Arrhythmogenic right ventricular cardiomyopathy/dysplasia on the basis of the revised diagnostic criteria in affected families with desmosomal mutations

Abstract

Aims: To evaluate arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) in affected families with desmosome mutations on the basis of the recently revised Task Force Criteria (TFC).

Methods and results: One hundred and three consecutive carriers of pathogenic desmosome mutations and 102 mutation-negative relatives belonging to 22 families with dominant and 14 families with recessive ARVC/D were evaluated according to the original and revised TFC. Serial cardiac assessment with 12-lead, signal-averaged, and 24 h ambulatory ECG and two-dimensional echocardiography was performed. Clinical events and outcome were prospectively analysed up to 24 years (median 4 years). With the revised criteria, 16 carriers were newly diagnosed on the basis of ECG abnormalities in 100%, ventricular arrhythmias in 79%, and functional/structural alterations in 31%, increasing diagnostic sensitivity from 57 to 71% (P = 0.001). Task Force Criteria specificity improved from 92 to 99% (P = 0.016). In dominant mutation carriers, penetrance changed significantly (61 vs. 42%, P = 0.001); no changes were observed in recessive homozygous carriers (97 vs. 97%, P = 1.00). Affected carriers according to the revised TFC (n = 73) had 12-lead ECG abnormalities in 96%, ventricular arrhythmias in 91%, and functional/structural alterations fulfilling echocardiographic criteria in 76%. Cumulative and event-free survival did not differ significantly between dominant and recessive affected carriers, being at 78.6 vs. 76 and 51.7 vs. 55.4%, respectively, by the age of 40 years.

Conclusion: Revised TFC increased diagnostic sensitivity particularly in dominant ARVC/D. Serial family evaluation may rely on electrocardiography which seems to have the best diagnostic utility particularly in early disease that is not detectable by two-dimensional echocardiography.

Figure 1

Recordings from 12-lead ECG (25 mm/s, 10 mm/mV) (top left) and signal-averaged ECG (filter 40–250 Hz) (top right) of a 12-year-old JUP homozygous carrier (see Supplementary material online, Table S3, Case 73) presenting >1000/24 h ventricular extrasystoles. There is prolonged terminal activation duration (58 ms) in lead V1 and all three parameters for late potentials are abnormal (filtered QRS duration = 125 ms, LAS = 42 ms, RMS = 11 μV). Two-dimensional echocardiographic images on parasternal long axis view (middle left) and apical four-chamber view (middle right). There are no morphological/functional abnormalities of the right and left ventricle; right ventricular end-diastolic diameters at outflow tract (RVOT) and inflow tract (RVIT) were within normal limits (corrected for body surface area, 14 and 21 mm/m², respectively). The boy shows the Naxos cutaneous phenotype (woolly hair and palmoplantar keratoderma) (bottom).

Figure 2

Recordings from 12-lead ECG (25 mm/s, 10 mm/mV) of a 24-year-old desmoplakin mutation carrier (see Supplementary material online, Table S3, Case 29) not diagnosed with original Task Force Criteria. During sinus rhythm (top) there is low voltage, T-wave inversion in leads V1 (−0.7 mm) and V2 (−0.2 mm), normal QRS complex width (≤100 ms) in leads V1 to V3, and prolonged TAD (56 ms) in lead V2. She presented sustained ventricular tachycardia of left bundle branch block morphology with superior axis (bottom) but she did not fulfil echocardiographic criteria.

Figure 3

Recording from 12-lead ECG (25 mm/s, 10 mm/mV) (top) of a 18-year-old PKP2 mutation carrier (see Supplementary material online, Table S3, Case 13) shortly before he died suddenly during sport activity. He presented >1000/24 h ventricular extrasystoles but he did not fulfil echocardiographic criteria. There is T-wave inversion in leads V1 to V4 and flattening in V5 and V6; abnormal Q waves are observed in inferolateral leads. Autopsy samples (bottom) reveal mild fibro-fatty replacement of the right ventricular myocardium (RV), with predominant involvement of the left ventricular myocardium (LV), with a subepicardial and midmural distribution and a preserved wall thickness (Heidenhain's trichrome stain).

Figure 4

The Kaplan–Meier survival curves for cumulative survival (left) and event-free survival (right) in dominant (D) (solid line) and recessive (R) (dotted line) affected carriers.