Phenotypic Expression and Clinical Outcomes in Patients With Arrhythmogenic Cardiomyopathies.

BACKGROUND: In recent years, it has become evident that arrhythmogenic cardiomyopathy (ACM) displays a wide spectrum of ventricular involvement. Furthermore, the influence of various clinical phenotypes on the prognosis of the disease is currently being assessed. OBJECTIVES: The purpose of this study was to evaluate the impact of phenotypic expression in ACM on patient outcomes. METHODS: We conducted an analysis of 446 patients diagnosed with ACM. These patients were categorized into 3 groups based on their phenotype: arrhythmogenic right ventricular cardiomyopathy (ARVC) (right-dominant ACM), arrhythmogenic left ventricular cardiomyopathy (ALVC) (left-dominant ACM), and biventricular arrhythmogenic cardiomyopathy (BIV). We compared clinical, instrumental, and genetic findings among these groups and also evaluated their outcomes RESULTS: Overall, 44% of patients were diagnosed with ARVC, 23% with ALVC, and 33% with BIV forms. Subjects showing with ARVC and BIV phenotype had a significantly higher incidence of life-threatening ventricular arrhythmias compared with ALVC (P < 0.001). On the other hand, heart failure, heart transplantation, and death caused by cardiac causes were more frequent in individuals with BIV forms compared to those with ALVC and ARVC (P < 0.001). Finally, patients with an ALVC phenotype had a higher incidence of hot phases compared with those with ARVC and BIV forms (P = 0.013). CONCLUSIONS: The comparison of ACM phenotypes demonstrated that patients with right ventricular involvement, such as ARVC and BIV forms, exhibit a higher incidence of life-threatening ventricular arrhythmias. Conversely, ACM forms characterized by left ventricular involvement, such as ALVC and BIV, show a higher incidence of heart failure, heart transplantation, and hot phases.

Genetic Background and Clinical Features in Arrhythmogenic Left Ventricular Cardiomyopathy: A Systematic Review.

In recent years a phenotypic variant of Arrhythmogenic cardiomyopathy has been described, characterized by predominant left ventricular (LV) involvement with no or minor right ventricular abnormalities, referred to as Arrhythmogenic left ventricular cardiomyopathy (ALVC). Different disease-genes have been identified in this form, such as Desmoplakin (DSP), Filamin C (FLNC), Phospholamban (PLN) and Desmin (DES). The main purpose of this critical systematic review was to assess the level of knowledge on genetic background and clinical features of ALVC. A search (updated to April 2022) was run in the PubMed, Scopus, and Web of Science electronic databases. The search terms used were "arrhythmogenic left ventricular cardiomyopathy" OR "arrhythmogenic cardiomyopathy" and "gene" OR "arrhythmogenic dysplasia" and "gene". The most represented disease-gene turned out to be DSP, accounting for half of published cases, followed by FLNC. Overall, ECG abnormalities were reported in 58% of patients. Major ventricular arrhythmias were recorded in 26% of cases; an ICD was implanted in 29% of patients. A total of 6% of patients showed heart failure symptoms, and 15% had myocarditis-like episodes. DSP is confirmed to be the most represented disease-gene in ALVC patients. An analysis of reported clinical features of ALVC patients show an important degree of electrical instability, which frequently required an ICD implant. Moreover, myocarditis-like episodes are common.

Novel pathogenic role for galectin-3 in early disease stages of arrhythmogenic cardiomyopathy.

BACKGROUND: Arrhythmogenic cardiomyopathy (AC) is a myocardial disease due to desmosomal mutations whose pathogenesis is incompletely understood. OBJECTIVE: The purpose of this study was to identify molecular pathways underlying early AC by gene expression profiling in both humans and animal models. METHODS: RNA sequencing for differentially expressed genes (DEGs) was performed on the myocardium of transgenic mice overexpressing the Desmoglein2-N271S mutation before phenotype onset. Zebrafish signaling reporters were used for in vivo validation. Whole exome sequencing was undertaken in 10 genotype-negative AC patients and subsequent direct sequencing in 140 AC index cases. RESULTS: Among 29 DEGs identified at early disease stages, Lgals3/GAL3 (lectin, galactoside-binding, soluble, 3) showed reduced cardiac expression in transgenic mice and in 3 AC patients who suffered sudden cardiac death without overt structural remodeling. Four rare missense variants of LGALS3 were identified in 5 human AC probands. Pharmacologic inhibition of Lgals3 in zebrafish reduced Wnt and transforming growth factor-ß signaling, increased Hippo/YAP-TAZ signaling, and induced alterations in desmoplakin membrane localization, desmosome integrity and stability. Increased LGALS3 plasma expression in genotype-positive AC patients and CD98 activation supported the galectin-3 (GAL3) release by circulating macrophages pointing toward the stabilization of desmosomal assembly at the injured regions. CONCLUSION: GAL3 plays a crucial role in early AC onset through regulation of Wnt/ß-catenin signaling and intercellular adhesion.