Arrhythmic phenotype of non-compaction cardiomyopathy

Purpose. To evaluate the genotype-phenotype association in Belarusian patients with non-compaction cardiomyopathy (NCCM) and clinically significant ventricular arrhythmias.Materials and methods. The study included 170 unrelated patients with NCCM prospectively observed in the RSPC “Cardiology” for 36 months. [6; 42,0], who underwent 24-hour Holter ECG monitoring for 12 months after entering the study. The median age of patients was 42 [18; 69] years, men - 63,2%. The arrhythmic phenotype of NCСM was diagnosed by the presence of unexplained syncope; nonsustained ventricular tachycardia, the presence of ≥500 ventricular premature beats (VPB) per day. The diagnosis of NCCM was established on the basis of the following criteria: 1) Echocardiography of the Jenny criteria; 2) CMR of the S. Petersen and A. Jaquier criteria. The mutations search in the coding sequences of 174 genes was performed in 30 unrelated patients with NCCM using next generation sequencing (NGS).Results. In 76 out of 170 (44,7%) patients, clinically significant arrhythmias were the leading manifestation of the disease. Nonsustained VT was recorded in 54 (71,1%) patients, sustained VT - in 11 (14,5%) patients, VPB more than 500 per day - in 50 (65,8%). During the follow-up period (median follow-up of 36 months), devices (ICD/CRT-D) were implanted in 16 (21,1%). NGS sequencing revealed 40 changes in the nucleotide sequence (5 pathogenic mutations, 30 variants with uncertain significance (VUS), 5 new substitutions) in 27 genes in 26 (86,7%) probands with the arrhythmic phenotype NCCM. The proportion of mutations in sarcomeric proteins genes of was 26,9%, and in ion channel proteins genes was 23,1%. Nucleotide changes in genes encoding structural proteins accounted for 11,5%. In 38,5% of cases, not one, but two or more rare mutations were detected, and in 30,8%, amino acid changes affected proteins of different functional classes.Conclusions. In the group of patients with the arrhythmic NCCM phenotype, the proportion of individuals with genes mutations associated with various cardiomyopathies was 86,7% and was significantly higher than reported in patients with NCCM generally (59%). The frequency of multiple mutations was also higher (38,5%) in this cohort. The genetic characteristics of patients, along with their clinical characteristics, are markers of a high risk of developing life-threatening arrhythmias and can be additionally used for predicting adverse events in patients with NCCM, as well as for early diagnosis of the disease in their relatives.