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Updated: Jun 10, 2025

Viral Transgene Expression in Rodent Hearts and the Assessment of Cardiac Arrhythmia Risk
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Targeting Canonical Wnt-signaling Through GSK-3β in Arrhythmogenic Cardiomyopathy: Conservative or Progressive?

Brandon Shu Huang Low1, Angeliki Asimaki2,3

  • 1College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.

Journal of Cardiovascular Translational Research
|October 11, 2024
PubMed

Insights

Inhibiting GSK3β may treat arrhythmogenic cardiomyopathy (ACM) by targeting Wnt signaling. However, potential risks like arrhythmias and cancer require careful consideration before clinical application.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Pharmacology

Background:

  • Arrhythmogenic cardiomyopathy (ACM) is a primary heart muscle disease causing sudden cardiac death worldwide.
  • Canonical Wnt signaling regulates crucial cellular processes, with GSK3β acting downstream to control protein degradation.
  • GSK3β inhibition shows promise in preclinical models for preventing and reversing ACM features.

Purpose of the Study:

  • To review the therapeutic potential of GSK3β inhibition for ACM.
  • To analyze the advantages and disadvantages of this strategy.
  • To contextualize findings in light of the ongoing TaRGET clinical trial for ACM patients.

Main Methods:

  • Literature review of studies on GSK3β inhibition in experimental ACM models.
  • Analysis of reported benefits, including prevention and reversal of pathognomonic ACM features.
  • Evaluation of potential risks and adverse effects associated with GSK3β inhibition.

Main Results:

  • GSK3β inhibition has demonstrated efficacy in preventing and reversing key ACM features in various experimental models.
  • Concerns exist regarding paradoxical arrhythmias, oncogenic potential, and off-target effects of GSK3β inhibitors.
  • The TaRGET phase 2 clinical trial will assess the therapeutic efficacy of GSK3β inhibition in human ACM patients.

Conclusions:

  • GSK3β inhibition presents a potential therapeutic avenue for arrhythmogenic cardiomyopathy.
  • Careful risk-benefit assessment is crucial due to potential adverse effects.
  • Clinical trials are essential to validate the safety and efficacy of this approach in patients.
Keywords:
Arrhythmogenic cardiomyopathyCHIR99021Canonical Wnt-signalingGlycogen synthase kinase 3βHippoSB216763Tideglusib

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