Role of arrhythmic phenotype in prognostic stratification and management of dilated cardiomyopathy

Abstract

Aims: Dilated cardiomyopathy (DCM) with arrhythmic phenotype combines phenotypical aspects of DCM and predisposition to ventricular arrhythmias, typical of arrhythmogenic cardiomyopathy. The definition of DCM with arrhythmic phenotype is not universally accepted, leading to uncertainty in the identification of high-risk patients. This study aimed to assess the prognostic impact of arrhythmic phenotype in risk stratification and the correlation of arrhythmic markers with high-risk arrhythmogenic gene variants in DCM patients.

Methods and results: In this multicentre study, DCM patients with available genetic testing were analysed. The following arrhythmic markers, present at baseline or within 1 year of enrolment, were tested: unexplained syncope, rapid non-sustained ventricular tachycardia (NSVT), ≥1000 premature ventricular contractions/24 h or ≥50 ventricular couplets/24 h. LMNA, FLNC, RBM20, and desmosomal pathogenic or likely pathogenic gene variants were considered high-risk arrhythmogenic genes. The study endpoint was a composite of sudden cardiac death and major ventricular arrhythmias (SCD/MVA). We studied 742 DCM patients (45 ± 14 years, 34% female, 410 [55%] with left ventricular ejection fraction [LVEF] <35%). During a median follow-up of 6 years (interquartile range 1.6-12.1), unexplained syncope and NSVT were the only arrhythmic markers associated with SCD/MVA, and the combination of the two markers carried a significant additive risk of SCD/MVA, incremental to LVEF and New York Heart Association class. The probability of identifying an arrhythmogenic genotype rose from 8% to 30% if both early syncope and NSVT were present.

Conclusion: In DCM patients, the combination of early detected NSVT and unexplained syncope increases the risk of life-threatening arrhythmic outcomes and can aid the identification of carriers of malignant arrhythmogenic genotypes.

Keywords: Arrhythmogenic cardiomyopathy; Arrhythmogenic genotype; Dilated cardiomyopathy; Dilated cardiomyopathy with arrhythmic phenotype; Non‐sustained ventricular tachycardia; Unexplained syncope.

Figure 1

Probability of sudden cardiac death/major ventricular arrhythmias (SCD/MVA), according to the occurrence of non-sustained ventricular tachycardia (NSVT), unexplained syncope, ventricular couplets ≥50/24 h, and ventricular premature ventricular contractions (PVCs) ≥1000/24 h within the first year of enrolment.

Figure 2

Probability of sudden cardiac death/major ventricular arrhythmias (SCD/MVA), based on the occurrence of early arrhythmic markers (non-sustained ventricular tachycardia [NSVT] and/or unexplained syncope—upper panel) and the family history of MVA (bottom panel). Curves show the graded risk of SCD/MVA, also considering when family history of MVA is or is not present: group 0 (none arrhythmic markers, neither early syncope nor NSVT—green curve), group 1 (one arrhythmic marker, early syncope or NSVT—yellow curve), group 2 (two arrhythmic markers, both early syncope and NSVT—red curve). CIF, cumulative incidence function.

Figure 3

Efficacy of arrhythmic markers in identifying arrhythmogenic (AR) genotypes. FLNC, filamin C; LMNA, lamin; NSVT, non-sustained ventricular tachycardia; RBM20, RNA binding motif 20; TTNtv, titin-truncating variant; cytoskeleton, structural cytoskeleton Z-disk variant.

Figure 4

Visual representation of the role of early arrhythmic phenotype (non-sustained ventricular tachycardia [NSVT] and unexplained syncope within the first year of enrolment) and family history of major ventricular arrhythmias (MVA) in identifying arrhythmogenic genotypes. The width of the flows and height of the nodes are directly proportional to the number of patients they represent. FLNC, filamin C; LMNA, lamin; RBM20, RNA binding motif 20; TTNtv, titin-truncating variant; cytoskeleton, structural cytoskeleton Z-disk variant.