Histopathological Features and Protein Markers of Arrhythmogenic Cardiomyopathy.

Carlos Bueno-Beti,Angeliki Asimaki

doi:10.3389/fcvm.2021.746321

Abstract

Arrhythmogenic cardiomyopathy (ACM) is a heritable heart muscle disease characterized by syncope, palpitations, ventricular arrhythmias and sudden cardiac death (SCD) especially in young individuals. It is estimated to affect 1:5,000 individuals in the general population, with >60% of patients bearing one or more mutations in genes coding for desmosomal proteins. Desmosomes are intercellular adhesion junctions, which in cardiac myocytes reside within the intercalated disks (IDs), the areas of mechanical and electrical cell-cell coupling. Histologically, ACM is characterized by fibrofatty replacement of cardiac myocytes predominantly in the right ventricular free wall though left ventricular and biventricular forms have also been described. The disease is characterized by age-related progression, vast phenotypic manifestation and incomplete penetrance, making proband diagnosis and risk stratification of family members particularly challenging. Key protein redistribution at the IDs may represent a specific diagnostic marker but its applicability is still limited by the need for a myocardial sample. Specific markers of ACM in surrogate tissues, such as the blood and the buccal epithelium, may represent a non-invasive, safe and inexpensive alternative for diagnosis and cascade screening. In this review, we shall cover the most relevant biomarkers so far reported and discuss their potential impact on the diagnosis, prognosis and management of ACM.

Highlights

DemographicsCurrent experts in the field estimate that Arrhythmogenic cardiomyopathy (ACM) affects 1:5,000 individuals in the general population regional differences exist [1]
glycogen synthase kinase 3β (GSK3β) and adenomatous polyposis coli (APC) redistribution from the cytosol to the Intercalated Disk (ID) was specific for ACM as it was not observed in other forms of heart disease including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), ischemic cardiomyopathy (ICM), or cardiac sarcoidosis (Figure 2) [85]
The localization of plakoglobin, desmoplakin, plakophilin-1 (PKP1; an isoform of plakophilin 2 (PKP2) expressed in the upper epithelia) and Connexin 43 (Cx43) was investigated in the buccal mucosa of 39 patients with a definite clinical diagnosis of ACM bearing desmosomal gene mutations

Summary

Introduction

DemographicsCurrent experts in the field estimate that ACM affects 1:5,000 individuals in the general population regional differences exist [1]. Patients carrying mutations in PKP2 gene often present LV involvement at advanced stages of the disease while mutations in DSG2 and DSC are often associated to biventricular forms of ACM. In 2004 Kaplan et al showed for the first time that even if the mutated plakoglobin was expressed in the hearts of Naxos disease patients it failed to reach the IDs where the protein executes its structural roles [74].

Results

Conclusion