Highly malignant disease in early-onset arrhythmogenic cardiomyopathy
Authors: Smedsrud M , Chivulescu M , Forsaa M I , Castrini I , Aabel E W , Rootwelt-Norberg C , Hasselberg N E , Fruh A , Haugaa K H 
Published: October 2022

Abstract

Background
Arrhythmogenic cardiomyopathy (AC) is an inheritable and progressive cardiomyopathy characterized by high risk of ventricular tachyarrhythmias and sudden cardiac death. Pediatric patients are underrepresented in AC publications, and the AC penetrance and incidence of cardiac events in children have yet to be determined. Current guidelines recommend initiating family screening in first-degree relatives after age 10–12 years, but the clinical value of this approach has not been systematically evaluated.

Purpose
We aimed to explore the incidence of severe cardiac events in pediatric patients with AC and to describe the phenotype in early-onset AC. Furthermore, we wanted to estimate the penetrance of AC disease in genotype positive pediatric family members.

Methods
In a single-center follow-up study, we included consecutive AC pediatric patients and genotype positive family members ≤18 years of age. The patients were followed regularly with electrocardiographic, structural and arrhythmic characteristics according to the AC 2010 Task Force Criteria (TFC). Penetrance of AC disease was defined as fulfilling definite AC diagnosis by the 2010 TFC. We defined severe cardiac events as cardiac death, heart transplantation (HTx) or severe ventricular arrhythmias (VAs) (sustained ventricular tachycardia or aborted cardiac arrest).

Results
We included 62 individuals (11 probands, 51 family members).
Fourteen events (5 HTx, 9 VAs) occurred during 6±4 years of follow-up, giving a cumulative incidence of 23% and a yearly incidence rate of 4%. Seven (50%) events occurred in patients ≤12 years of age (Figure 1). All children who underwent heart transplantation were ≤12 years.
At inclusion, 13 patients (21%) fulfilled definite AC diagnosis (10 probands, 3 family members). At end of follow-up, AC diagnosis were fulfilled in 20 (32%) patients (11 probands, 9 family members), indicating progression of disease in 7 patients. Mean age at definite AC diagnosis was 13±4 years and 8 patients (40%) were ≤12 years old (Figure 1). All patients diagnosed with AC &lt;12 years of age had biventricular disease with mean LVEF 30±9% and right ventricular fractional area change 21±5% at end of follow-up.
Among the family members, 5 (10%) had signs of AC disease at the time of genetic diagnosis. At end of follow-up, AC penetrance was 18% and 3 (6%) experienced severe cardiac events at a mean age of 13±6 years.

Conclusion
In a pediatric AC cohort of probands and genotype positive family members, we found a high incidence of VA and HTx. Half of the events occurred in children ≤12 years of age, supporting a markedly severe phenotype in early-onset AC. AC penetrance among pediatric family members identified by screening was high, with a significant incident of events. Our findings emphasize the high risk features of early-onset AC disease and indicate a need to start AC family screening in children at an younger age than recommended by current guidelines.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The Norwegian Research Council