| Summary: | Arrhythmogenic Cardiomyopathy (AC) is a rare inherited heart disease, manifesting with progressive myocardium degeneration and dysfunction, and life-threatening arrhythmic events that lead to sudden cardiac death. Despite genetic determinants, most of AC patients admitted to hospital are athletes or very physically active people, implying the existence of other disease-causing factors. It is recognized that AC phenotypes are enhanced and triggered by strenuous physical activity, while excessive mechanical stretch and load, and repetitive adrenergic stimulation are mechanisms influencing disease penetrance. Different approaches have been undertaken to recapitulate and study both mechanotransduction and adrenergic signaling in AC, including the use of in vitro cellular and tissue models, and the development of in vivo models (particularly rodents but more recently also zebrafish). However, it remains challenging to reproduce mechanical load stimuli and physical activity in laboratory experimental settings. Thus, more work to drive the innovation of advanced AC models is needed to recapitulate these subtle physiological influences. Here, we review the state-of-the-art in this field both in clinical and laboratory-based modeling scenarios. Specific attention will be focused on highlighting gaps in the knowledge and how they may be resolved by utilizing novel research methodology.
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