical tissue mechanisms are incompletely understood. Therefore, for the first time, adult zebrafish Einthoven's triangle was systematically constructed, and zebrafish heart electrical axis in the frontal plane was determined using the Cabrera (or hexaxial reference) system. Additionally, zebrafish translatability was evaluated by defining how digitalis at therapeutic vs supratherapeutic doses modulate Einthoven's triangle. Comparing zebrafish and human Einthoven's triangles under baseline condition reveal that their ventricular activation propagated in opposite directions, indicating that their electrical axes are antiparallel. Their ventricular repolarization also propagated in opposite directions, accounting for their opposite QRS and T wave concordances. Moreover, digitalis modulation of zebrafish Einthoven's triangle recapitulated classic human ECG manifestations of the ‘digitalis effect’ at therapeutic dose and digitalis cardiotoxicity at supratherapeutic dose, but in mirror image along the main cardiac axis. These findings validate zebrafish Einthoven's triangle as a useful, sensitive, and clinically relevant diagnostic tool. This study is the first systematic analysis of the actual differences and similarities between normal adult zebrafish and human Einthoven's triangles to unmask differences and similarities in the underlying tissue mechanisms. These new insights provide additional, necessary contextual framework to properly interpret the clinical relevance of the adult zebrafish heart model for human cardiac electrophysiology and arrhythmia studies.