New pathological insights into arrhythmogenic cardiomyopathy: implications for non-invasive diagnosis

Background Arrhythmogenic cardiomyopathy (ACM) is a rare inherited heart muscle disease characterized by fibro-fatty or fibrous replacement of the ventricular myocardium. Our aims are: 1) to assess the transmural extent and pattern of distribution of fibro-fatty replacement in juvenile SCD and HTx with a pathologic diagnosis of ACM; 2) to correlate the pathology features with clinical findings; 3) to assess the burden of ACM as a cause of SCD in young competitive athletes; 4) to provide genotype-phenotype correlation. Methods The databases of SCD and HTx of the Cardiovascular Pathology Unit were inquired. All cases with a diagnosis of ACM at histopathological evaluation and availability of the whole heart for revision were included. A complete mid-ventricular transverse section was processed for histology. Ventricular segmentation was obtained dividing the right ventricle (RV), interventricular septum (IVS), and left ventricle (LV) in three portions (anterior, lateral, and posterior for each ventricle and anterior, mid, and posterior for the IVS); each ventricular portion was then partitioned in four layers (subepicardial, midmural, subendocardial, and trabecular) and every IVS sample in three layers (RV-side, mid-mural, and LV-side). The presence and extent of fibrous or fibro-fatty replacement was qualitative assessed, by excluding para-physiological fat infiltration. Clinical data were reviewed and genetic testing was performed. Results ACM was diagnosed in 97 out of 912 juvenile SCD (10.6%) and in 58 out of 1149 explanted hearts (5.0%). A total of 135 ACM cases fulfilled the inclusion criteria (91 SCD and 44 HTx). Mean age was 26.6±7.1 and 43.4±16.6 years respectively, with 6.6% and 43.2% of females. The segments most frequently involved in the SCD cohort were the LV lateral and posterior subepicardial, while in the HTx subgroup the whole RV (excluding the trabecular portions) and the LV lateral and posterior subepicardial. The interventricular septum (IVS) resulted affected in 40.7% of the SCD cases vs. 90.9% of the HTx. Isolated LV involvement was more frequent in SCD than HTx (29.6% vs 4.5%). Transmural scarring was almost constant in the RV in HTx (91%), less common in the RV in SCD (38.5%) and infrequent in the LV in both cohorts (7.7% SCD and 31.8% HTx). 54 competitive athletes were available for clinicopathologic correlations. ECG showed negative T waves in 23 cases (42.6%) and low QRS voltages in 16 (29.6%). The presence of negative T waves in the right precordial leads was associated with a higher prevalence of RV transmurality and biventricular involvement. The LV was more frequently involved compared to the RV (94.4% vs. 70.4%). A P/LP genetic variant in a causative gene was identified in 47/106 cases (44.3%): 33.3% of the SCD, 62.9% of the HTx and 45.5% of the “extra” ACM cases. PKP2 (15 cases), DSP (6), DES (4), DSG2 (4), TTN (3), DSC2 (3), FLNC (3), SCN5A (2); MYBPC3 (1); LMNA (1). Six cases hosted two pathogenic variants. Desmosomal mutations and particularly PKP2, DSG2, and DSC2 were associated with a more frequent involvement of the RV and RV-side of the IVS. DSP and non-desmosomal mutations showed instead a variable RV involvement with a prevalent posterior and lateral subepicardial lesions in the LV, coupled with more frequent midmural IVS lesions. Conclusions Different patterns of scarring are identifiable in SCD and HTx with transmural lesions being almost constant in the RV in HTx and extremely rare in the LV, IVS more frequently involved in HTx and exclusive LV involvement almost unique to the SCD cohort. Genotype-phenotype correlations confirms that the classical RV ACM is mostly linked to PKP2, DSG2 and DSC2 mutations. Awareness of the morphologic variability can help the interpretation of ECGs, echocardiograms and magnetic resonance imaging.