Genotype-phenotype association in patients with arrhythmic variant of non-compaction cardiomyopathy

Abstract

Abstract Funding Acknowledgements Type of funding sources: None. Purpose. To evaluate the genotype-phenotype association in Belarusian patients with non-compaction cardiomyopathy (NCCM) and clinically significant ventricular arrhythmias. Methods. The study included 170 unrelated pts with NCCM prospectively observed in the RSPC "Cardiology", who underwent 24-hour Holter ECG monitoring for 12 months after entering the study. The median follow-up was 36 months [6; 152,0]. The median age of pts was 42 [18; 69] years, men – 63,2%. The arrhythmic phenotype of NCСM was diagnosed by the presence of unexplained syncope; nonsustained ventricular tachycardia, defined as ≥3 consecutive ventricular contractions lasting <30 seconds with a frequency of ≥120 bpm; 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 R. Jenni 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 pts with NCCM using next generation sequencing (NGS). Results. In 76 out of 170 (44,7%) pts, clinically significant arrhythmias were the leading manifestation of the disease. Nonsustained VT was recorded in 54 (71,1%) pts, sustained VT – in 15 (19,7%) pts, VPB more than 500 per day – in 50 (65,8%), chronic AF with episodes of nonsustained VT was noted in 34 (44,7%) pts. During the follow-up period (median follow-up of 36 months), devices (ICD/CRT-D) were implanted in 15 (19,7%) pts, appropriate shocks were observed in two of them; three pts died, among which SCD occurred in one patient with CRT-D therapy, which was ineffective in stopping sustained VT. 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. The proportion of mutations in sarcomeric proteins genes 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 replacements were found in proteins of different functional classes. Conclusions. The frequency of multiple mutations was higher (38,5%) in the group of pts with the arrhythmic NCCM phenotype. In the group of pts with implantable devices (ICD/CRT-D), mutations in the genes of sarcomeric proteins were observed more often. The genetic characteristics of pts, 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 pts with NCCM, as well as for early diagnosis of the disease in their relatives.