A novel genotype-based clinicopathology classification of arrhythmogenic cardiomyopathy provides novel insights into disease progression

Abstract Aims Arrhythmogenic cardiomyopathy (AC) shows large heterogeneity in its clinical, genetic, and pathological presentation. This study aims to provide a comprehensive atlas of end-stage AC and illustrate the relationships among clinical characteristics, genotype, and pathological profiles of patients with this disease. Methods and results We collected 60 explanted AC hearts and performed standard pathology examinations. The clinical characteristics of patients, their genotype and cardiac magnetic resonance imaging findings were assessed along with pathological characteristics. Masson staining of six representative sections of each heart were performed. Digital pathology combined with image segmentation was developed to calculate distribution of myocardium, fibrosis, and adipose tissue. An unsupervised clustering based on fibrofatty distribution containing four subtypes was constructed. Patients in Cluster 1 mainly carried desmosomal mutations (except for desmoplakin) and were subjected to transplantation at early age; this group was consistent with classical ‘desmosomal cardiomyopathy’. Cluster 2 mostly had non-desmosomal mutations and showed regional fibrofatty replacement in right ventricle. Patients in Cluster 3 showed parallel progression, and included patients with desmoplakin mutations. Cluster 4 is typical left-dominant AC, although the genetic background of these patients is not yet clear. Multivariate regression analysis revealed precordial QRS voltage as an independent indicator of the residual myocardium of right ventricle, which was validated in predicting death and transplant events in the validation cohort (n = 92). Conclusion This study provides a novel classification of AC with distinct genetic backgrounds indicating different potential pathogenesis. Cluster 1 is distinct in genotype and clinicopathology and can be defined as ‘desmosomal cardiomyopathy’. Precordial QRS amplitude is an independent indicator reflecting the right ventricular remodelling, which may be able to predict transplant/death events for AC patients.