Fenotypic expressions and clinical manifestations of arrhythmogenic cardiomyopathy

Abstract

Arrhythmogenic cardiomyopathy (ACM) is a cardiac disorder characterized by structural alterations of the myocardium, which predisposes individuals to ventricular arrhythmias and increases the risk of sudden cardiac death. Initially described as arrhythmogenic right ventricular cardiomyopathy, the involvement of the left ventricle (LV) has been subsequently recognized, leading to the classification of various phenotypes under LV non-dilated cardiomyopathy. The clinical spectrum of ACM ranges from life-threatening ventricular arrhythmias to overt heart failure, sometimes presenting with acute myocarditis-like episodes and extracardiac symptoms, further contributing to the disease's heterogeneity. Diagnosis relies on imaging modalities, such as echocardiogram and cardiac magnetic resonance imaging, to detect areas of fibro-fatty replacement and/or non-ischemic ventricular scarring, integrated with genetic analysis. The 2023 European Society of Cardiology guidelines on Cardiomyopathies underscore the importance of a comprehensive diagnostic approach, combining imaging and genetics for arrhythmic risk stratification and comprehensive patient management. Growing evidence on genotype-phenotype correlation, along with the validation of specific predictive scores, is improving ACM clinical management and promoting personalized treatment tailored to individual and familial characteristics.

Keywords: Arrhythmogenic cardiomyopathy; Sudden death; Ventricular arrhythmias.

Figure 1

arrhythmogenic cardiomyopathy includes right-sided (arrhythmogenic right ventricular cardiomyopathy, blue), left-sided (non-dilated left ventricular cardiomyopathy, yellow), and biventricular forms, with clinical, instrumental, and genetic overlap. Arrhythmogenic right ventricular cardiomyopathy is characterized by regional kinetics abnormalities (akinesia, dyskinesia, or aneurysm) associated with right ventricle dilation or reduced global systolic function, due to fibro-adipose infiltration. ECG findings typically include inverted T waves extending to V3 or beyond, sometimes accompanied by epsilon waves. Genes typically associated with arrhythmogenic right ventricular cardiomyopathy are PKP2, DSG2, DSC2, and JUP. NDLVC is characterized by left ventricle global systolic dysfunction without dilation and/or presence of more or less extensive late gadolinium enhancement (up to a ‘ring-like’ late gadolinium enhancement pattern), due to fibrous replacement of the myocardium. ECG findings typically include inverted T waves in V4–V6 leads and low QRS voltages. Genes typically associated with non-dilated left ventricular cardiomyopathy are DSP, LMNA, FLNC, TMEM43, PLN, and SCN5A. ACM, arrhythmogenic cardiomyopathy; ARVC, arrhythmogenic right ventricular cardiomyopathy; NDLVC, non-dilated left ventricular cardiomyopathy; DSC2, desmocollin2; DSG2, desmoglein2; DSP, desmoplakin; FLNC, filamin C; JUP, plakoglobin; LMNA, lamin A/C; PLN, phospholamban; PKP2, plakophilin; SCN5A, sodium channel alpha subunit; TMEM43, transmembrane protein 43.

Figure 2

Evolution of the diagnostic approach to cardiomyopathies. On the left, the approach proposed by the European Society of Cardiology 2023 guidelines on cardiomyopathies is illustrated, which starts from clinical red flags to identify the phenotype and uses genetic testing and magnetic resonance imaging to arrive at an aetiological diagnosis. On the right, the controversies on the phenotypes defined in the guidelines are shown through cardiac magnetic resonance images of an individual with desmoplakin cardiomyopathy. These images highlight the overlapping zones and grey areas between arrhythmogenic right ventricular cardiomyopathy and non-dilated left ventricular cardiomyopathy, previously included under the umbrella term of arrhythmogenic cardiomyopathy. Reproduced with permission of the authors. ACM, arrhythmogenic cardiomyopathy; ARVC, arrhythmogenic right ventricular cardiomyopathy; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; NDLVC, non-dilated left ventricular cardiomyopathy; RCM, restrictive cardiomyopathy.