Genotype-phenotype correlation in arrhythmogenic right ventricular cardiomyopathy-risk of arrhythmias and heart failure

• Published in: Journal of medical genetics Vol. 59; no. 9; p. 858
• Main Authors: Christensen, Alex Hørby, Platonov, Pyotr G, Jensen, Henrik Kjærulf, Chivulescu, Monica, Svensson, Anneli, Dahlberg, Pia, Madsen, Trine, Frederiksen, Tanja Charlotte, Heliö, Tiina, Lie, Øyvind Haugen, Haugaa, Kristina H, Hastrup Svendsen, Jesper, Bundgaard, Henning
• Format: Journal Article
• Language: English
• Published: England 01-09-2022
• Subjects: Arrhythmias, Cardiac - genetics; Arrhythmogenic Right Ventricular Dysplasia - complications; Arrhythmogenic Right Ventricular Dysplasia - genetics; Desmosomes; Female; Genetic Association Studies; Heart Failure; Humans; Male; Plakophilins - genetics; Stroke Volume - genetics; Ventricular Function, Left; cardiomyopathy; genetics
• ISSN: 1468-6244
• DOI: 10.1136/jmedgenet-2021-107911

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is predominantly caused by desmosomal genetic variants, and clinical hallmarks include arrhythmias and systolic dysfunction. We aimed at studying the impact of the implicated gene(s) on the disease course.
The Nordic ARVC Registry holds data on a multinational cohort of ARVC families. The effects of genotype on electrocardiographic features, imaging findings and clinical events were analysed.
We evaluated 419 patients (55% men), with a mean follow-up of 11.2±7.4 years. A pathogenic desmosomal variant was identified in 62% of the 230 families:
in 41%,
in 13%,
in 7% and
in 3%. Reduced left ventricular ejection fraction (LVEF) ≤45% on cardiac MRI was more frequent among patients with
/
/
than
ARVC (27% vs 4%, p<0.01). In contrast, in Cox regression modelling of patients with definite ARVC, we found a higher risk of arrhythmias among
than
/
/
carriers: HR 0.25 (0.10-0.68, p<0.01) for atrial fibrillation/flutter, HR 0.67 (0.44-1.0, p=0.06) for ventricular arrhythmias and HR 0.63 (0.42-0.95, p<0.05) for any arrhythmia. Gene-negative patients had an intermediate risk (16%) of LVEF ≤45% and a risk of the combined arrhythmic endpoint comparable with
/
/
carriers. Male sex was a risk factor for both arrhythmias and reduced LVEF across all genotype groups (p<0.01).
In this large cohort of ARVC families with long-term follow-up, we found
genotype to be more arrhythmic than
/
2/
or gene-negative carrier status, whereas reduced LVEF was mostly seen among
/
2/
carriers. Male sex was associated with a more severe phenotype.