Genetic Risk of Arrhythmic Phenotypes in Patients With Dilated Cardiomyopathy

• Published in: Journal of the American College of Cardiology Vol. 74; no. 11; pp. 1480 - 1490
• Main Authors: Gigli, Marta, Merlo, Marco, Graw, Sharon L., Barbati, Giulia, Rowland, Teisha J., Slavov, Dobromir B., Stolfo, Davide, Haywood, Mary E., Dal Ferro, Matteo, Altinier, Alessandro, Ramani, Federica, Brun, Francesca, Cocciolo, Andrea, Puggia, Ilaria, Morea, Gaetano, McKenna, William J., La Rosa, Francisco G., Taylor, Matthew R.G., Sinagra, Gianfranco, Mestroni, Luisa
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.09.2019; Elsevier Limited
• Subjects: Adult; Arrhythmias, Cardiac - genetics; Arrhythmias, Cardiac - mortality; Cardiac arrhythmia; Cardiology; Cardiomyopathy; Cardiomyopathy, Dilated - complications; Cardiomyopathy, Dilated - genetics; Congestive heart failure; Connectin; Cross-Sectional Studies; Cytoskeleton; desmosomal mutations; Dilated cardiomyopathy; Female; Fibrillation; Gene sequencing; Genes; Genetic diversity; Genetic variance; Genetic Variation; genotype-phenotype correlation; Genotypes; Heart; Heart failure; Heart transplantation; Humans; Implantation; Ion channels; Male; Medical prognosis; Middle Aged; Mortality; Mutation; Next-generation sequencing; Patients; Phenotype; Phenotypes; Prognosis; Risk Assessment; Risk Factors; Tachycardia; Transplantation; Ventricle; Ventricular fibrillation; ARVC; desmosomal mutations; genotype-phenotype correlation; DHF/HTx/VAD; LVEF; ICD; NGS; SCD/VT/VF; prognosis; HF; dilated cardiomyopathy; DCM
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2019.06.072

Genotype-phenotype correlations in dilated cardiomyopathy (DCM) and, in particular, the effects of gene variants on clinical outcomes remain poorly understood. The purpose of this study was to investigate the prognostic role of genetic variant carrier status in a large cohort of DCM patients. A total of 487 DCM patients were analyzed by next-generation sequencing and categorized the disease genes into functional gene groups. The following composite outcome measures were assessed: 1) all-cause mortality; 2) heart failure–related death, heart transplantation, or destination left ventricular assist device implantation (DHF/HTx/VAD); and 3) sudden cardiac death/sustained ventricular tachycardia/ventricular fibrillation (SCD/VT/VF). A total of 183 pathogenic/likely pathogenic variants were found in 178 patients (37%): 54 (11%) Titin; 19 (4%) Lamin A/C (LMNA); 24 (5%) structural cytoskeleton-Z disk genes; 16 (3.5%) desmosomal genes; 46 (9.5%) sarcomeric genes; 8 (1.6%) ion channel genes; and 11 (2.5%) other genes. All-cause mortality was no different between variant carriers and noncarriers (p = 0.99). A trend toward worse SCD/VT/VF (p = 0.062) and DHF/HTx/VAD (p = 0.061) was found in carriers. Carriers of desmosomal and LMNA variants experienced the highest rate of SCD/VT/VF, which was independent of the left ventricular ejection fraction. Desmosomal and LMNA gene variants identify the subset of DCM patients who are at greatest risk for SCD and life-threatening ventricular arrhythmias, regardless of the left ventricular ejection fraction. [Display omitted]