TY - JOUR
T1 - Genotype-phenotype correlation in arrhythmogenic right ventricular cardiomyopathy-risk of arrhythmias and heart failure
AU - Christensen, Alex Hørby
AU - Platonov, Pyotr G.
AU - Jensen, Henrik Kjærulf
AU - Chivulescu, Monica
AU - Svensson, Anneli
AU - Dahlberg, Pia
AU - Madsen, Trine
AU - Frederiksen, Tanja Charlotte
AU - Heliö, Tiina
AU - Lie, Øyvind Haugen
AU - Haugaa, Kristina H.
AU - Hastrup Svendsen, Jesper
AU - Bundgaard, Henning
PY - 2022/9
Y1 - 2022/9
N2 - BACKGROUND: 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. METHODS: 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. RESULTS: 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: PKP2 in 41%, DSG2 in 13%, DSP in 7% and DSC2 in 3%. Reduced left ventricular ejection fraction (LVEF) ≤45% on cardiac MRI was more frequent among patients with DSC2/DSG2/DSP than PKP2 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 PKP2 than DSC2/DSG2/DSP 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 DSC2/DSG2/DSP carriers. Male sex was a risk factor for both arrhythmias and reduced LVEF across all genotype groups (p<0.01). CONCLUSION: In this large cohort of ARVC families with long-term follow-up, we found PKP2 genotype to be more arrhythmic than DSC2/DSG2/DSP or gene-negative carrier status, whereas reduced LVEF was mostly seen among DSC2/DSG2/DSP carriers. Male sex was associated with a more severe phenotype.
AB - BACKGROUND: 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. METHODS: 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. RESULTS: 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: PKP2 in 41%, DSG2 in 13%, DSP in 7% and DSC2 in 3%. Reduced left ventricular ejection fraction (LVEF) ≤45% on cardiac MRI was more frequent among patients with DSC2/DSG2/DSP than PKP2 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 PKP2 than DSC2/DSG2/DSP 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 DSC2/DSG2/DSP carriers. Male sex was a risk factor for both arrhythmias and reduced LVEF across all genotype groups (p<0.01). CONCLUSION: In this large cohort of ARVC families with long-term follow-up, we found PKP2 genotype to be more arrhythmic than DSC2/DSG2/DSP or gene-negative carrier status, whereas reduced LVEF was mostly seen among DSC2/DSG2/DSP carriers. Male sex was associated with a more severe phenotype.
KW - cardiomyopathy
KW - genetics
U2 - 10.1136/jmedgenet-2021-107911
DO - 10.1136/jmedgenet-2021-107911
M3 - Article
C2 - 34400560
AN - SCOPUS:85137008480
SN - 0022-2593
VL - 59
SP - 858
EP - 864
JO - Journal of Medical Genetics
JF - Journal of Medical Genetics
IS - 9
ER -