Abnormal Cell-Cell Adhesion

Even before the discovery of desmosomal genes in AC, electron microscopy studies, demonstrating intercalated disc disruption, first raised the hypothesis of an abnormal cell-cell adhesion in disease pathogenesis. However, more recent studies point to the possible role of mutant desmosomal proteins in intracellular signaling rather than adhesion remodeling, as initially assumed.

Abnormal Intercellular Junction Proteins and Intracellular Signaling

The role of mutant desmosomal proteins in the intracellular signaling was first demonstrated in a Desmoplakin (DSP)-deficient mouse model, with the Wnt signaling pathway suppression leading to adipogenesis as a consequence of the abnormal distribution of intercalated disc proteins. More recent studies in different experimental models further support this hypothesis, showing an additional suppression of the canonical Wnt signaling leading due to aberrant activation of the Hippo kinase cascade pathway, which resulted into phosphorylation and cytoplasmic retention of yes associated protein (YAP) leading to enhanced myocyte death and fibroadipogenesis as a consequence of β-catenin and junctional plakoglobin (JUP) cytoplasmic sequestration.

However, cellular reprogramming of patient-derived somatic cells (ie, dermal fibroblasts) into iPSCs from AC patients with plakophilin-2 (PKP2) mutations, demonstrated that the abnormal JUP nuclear translocation and decreased β-catenin activity is insufficient to reproduce the pathologic phenotype in standard conditions and only the induction of an adult-like metabolism in a lipogenic milieu coactivated peroxisome proliferator-activated receptor (PPAR)-γ pathway with lipogenesis, apoptosis, and calcium-handling deficit.

It is noteworthy that transgenic experimental animal models and iPSC-derived cardiomyocytes demonstrated only abnormal “lipogenesis,” but not adipocyte formation or sudden death. Thus cells other than cardiomyocytes must be involved in the abnormal adipogenesis and fibrosis, which is also an essential feature of AC phenotype. A role of cardiac mesenchymal stromal cells as a source of adipocytes in AC has been recently advanced.

Gap Junction and Ion Channel Remodeling

Desmosomes, gap junctions, and sodium channels act as a functional triad in which changes in the composition of one constituent can affect the function and integrity of the others. Recent studies demonstrated diminished connexin-43 expression at intercellular junctions of most AC human myocardial specimens and reduced cardiac sodium current in experimental models of AC. These findings led to the hypothesis that life-threatening ventricular arrhythmias could occur in AC patients, even preceding the structural abnormalities (prephenotypic stage) due to electrical uncoupling and reduced sodium current prevention. However, it remains to be proven in humans.

From Experimental Models to Target Therapy

Finally, in a transgenic AC zebrafish model with cardiac specific expression of the human JUP deletion, high-throughput drug screening identified SB216763, an activator of the canonical Wnt signaling pathway, as able to prevent heart failure and normalize survival. Treatment with the SB216763 compound restores the subcellular distribution of JUP, connexin 43, Nav1.5, and SAP97, a protein known to mediate the forward trafficking of Nav1.5 and Kir2.1, opening the door to the identification of a curative therapy in AC by targeting a final common pathway of disease pathogenesis.

Arrhythmogenic Cardiomyopathy Diagnosis

There is no single gold-standard feature in the diagnosis of AC. Multiple criteria are needed, combining different sources of diagnostic information, such as morphofunctional (by echocardiography and/or angiography and/or cardiac magnetic resonance [CMR]), histopathologic on endomyocardial biopsy, ECG, arrhythmias, and familial history, including genetics ( Fig. 63.1 ). The diagnostic criteria, originally put forward in 1994, were revised in 2010 to improve diagnostic sensitivity, but with the important prerequisite of maintaining diagnostic specificity ( Table 63.1 ). To this aim, quantitative parameters have been included and abnormalities are defined, based on the comparison with normal subject data. Moreover, T wave inversion in V1 to V3 and VT with a LBBB morphology with superior or indeterminate QRS axis (either sustained or no sustained) have become major diagnostic criteria ; and T wave inversion in V ₁ to V ₂ in the absence of right bundle branch block (RBBB) and in V ₁ to V ₄ , in the presence of complete RBBB have been included among the minor criteria. Finally, in the family history category, the confirmation of AC in a first-degree relative, by either meeting current criteria or pathologically (at autopsy or transplantation), and the identification of a pathogenic mutation, categorized as associated or probably associated with AC, are considered major criteria. However, because of the diagnostic implications, caution is highly recommended, since the pathogenic significance of a single mutation is increasingly questioned (see Genetics section).

Diagnostic tools to achieve a clinical diagnosis of classic right ventricle (RV) arrhythmogenic cardiomyopathy.

A–C, echocardiographic, Cardiac magnetic resonance and angiography showing RV dilatation and aneurysms; D, tissue characterization through endomyocardial biopsy; E, 12-lead electrocardiogram with inverted T waves V ₁ to V ₃ , left bundle branch block morphology premature ventricular complexes and ventricular tachycardia; F, post-excitation epsilon wave in precordial leads V ₁ to V ₃ (arrows) ; G, Signal-averaged electrocardiogram with late potentials (40-Hz high-pass filtering); H, Family pedigree with autosomal dominant inheritance of the disease. AoV, Aortic valve; RVOT, right ventricular outflow tract.

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