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.

Cardiomyocyte adhesion and hyperadhesion differentially require ERK1/2 and plakoglobin

“…In addition, these signaling mechanisms may be involved in pathogenesis or therapy of AC and other cardiac disorders, especially as the decreased adhesion upon Ca 2+ depletion could be overcome by adrenergic signaling, p38MAPK inhibition, or PKC activation in murine cardiac slice cultures and HL-1 cells. Furthermore, deregulation of Ca 2+ signaling is known to be causative for several arrhythmic disorders ( 36 – 38 ), indicating that our findings might be of interest when studying other cardiomyopathies.…”

Fibrosis in Arrhythmogenic Cardiomyopathy: The Phantom Thread in the Fibro-Adipose Tissue

“…Specifically, binding of TGFβ to its receptors is the starting point for the activation of downstream signaling cascade that involves different mediators of the canonical (SMADs proteins) or non-canonical (ERK, JNK, and p38 MAPK) pathways. Although ACM is commonly defined as a "desmosomal disease" being the majority of the patients mutated in desmosomal genes, additional mutations have been identified in genes that encode for non-desmosomal proteins (Moccia et al, 2019). One of those in TGFB3, responsible for the ARVD1 form (Beffagna et al, 2005).…”

“…It has been hypothesized that, in ACM, desmosome mutations cause PG translocation from intercalated discs to the nucleus where it competes with β-catenin for the binding to TCF/LEF transcription factors based on the high structural homology (Garcia-Gras et al, 2006;Miravet et al, 2016). The abnormal PG translocation causes the altered canonical activation of Wnt/β-catenin signaling pathway promoting the pathological fibro-adipose myocardial tissue substitution (Garcia-Gras et al, 2006;Moccia et al, 2019).…”

The anesthetic bupivacaine induces cardiotoxicity by targeting L-type voltage-dependent calcium channels

“…Heart arrhythmia may predispose individuals to complications such as stroke or heart failure and can eventually lead to sudden death. 14 , 15 The side effects of clinical drugs include cardiotoxicity, and the most common symptom of cardiotoxicity is arrhythmia. 16 – 18 Drug inhibition or blockade of ion channels is the most common treatment for heart arrhythmia.…”