Calcium as a key player in arrhythmogenic cardiomyopathy: Adhesion disorder or intracellular alteration?

Francesco Moccia, Francesco Lodola, Ilaria Stadiotti, Chiara Assunta Pilato, Milena Bellin, Stefano Carugo, Giulio Pompilio, Elena Sommariva, Angela Serena Maione

Research output: Contribution to journalReview articlepeer-review


Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disease characterized by sudden death in young people and featured by fibro-adipose myocardium replacement, malignant arrhythmias, and heart failure. To date, no etiological therapies are available. Mutations in desmosomal genes cause abnormal mechanical coupling, trigger pro-apoptotic signaling pathways, and induce fibro-adipose replacement. Here, we discuss the hypothesis that the ACM causative mechanism involves a defect in the expression and/or activity of the cardiac Ca2+ handling machinery, focusing on the available data supporting this hypothesis. The Ca2+ toolkit is heavily remodeled in cardiomyocytes derived from a mouse model of ACM defective of the desmosomal protein plakophilin-2. Furthermore, ACM-related mutations were found in genes encoding for proteins involved in excitation-contraction coupling, e.g., type 2 ryanodine receptor and phospholamban. As a consequence, the sarcoplasmic reticulum becomes more eager to release Ca2+, thereby inducing delayed afterdepolarizations and impairing cardiac contractility. These data are supported by preliminary observations from patient induced pluripotent stem-cell-derived cardiomyocytes. Assessing the involvement of Ca2+ signaling in the pathogenesis of ACM could be beneficial in the treatment of this life-threatening disease.

Original languageEnglish
Article number3986
JournalInternational Journal of Molecular Sciences
Issue number16
Publication statusPublished - Aug 2 2019


  • Arrhythmogenic cardiomyopathy
  • Ca sparks
  • Desmosomes
  • Phospholamban
  • Plakophilin-2
  • Type 2 ryanodine receptors

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry


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