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

被引:15
作者
Christensen, Alex Horby [1 ,2 ,3 ]
Platonov, Pyotr G. [4 ]
Jensen, Henrik Kjaerulf [5 ,6 ]
Chivulescu, Monica [7 ,8 ]
Svensson, Anneli [9 ,10 ]
Dahlberg, Pia [11 ]
Madsen, Trine [12 ]
Frederiksen, Tanja Charlotte [5 ,6 ]
Helio, Tiina [13 ]
Lie, Oyvind Haugen [7 ,8 ]
Haugaa, Kristina H. [7 ,8 ]
Svendsen, Jesper Hastrup [2 ,3 ]
Bundgaard, Henning [2 ,3 ]
机构
[1] Herlev Gentofte Hosp, Dept Cardiol, Herlev, Denmark
[2] Rigshosp, Heart Ctr, Dept Cardiol, Copenhagen, Denmark
[3] Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark
[4] Lund Univ, Dept Cardiol, Clin Sci, Lund, Sweden
[5] Aarhus Univ Hosp, Dept Cardiol, Aarhus, Denmark
[6] Aarhus Univ, Dept Clin Med, Aarhus, Denmark
[7] Oslo Univ Hosp, Dept Cardiol, Rikshosp, Oslo, Norway
[8] Univ Oslo, Inst Clin Med, Oslo, Norway
[9] Linkoping Univ, Dept Cardiol, Linkoping, Sweden
[10] Linkoping Univ, Dept Hlth Med & Caring Sci, Linkoping, Sweden
[11] Sahlgrens Univ Hosp, Dept Cardiol, Gothenburg, Sweden
[12] Aalborg Univ Hosp, Dept Cardiol, Aalborg, Denmark
[13] Helsinki Univ Hosp, Dept Cardiol, Helsinki, Finland
关键词
cardiomyopathy; genetics; MUTATIONS; COMPOUND; SPECTRUM; GENETICS; IMPACT;
D O I
10.1136/jmedgenet-2021-107911
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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.
引用
收藏
页码:858 / 864
页数:7
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