Definition and treatment of arrhythmogenic cardiomyopathy: an updated expert panel report

Abstract

It is 35 years since the first description of arrhythmogenic right ventricular cardiomyopathy (ARVC) and more than 20 years since the first reports establishing desmosomal gene mutations as a major cause of the disease. Early advances in the understanding of the clinical, pathological and genetic architecture of ARVC resulted in consensus diagnostic criteria, which proved to be sensitive but not entirely specific for the disease. In more recent years, clinical and genetic data from families and the recognition of a much broader spectrum of structural disorders affecting both ventricles and associated with a propensity to ventricular arrhythmia have raised many questions about pathogenesis, disease terminology and clinical management. In this paper, we present the conclusions of an expert round table that aimed to summarise the current state of the art in arrhythmogenic cardiomyopathies and to define future research priorities.

Keywords: Arrhythmogenic cardiomyopathy; Arrhythmogenic right ventricular cardiomyopathy; Ventricular arrhythmias.

Figure 1

Ideogram showing current terms that describe different arrhythmogenic cardiomyopathy phenotypes and their possible relationship to left (LV) and right ventricular (RV) disease. By definition, arrhythmogenic RV cardiomyopathy affects predominantly the right ventricle but biventricular forms are frequently seen. Arrhythmogenic dilated cardiomyopathy and left-dominant arrhythmogenic cardiomyopathy describe overlapping entities that mostly affect the left ventricle but RV involvement is also observed. Isolated non-ischaemic scar and hypokinetic non-dilated cardiomyopathy mostly refer to predominantly LV scarring identified using cardiac magnetic resonance imaging.^–

Figure 2

This schematic shows the complex integration of mechanical and electrochemical signalling at cardiac intercalated discs and highlights the proposed remodelling of desmosomes, gap junctions and ion channels in arrhythmogenic cardiomyopathy. Desmosomes, which are a primary target for arrhythmogenic cardiomyopathy-causing mutations, are distributed in close proximity with adherens junctions, gap junctions (made of connexins) and sodium channels. Both desmosomes and adherens junctions have at their central adhesive core members of the cadherin family of calcium-dependent adhesion molecules [desmoglein 2 (DSG2) and desmocollin 2 (DSC2) in desmosomes, and N-cadherin (N-Cad) in adherens junctions]. Linking these molecules to the desmin intermediate filament and actin cytoskeletons, respectively, are a complex of armadillo and cytoskeletal linker proteins consisting of plakophilin 2 (PKP2), plakoglobin (PG) and the intermediate filament anchoring protein desmoplakin (DP) in desmosomes; and beta-catenin (β-Cat), p120 catenin and the actin binding protein alpha T-catenin (αT-Cat) in adherens junctions. In the heart, alpha-T catenin can interlink with PKP2, providing a structural link between desmosome and adherens junctions that results in inter-mixing and stabilizes the cortical cytoskeleton. Mixed junctions appearing in vertebrates are called the ‘area composita’. Examples of functional interactions at the intercalated discs relevant to arrhythmogenic cardiomyopathy are shown. These include DP-dependent trafficking and stabilization of connexin-43 (Cx43) and associated gap junction communication through(ia) EB1-dependent microtubule stabilization at junctions, and (ii) DP-dependent regulation of Erk1/2-dependent turnover of Cx43 through dampening Ras. In addition, distribution and function of the voltage-gated sodium channel (VGSC) Na_v1.5 depends on PKP2 and its associated adaptor protein ankyrin G (AnkG). Conflicting data associate perturbation of Wnt/β-Cat signalling through alterations in PG, β-Cat distribution and Hippo signalling (blocks Wnt), with adipogenic vs. fibrotic cell fate during arrhythmogenic cardiomyopathy development. Desmosomes can themselves be regulated by a combination of the ectodomain sheddase ADAM17 and epidermal growth factor receptor (EGFR) signalling [which is itself regulated via the release of EGFR ligands, such as EGF-like growth factor (HB-EGF) in cardiac muscle, by ADAM17], which cooperate to regulate cleavage of DSG2. This serves to remodel desmosomes and coordinates this remodelling with gene expression changes associated with arrhythmogenic cardiomyopathy. PI3K, phosphoinositide 3-kinase; TNFα, tumour necrosis factor alpha; TNFR, tumour necrosis factor receptor.

Figure 3

Myocardial histology from a 31-year-old male competitive athlete who died suddenly as first manifestation of arrhythmogenic cardiomyopathy. Autopsy revealed biventricular arrhythmogenic cardiomyopathy and evidence of myocardial inflammation: (A) subepicardial fibrofatty replacement of the left ventricular free wall (Trichrome stain); (B) abnormal cardiomyocytes with dysmorphic nuclei, replacement fibrosis and inflammatory infiltrates with myocytolysis (arrow); (C) immunotyping for macrophages (CD68 antibody); (D) immunotyping for T lymphocytes (CD3 antibody).

Figure 4

Suggested flow chart for the general management of ventricular arrhythmia in arrhythmogenic cardiomyopathies. The pathways for management are critically dependent on aetiology as well as the clinical profile of individual patients. ICD, implantable cardioverter-defibrillator; LV, left ventricular; RV, right ventricular; VA, ventricular arrhythmia; VE, ventricular ectopy.