LEPrognostic implications of family screening in Dilated and Arrhythmogenic Cardiomyopathies

Abstract Introduction Dilated cardiomyopathy (DCM) and arrhythmogenic left dominant cardiomyopathy (ALVC) are overlapping phenotypes of inherited cardiomyopathies characterized by left ventricular systolic dysfunction (LVSD), sharing the same genetic background. The risk of disease development in relatives is relevant and influenced by multiple factors. The purpose of familial screening (FS) is to early detect cardiac manifestations by ECG and echocardiogram every 2-5 years. Recent studies suggested a possible role of Holter-ECG and Global Longitudinal Strain (GLS) for disease prediction. However, these are not strongly recommended in the current FS guidelines. Moreover, it is unclear if FS represents a useful tool to prevent cardiac events in family members. Purpose Our study aims to 1) elucidate the role of genetic and environmental factors for cardiac disease development in relatives of probands affected by DCM/ALVC, 2) quantify the predictive role of FS for LVSD, and 3) assess the prognostic impact of FS on relatives. Methods Reasons for first medical contact, genetic data, baseline and follow-up (FU) clinical, ECG, echocardiogram, GLS, Holter-ECG data and outcomes were compiled. LVSD was defined as ejection fraction < 50%. Moreover, a primary outcome including all-cause death (D) and heart transplantation (HT) and an arrhythmic secondary outcome including sudden cardiac death (SCD) and major ventricular arrhythmias (MVA) were evaluated in affected relatives. Results A total of 385 relatives (85% with a proband affected by DCM) were enrolled. Among these, 223 (58%) were unaffected at baseline. During a median follow-up of 60 (IQR 30-110) months, 81 (36%) developed LVSD. Being carrier of pathogenic variants and having a family history of SCD were the main clinical factors significantly associated with LVSD development in the multivariable model, whereas environmental factors were not. Moreover, the GLS value at baseline was significantly lower in relatives developing LVSD compared to persistent unaffected relatives (-14.9 ±3.2 vs -19.8 ±3.2, p<0.001), and its value was an independent predictor of LVSD. Furthermore, in comparison to previously published predictive models which included age, ECG and echocardiographic abnormalities (C-index 0.64), adding Holter-ECG offers a better fit and increases the concordance by 20% (C-index 0.77). In conclusion, in the total population of 243 relatives (63%) with LVSD (at the baseline or at FU), cardiac events were less frequent among relatives detected by FS. Conclusions Genetic background plays a major role in the development of LVSD in relatives of DCM/ALVC probands. GLS and Holter-ECG could be useful tools to improve the efficiency of FS to predict LVSD, suggesting early FU visits. FS shows a significant prognostic protective impact in this study population.