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

Abstract

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.

Figure 1

Molecular mechanisms associated with ACM pathogenesis. GPCR: G protein-coupled receptors, YAP: yes-associated protein, PG: Plakoglobin, TCF/LEF: T-cell factor/lymphoid enhancer-binding factor, Wnt: homologous wingless, APC: adenomatous polyposis coli, RYR2: type 2 ryanodine receptor, CASQ2: calsequestrin 2, CACNA1C: calcium voltage-gated channel subunit alpha1 C, SR: sarcoplasmic reticulum, SERCA: sarco-endoplasmic reticulum Ca²⁺ ATPase, PLN: phospholamban, LTCC: L-type calcium channel. ( Activation/Phosphorylation, Translocation, Inhibition).

Figure 2

Ca²⁺-dependent desmosomes stability. Ca²⁺: calcium, DSG2: desmoglein 2, DSC2: desmocollin 2, PG: plakoglobin, PKP2: plakophilin 2, DSP: desmoplakin.