CLINICAL FEATURES AND FOLLOW-UP ANALYSIS OF PATIENTS AFFECTED WITH ARRHYTHMOGENIC LEFT VENTRICULAR CARDIOMYOPATHY ​

Background. Arrhythmogenic cardiomyopathy (ACM) is a genetically determined myocardial disease characterized by myocyte necrosis and fibro-adipose replacement, leading to ventricular dysfunction and onset of life-threatening ventricular arrhythmias (LTA). In the last years mainly through cardiovascular magnetic resonance (CMR) studies, a left-dominant form of the disease was described (arrhythmogenic left ventricular cardiomyopathy: ALVC). Aims. To characterize the genetic background, the clinical features, and the outcome of an ALVC cohort of patients and to compare this phenotype with the right dominant (ARVC) and biventricular (BIV) forms. Moreover, we sought to investigate possible prognostic predictive factors for LTA in ALVC patients. Methods. From the entire cohort of 544 patients (both probands and family members), we selected 434 patients affected by ACM (80%). According to phenotype the patients were divided into three groups: ARVC, ALVC and BIV. Family and personal history, genetic analysis, instrumental findings (ECG, 24-h Holter ECG, and CMR) and follow-up data were compared. Results. The study population was composed of 436 ACM patients, of whom 273 (63%) were male and 284 (65%) were probands. According to the phenotype, the general population was divided into three groups: 184 ARVC patients (42%), 112 ALVC (26%), 140 BIV (32%). In ALVC cohort 70 patients (63%) were male and 66 (59%) were probands. The median age at diagnosis was 38 years (IQR 26-49). Genetic analysis identified the presence of a pathogenic/likely pathogenic genetic variant in a causative gene in 61 patients (54%) with the most common disease-genes being Desmoplakin (DSP) (39, 63%). The ECG was abnormal in 74 (66%) cases, mainly due to the presence of low QRS complex voltages in the peripheral leads in (52, 46%) and T wave inversion (TWI) in V4-V6 (22, 20%). A total of 106 patients (95%) underwent CMR. A significant negative association was observed between LV ejection fraction and the extent of LV-LGE (β= -0.853, p=0,007). Overall, 18 patients (16%) had LTA episodes and in 9 (8%) this was the first clinical manifestation of the disease leading to ACM diagnosis. Five patients (5%) experienced heart failure (HF) and 2 (2%) underwent cardiac transplantation, while 2 (2%) died due to refractory HF. Four patients (4%) died suddenly, in all cases as first manifestation of the disease. Finally, 11 patients (10%) presented at least one hot phase episode. Proband status (HR 1.21), history of syncope (HR 2.53), and TWI in V4-V6 (HR 1.26) were associated with an increased arrhythmic burden. Comparison between the three phenotypes revealed that patients belonging to ALVC group showed a significantly lower incidence of LTA (16%), compared to ARVC (30%) and BIV (37%), p=0.001. HF was more frequent in BIV forms (20%) than in ALVC (5%) and ARVC (1%), p<0.001. Similarly, mortality rate was observed to be significantly higher in BIV patients (11%), compared to ALVC (2%) and ARVC (1%), as well as heart transplantation (0% in ARVC, 2% in ALVC and 10% BIV, p<0.001). No statistical differences between the three groups were observed regarding incidence of hot phase episodes (p=0.121). Conclusions. Differential diagnosis between ALVC and phenocopies can be challenging. Padua criteria seem to improve the diagnostic sensitivity, allowing a significant increase in definite diagnoses in ALVC patients. Genetic test showed the presence of a causative genetic variant in 54% of patients, mostly on the DSP gene. Proband status, history of syncope and presence of TWI from V4-V6 were found to be associated with an increased risk of LTA in the ALVC population. The comparison between the three phenotypes revealed that ALVC showed a lower incidence of LTA, HF and death compared to BIV and ARVC groups.