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. 2019 Sep 17;74(11):1480-1490.
doi: 10.1016/j.jacc.2019.06.072.

Genetic Risk of Arrhythmic Phenotypes in Patients With Dilated Cardiomyopathy

Marta Gigli  1 , Marco Merlo  2 , Sharon L Graw  3 , Giulia Barbati  4 , Teisha J Rowland  3 , Dobromir B Slavov  3 , Davide Stolfo  2 , Mary E Haywood  3 , Matteo Dal Ferro  2 , Alessandro Altinier  2 , Federica Ramani  2 , Francesca Brun  2 , Andrea Cocciolo  1 , Ilaria Puggia  1 , Gaetano Morea  1 , William J McKenna  5 , Francisco G La Rosa  6 , Matthew R G Taylor  7 , Gianfranco Sinagra  2 , Luisa Mestroni  8
Affiliations

Genetic Risk of Arrhythmic Phenotypes in Patients With Dilated Cardiomyopathy

Marta Gigli et al. J Am Coll Cardiol. .

Abstract

Background: Genotype-phenotype correlations in dilated cardiomyopathy (DCM) and, in particular, the effects of gene variants on clinical outcomes remain poorly understood.

Objectives: The purpose of this study was to investigate the prognostic role of genetic variant carrier status in a large cohort of DCM patients.

Methods: 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).

Results: 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.

Conclusions: 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.

Keywords: desmosomal mutations; dilated cardiomyopathy; genotype-phenotype correlation; prognosis.

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Figures

Figure 1.
Figure 1.. Survival Kaplan-Meier curves in variant positive (red line) vs. variant negative patients (black line).
Survival rate was not different according to variant status (p=0.99).
Figure 2.
Figure 2.. Cumulative incidence curves for DHF/HTx/VAD in variant positive (red line) vs. variant negative (black line).
Mutation carriers exhibited a borderline higher rate of DHF/HTx/VAD (p=0.061). DHF/HTx/VAD = Death for heart failure/Heart Transplant/Ventricular assist device. CIF= Cumulative Incidence Function.
Figure 3.
Figure 3.. Cumulative incidence curves for DHF/HTx/VAD in LMNA carriers (blue line) and desmosomal carriers (red line) vs other patients.
LMNA patients showed a higher risk of DHF/HTc/VAD (p<0.001 for all). DHF/HTx/VAD = Death for heart failure/Heart Transplant/Ventricular assist device. CIF= Cumulative Incidence Function.
Figure 4.
Figure 4.. Cumulative incidence curves for SCD-related secondary endpoints (SCD/VT/VF) in patients with desmosomal variants according to LVEF > and ≤ 35%.
The arrhythmic risk was not related to the degree of LV dysfunction as the likelihood of events was similar in desmosomal variant carriers with LVEF>35% Vs LVEF≤ 35% (p=0.79). LVEF= Left ventricular ejection fraction; SCD/VT/VF= Sudden Cardiac Death/sustained ventricular tachycardia/ventricular fibrillation. CIF= Cumulative Incidence Function.
Figure 5.
Figure 5.
Left panel shows the ECG of a DSP mutation (c.1816C>T p.Arg606Trp) carrier with DCM phenotype. Note the negative T waves in the antero-lateral leads and the fragmented QRS that are not typical of classic DCM. Right panel reports the histopathology of patient with a DSP mutation (c.7430_7433delTGTC p.Met2477fs8aaX): section of the right ventricle showed moderate infiltration of the myocardium with adipose tissue.
Central Illustration:
Central Illustration:. Effect of Genotype on Outcome in Dilated Cardiomyopathy.
Left upper panel: Distribution of Pathogenic/Likely Pathogenic variants in the overall study cohort. Left bottom panel: Distribution of pathogenic/Likely Pathogenic variants in the study cohort according to each functional gene cluster. Right upper panel: Cumulative incidence curves for SCD/VT/VF in variant positive vs variant negative. SCD/VT/VF= Sudden Cardiac Death/Ventricular tachycardia/Ventricular fibrillation. Right bottom panel: Kaplan-Meier survival curves for SCD/VT/VF in desmosomal and LMNA variant carriers compared to the other patients. bSCD/VT/VF= Sudden Cardiac Death/Ventricular tachycardia/Ventricular fibrillation. The yield of genetic testing in our cohort was 37%. TTN was most frequently identified (n=54, 11% of the total population), while LMNA and desmosomal variant carriers were respectively 19 (4% and 16 (3%). Variant positive patients carried a borderline higher arrhythmic risk compared to variant negative (p=0.062). Among different genetic clusters, Desmosomal variants (red line) experienced a similar rate of SCD/VT/VF compared to LMNA variants (blue line; p=ns) and higher compared to variant negative (black line, p=0.006) and to the remaining carriers (grey line; p=0.015).
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