Calcium as a Key Player in Arrhythmogenic Cardiomyopathy: Adhesion Disorder or Intracellular Alteration?

Int J Mol Sci. 2019 Aug 16;20(16):3986. doi: 10.3390/ijms20163986.


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.

Keywords: Ca2+ sparks; arrhythmogenic cardiomyopathy; desmosomes; phospholamban; plakophilin-2; type 2 ryanodine receptors.

Publication types

  • Review

MeSH terms

  • Animals
  • Arrhythmias, Cardiac / metabolism
  • Arrhythmias, Cardiac / pathology*
  • Calcium / metabolism*
  • Calcium Signaling
  • Cardiomyopathies / metabolism
  • Cardiomyopathies / pathology*
  • Desmosomes / metabolism
  • Desmosomes / pathology*
  • Humans
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology*
  • Plakophilins / metabolism
  • Ryanodine Receptor Calcium Release Channel / metabolism


  • Plakophilins
  • Ryanodine Receptor Calcium Release Channel
  • Calcium