Importance of genotype for risk stratification in arrhythmogenic right ventricular cardiomyopathy using the 2019 ARVC risk calculator

Abstract

Aims To study the impact of genotype on the performance of the 2019 risk model for arrhythmogenic right ventricular cardiomyopathy (ARVC). Methods and results The study cohort comprised 554 patients with a definite diagnosis of ARVC and no history of sustained ventricular arrhythmia (VA). During a median follow-up of 6.0 (3.1,12.5) years, 100 patients (18%) experienced the primary VA outcome (sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator intervention, aborted sudden cardiac arrest, or sudden cardiac death) corresponding to an annual event rate of 2.6% [95% confidence interval (CI) 1.9–3.3]. Risk estimates for VA using the 2019 ARVC risk model showed reasonable discriminative ability but with overestimation of risk. The ARVC risk model was compared in four gene groups: PKP2 (n = 118, 21%); desmoplakin (DSP) (n = 79, 14%); other desmosomal (n = 59, 11%); and gene elusive (n = 160, 29%). Discrimination and calibration were highest for PKP2 and lowest for the gene-elusive group. Univariable analyses revealed the variable performance of individual clinical risk markers in the different gene groups, e.g. right ventricular dimensions and systolic function are significant risk markers in PKP2 but not in DSP patients and the opposite is true for left ventricular systolic function. Conclusion The 2019 ARVC risk model performs reasonably well in gene-positive ARVC (particularly for PKP2) but is more limited in gene-elusive patients. Genotype should be included in future risk models for ARVC.

Impaired heart rate variability in patients with arrhythmogenic cardiomyopathy: A multicenter retrospective study in China

“…Identification of patients with high risk of SCD is the primary goal in management of ACM patients. During the past decades, some predictors based on demography, genetics, surface ECG and echocardiography have been identified to screen ACM patients with high risk of SCD ( 3 , 27 – 29 ). This study identified SDNN as a new predictor of sVT in ACM patients.…”

Non Coding RNAs as Regulators of Wnt/β-Catenin and Hippo Pathways in Arrhythmogenic Cardiomyopathy

“…Arrhythmogenic cardiomyopathy (ACM) is a rare disease with an estimated prevalence between 1:1000 and 1:5000 (OMIM #107970; ORPHA247) characterized by fibrofatty replacement of the ventricular myocardium and a high ventricular arrhythmia burden with increased risk of sudden cardiac death [ 1 , 2 , 3 , 4 , 5 , 6 ], sometimes as the first manifestation of the disease. ACM has been defined as a desmosomal disease caused by mutations in any of the five genes encoding desmosomal proteins: desmocollin-2 ( DSC2 ), desmoglein-2 ( DSG2 ), desmoplakin ( DSP ), plakoglobin ( JUP ), and plakophilin-2 ( PKP2 ).…”

“…Mutations in these genes are responsible of more than 60% of genotyped ACM cases. However, mutations in 14 non-desmosomal genes have also been identified in 5% of patients, namely in α-actinin-2 ( ACTN2 ), cadherin-2 ( CDH2 ), αT-catenin ( CTNNA3 ), desmin ( DES ), filamin C ( FLNC ), LIM domain binding protein 20 ( LDB3 ), lamin A/C ( LMNA ), transmembrane protein 43 ( TMEM43 ), transforming growth factor beta 3 ( TGFB3 ), tight junction protein 1( TJP1 ), titin ( TTN) , RNA-binding motif protein 20 ( RBM20 ), sodium voltage-gated channel, alpha subunit 5 ( SCN5A ), and phospholamban ( PLN ) ( Table 1 ) [ 1 , 3 , 4 , 5 , 6 , 7 ]. Historically, ACM caused by mutations in desmosomal genes was associated with isolated or predominantly right ventricular disease (RV-ACM).…”

“…Historically, ACM caused by mutations in desmosomal genes was associated with isolated or predominantly right ventricular disease (RV-ACM). However, recent studies have highlighted a high prevalence of left ventricular involvement along with isolated and left-dominant ACM forms (LV-ACM) in patients carrying FLNC , DSP , or DSG2 mutations, for instance [ 3 , 8 , 9 , 10 ].…”

Programmed Ventricular Stimulation as an Additional Primary Prevention Risk Stratification Tool in Arrhythmogenic Right Ventricular Cardiomyopathy: A Multinational Study

“…Its utility has been replicated in independent cohorts, and it has been shown to perform better than risk stratification algorithms currently proposed by consensus statements. [6][7][8][9][10][11][12] Since its publication, the possibility of integrating additional parameters such as ventricular tachycardia (VT) inducibility on programmed ventricular stimulation (PVS) with the risk calculator has been suggested. 13 The role of PVS for arrhythmic risk stratification in primary prevention ARVC has been debated.…”