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. 

1. Elliott P, Andersson B, Arbustini F, et al. Classification of the cardiomyopathies: a position statement from the European society of cardiology working group on myocardial and pericardial disease. Eur Heart J 2008;29 (2); 270-6. DOI:10.1093/eurheart/ehm342.

2. Kovacevic-Preradovic T, Jenni R, Oechslin E et al. Isolated left ventricular noncompaction as a cause for heart failure and heart transplantation: a single center experience. Cardiology. 2009; 112: 158-64. DOI: 10.1159/000147899.

3. van Waning J, Caliskan K, Michels M, et al. Cardiac phenotypes, genetics, and risk familian noncompaction cardiomyopathy. J Am Coll Cardiol. 2019; 73:1601-11. DOI: 10.1016/j.jacc.2018.12.085.

4. Jefferies J. Barth Syndrome. Am J Med Genet C Semin Med Genet. 2013; 163 С: 198 -205. DOI: 10.1002/ajmg.c.31372.

5. Timolo A.Z, Nguyen T, et al. Spectrum of Cardiac Arrhythmias in isolated ventricular n0n-compaction. The J of innovations in cardiac rhythm management.2018: 2777-2783. DOI: 10.19102/icrm. 2017.080701.

6. Muser D, Liang J, Witsehey W, et al. Ventricular arrhythmias associated with left ventricular noncompaction: electrophysiological characteristics, mapping, and ablation. Heart Rhythm. 2017; 14 (2): 166 – 75. DOI: 10.1016/j.hrhythm 2016.11.01.14.

7. Kayvanpour E, Sedaghat-Hamedani F, Gi W, et al. Clinical and genetic insights into non-compaction: a meta-analysis and systematic review on 7598 individuals. Clin Res Cardiol. 2019. DOI: 10.1007/s00392-019-01465-3.

8. Haugaa KH, Dan GA, Iliodromitis K. Management of patients with ventricular arrhythmias and prevention of sudden cardiac deathtranslating guidelines into practice: results of the European Heart Rhythm Association survey. Europace. 2018;20:f249-f253. DOI: 10.1093/europace/euy112.

9. Towbin JA, McKenna WJ, Abrams DJ. 2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy. Heart Rhythm. 2019;16(11):e301-e372. DOI: 10.1016/j.hrthm.2019.05.007.

10. Towbin J, Lorts A, Jefferies J. Left ventricular non-compaction cardiomyopathy. The Lancet, 2015; 386: 813-25. DOI: 10.1016/S0140-6736(14)61282-4.

11. Towbin J, McKenna W, Abrams D, et al. 2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy: Executive summary. Heart Rhythm. 2019;16(11):e373-e407. DOI: 10.1016/j.hrthm.2019.09.019.

12. van Waning J, Moesker J, Heijsman D, et al. Systematic Review of Genotype-Phenotype Correlations in Noncompaction Cardiomyopathy. J Am Heart Assoc. 2019;8(23):e012993. DOI: 10.1161/JAHA.119.012993.

13. Jenni R, Oechslin E, Schneider J, et al. Echocardiographic and pathoanatomical characteristics of isolated left ventricular noncompaction: a step towards classification as a distinct cardiomyopathy. Heart (British Cardiac Society). 2001;86 (6):666–71. DOI: 10.1136/heart.86.6.666.

14. Petersen SE, Selvanayagam JB, Wiesmann F, et al. Left ventricular noncompaction: in- sights from cardiovascular magnetic resonance imaging. Journal of the American College of Cardiology. 2005;46 (1):101–5. DOI: 10.1016/j.jacc.2005.03.045.

15. Jacquier A, Thuny F, Jop B, et al. Measurement of trabeculated left ventricular mass using cardiac magnetic resonance imaging in the diagnosis of left ventricular non-compaction. European Heart Journal. 2010;31 (9):1098– 104. DOI: 10.1093/eurheartj/ehp595.

16. Wang K, et al. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Research – 2010. – Vol. 38. – P. 164. DOI: 10.1093/nar/gkq603.

17. Roberts A, Ware J, Herman D, et al, Integrated allelic transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. Sci Transl Med. 2015; 7: 270 – 6. DOI: 10.1126/Scitransmed.3010134.

18. Ware J, Cook S. Role of titin in Cardiomyopathy from DNA Variants to patient’s stratification. Nat Rev Cardiol 2017; 15 (4): 241 - 52. DOI: 101038/nrcardio.2017.190.

19. Sedaghat-Hamedani F, Haas J, Zhu F, et al. Clinical genetics and outcome of left ventricular non-compaction cardiomyopathy. Eur Heart J. 2017;38(46):3449-3460. DOI: 10.1093/eurheartj/ehx545

20. Miszalski-Jamka K, Jefferies JL, Mazur W, et al. Novel Genetic Triggers and Genotype-Phenotype Correlations in Patients with Left Ventricular Noncompaction. Circulation: Cardiovascular Genetics. 2017;10(4):e001763. DOI: 10.1161/CIRCGENETICS.117.001763.

21. Richard P, Ader F, Roux M, et al. Targeted panel sequencing in adult patients with left ventricular non-compaction reveals a large genetic heterogeneity. Clin Genet. 2019;95:356-367. DOI: 10.1111/cge.13484.

22. Trenkwalder T, Deisenhofer J, Hadamitzky M, et al. Novel frome-scift mutations in PKP2 associated with arrhythmogenic right ventricular cardiomyopathy. A case report. BMC Med Genet.2015; 16:117. DOI: 10.1186/s12881-015-0263-1.

23. Ramond F, Janin A, Filipo SD, et al. Homozygous PKP2 associated with neonatal left ventricle noncompaction. Clin Genet. 2017;91(1):126-130. DOI: 10.1111/cge.12780.

24. Posch M, Perrot A, Geier C, et al. Genetic detection of arginine 14 in causes dilated cardiomyopathy with attenuated electrocardiographic R amplitudes. Heart Rhythm. 2009; 6: 480-6. DOI: 10.1016/j.hrthm.2009.01.016.

25. Van Rijsingen J, van der Zwaag P, Groeneweg J, et al. Outome in phospholamban R14del Carries Result of a large multicenter cohort study. Circ Cardiovasc Genet. 2014; 8: 1942-48. DOI 10.1161/CIRGENETICS.113.000374.

26. Haghighi K, Kolokathis F, Pater L, et al. Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human. J Clin Invest. 2003;111(6):869-876. DOI:10.1172/JCI17892.