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Original research
Genotype–phenotype correlation in arrhythmogenic right ventricular cardiomyopathy—risk of arrhythmias and heart failure
  1. Alex Hørby Christensen1,2,3,
  2. Pyotr G Platonov4,
  3. Henrik Kjærulf Jensen5,6,
  4. Monica Chivulescu7,8,
  5. Anneli Svensson9,
  6. Pia Dahlberg10,
  7. Trine Madsen11,
  8. Tanja Charlotte Frederiksen5,6,
  9. Tiina Heliö12,
  10. Øyvind Haugen Lie7,8,
  11. Kristina H Haugaa7,8,
  12. Jesper Hastrup Svendsen2,3,
  13. Henning Bundgaard2,3
  1. 1 Department of Cardiology, Herlev-Gentofte Hospital, Herlev, Denmark
  2. 2 Department of Cardiology, The Heart Centre, Rigshospitalet, Copenhagen, Denmark
  3. 3 Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  4. 4 Department of Cardiology, Clinical sciences, Lund University, Lund, Sweden
  5. 5 Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark
  6. 6 Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
  7. 7 Department of Cardiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
  8. 8 Institute of Clinical Medicine, University of Oslo, Oslo, Norway
  9. 9 Department of Cardiology and Department of Health, Medicine and Caring Sciences, Linköping University, Linkoping, Sweden
  10. 10 Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden
  11. 11 Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark
  12. 12 Department of Cardiology, Helsinki University Hospital, Helsinki, Finland
  1. Correspondence to Dr Alex Hørby Christensen, Department of Cardiology, Herlev-Gentofte Hospital, Herlev, Denmark; alexhc{at}


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.

  • cardiomyopathy
  • genetics

Data availability statement

The full data set cannot be made available due to patient confidentiality. The data cannot be made publicly available due to patient confidentiality.

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Data availability statement

The full data set cannot be made available due to patient confidentiality. The data cannot be made publicly available due to patient confidentiality.

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  • JHS and HB are joint senior authors.

  • Contributors AHC conceptualised the study, performed the data analyses, and drafted and revised the manuscript. PGP, HKJ, MC, AS, PD, TM, TCF, TH, ØHL, KHH, JHS and HB collected data for the study, participated in data analyses and revised the manuscript.

  • Funding This work was supported by the Research Council at Herlev-Gentofte Hospital (AHC), the Independent Research Fund Denmark (grant 0134-00363B, AHC), the Novo Nordisk Foundation, Denmark (NNF20OC0065799, AHC; NNF18OC0031258, HKJ), the Aarno Koskelo Foundation (TH), and the Special Governmental Subsidy and the Finnish Cardiovascular Research Foundation (TH). The Nordic ARVC Registry has been supported by the Heart Centre Research Foundation at Rigshospitalet (JHS and HB), the Swedish Heart-Lung Foundation (PGP) and ALF Foundation (PGP), and the South Eastern Health Authorities, Norway (MC and OHL).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.