Targeting Canonical Wnt-signaling Through GSK-3β in Arrhythmogenic Cardiomyopathy: Conservative or Progressive?

Arrhythmogenic cardiomyopathy is a primary myocardial disease and a major cause of sudden death in all populations of the world. Canonical Wnt signalling is a critical pathway controlling numerous processes including cellular differentiation, hypertrophy and development. GSK3β is a ubiquitous serine/threonine kinase, which acts downstream of Wnt to promote protein ubiquitination and proteasomal degradation. Several studies now suggest that inhibiting GSK3β can prevent and reverse key pathognomonic features of ACM in a range of experimental models. However, varying concerns are reported throughout the literature including the risk of paradoxical arrhythmias, cancer and off-target effects in upstream or downstream pathways. CLINICAL RELEVANCE: In light of the start of the phase 2 TaRGET clinical trial, designed to evaluate the potential therapeutic efficacy of GSK3β inhibition in patients with arrhythmogenic cardiomyopathy, this report aims to review the advantages and disadvantages of this strategy.