| Abstract: | Introduction: Our understanding of the complexity of arrhythmogenesis has grown progressively over the last two decades. The range of established arrhythmia mechanisms now includes numerous pathways including ion channels, membrane adaptor proteins, transcription factors and cytoplasmic signaling cascades. Areas covered: This review outlines the emerging biology underlying potentially lethal rhythm disturbances, and highlights the problems that these novel mechanisms present for rational target identification in the traditional framework of drug discovery. The article describes the fundamental rationale for in vivo screening and highlights the utility of the zebrafish for this approach. The article also outlines initial efforts exploiting in vivo antiarrhythmic discovery and the potential for this approach to be disruptive even in the setting of disease mechanisms that operate across multiple timescales in multiple tissues. Expert opinion: In vivo screening in genetically faithful model organisms offers access to existing and unimagined arrhythmia pathways. Rate limiting steps are the rigor of the modeling of specific arrhythmias and the downstream identification of the molecular targets once specific disease suppressors have been identified. |
