Desmosomal Arrhythmogenic Cardiomyopathy: The Story Telling of a Genetically Determined Heart Muscle Disease

Abstract

The history of arrhythmogenic cardiomyopathy (AC) as a genetically determined desmosomal disease started since the original discovery by Lancisi in a four-generation family, published in 1728. Contemporary history at the University of Padua started with Dalla Volta, who haemodynamically investigated patients with “auricularization” of the right ventricle, and with Nava, who confirmed familiarity. The contemporary knowledge advances consisted of (a) AC as a heart muscle disease with peculiar electrical instability of the right ventricle; (b) the finding of pathological substrates, in keeping with a myocardial dystrophy; (c) the inclusion of AC in the cardiomyopathies classification; (d) AC as the main cause of sudden death in athletes; (e) the discovery of the culprit genes coding proteins of the intercalated disc (desmosome); (f) progression in clinical diagnosis with specific ECG abnormalities, angiocardiography, endomyocardial biopsy, 2D echocardiography, electron anatomic mapping and cardiac magnetic resonance; (g) the discovery of left ventricular AC; (h) prevention of SCD with the invention and application of the lifesaving implantable cardioverter defibrillator and external defibrillator scattered in public places and playgrounds as well as the ineligibility for competitive sport activity for AC patients; (i) genetic screening of the proband family to unmask asymptomatic carriers. Nondesmosomal ACs, with a phenotype overlapping desmosomal AC, are also treated, including genetics: Transmembrane protein 43, SCN5A, Desmin, Phospholamban, Lamin A/C, Filamin C, Cadherin 2, Tight junction protein 1.

Understanding Arrhythmogenic Cardiomyopathy: Advances through the Use of Human Pluripotent Stem Cell Models

“…Desminopathies, caused by mutations in DES, represent one of the most common IF human disorders, some of which have been linked directly to ACM [12,[144][145][146][147]. It is located on chromosome 2q35 and is prevalent in heart and in skeletal muscle.…”

Desmosomes in Cell Fate Determination: From Cardiogenesis to Cardiomyopathy

“…This paper does not intend to provide a comprehensive review of AC pathogenesis and its clinical outcomes. Readers are referred to recent excellent reviews [9][10][11][12]. Instead, we will focus on the much less investigated and poorly understood functions of desmosomes in embryogenesis.…”

The role of genetic testing in suspected fulminant myocarditis: A case report

“…ACM is a rare inherited cardiac disease characterized by a progressive fibro-fatty replacement of the myocardium. It is caused mostly by variants in desmosome genes with autosomal dominant transmission and incomplete penetrance [ 3 , 4 ]. To date, according to Clinical Genome Resource (ClinGen, https://clinicalgenome.org/ ), 17 genes are classified as having definitive evidence for ACM: PKP2, DSG2, DES, DSP , JUP , DSC2 , PLN, CTNNA3, MYL3, TTN, SCN5A, TJP1, LMNA, CDH2, MYBPC3, TGFB3 and MYH7 [ 5 ].…”