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  • Dilated cardiomyopathy caused by truncating titin variants: long-term outcomes, arrhythmias, response to treatment and sex differences

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Genotype-phenotype correlations
Original research
Dilated cardiomyopathy caused by truncating titin variants: long-term outcomes, arrhythmias, response to treatment and sex differences
  1. Christoffer Rasmus Vissing1,
  2. Torsten Bloch Rasmussen2,
  3. Anne Mette Dybro2,
  4. Morten Salling Olesen3,4,
  5. Lisbeth Nørum Pedersen5,
  6. Morten Jensen2,
  7. Henning Bundgaard1,
  8. Alex Hørby Christensen1,6
  1. 1 The Capital Region’s Unit for Inherited Cardiac Diseases, Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  2. 2 Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark
  3. 3 Laboratory of Molecular Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  4. 4 Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
  5. 5 Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark
  6. 6 Department of Cardiology, Herlev-Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark
  1. Correspondence to Dr Christoffer Rasmus Vissing, The Capital Region’s Unit for Inherited Cardiac Diseases, Department of Cardiology, Rigshospitalet, 2100 Copenhagen, Denmark, Denmark; christoffervi{at}gmail.com

Abstract

Background Truncating variants in titin (TTNtv) are the most common cause of dilated cardiomyopathy (DCM). We evaluated the genotype-phenotype correlation in TTNtv-DCM, with a special focus on long-term outcomes, arrhythmias, response to treatment and sex-related presentation.

Methods Data on patient characteristics and outcomes were collected retrospectively from electronic health records of patients genotyped at two Danish heart transplantation centres.

Results We included 115 patients (66% men). At diagnosis of DCM, mean age was 46±13 years and left ventricular ejection fraction (LVEF) was 28%±13%. During a median follow-up of 7.9 years, 26% reached a composite outcome of left ventricular assist device implantation, heart transplantation or death. In 20% an arrhythmia preceded the DCM diagnosis. In total, 43% had atrial fibrillation (AF) and 23% had ventricular arrhythmias. Long-term left ventricular reverse remodelling (LVRR; LVEF increase ≥10% points or normalisation) was achieved in 58% and occurred more frequently in women (72% vs 51%, p=0.042).

In multivariable proportional hazards analyses, occurrence of LVRR was a strong independent negative predictor of the composite outcome (HR: 0.05 (95% CI 0.02 to 0.14); p<0.001). Female sex independently predicted lower rates of ventricular arrhythmias (HR: 0.33 (95% CI 0.11 to 0.99); p=0.05), while the location of the TTNtv was not associated with cardiovascular outcomes.

Conclusion DCM caused by TTNtv presented in midlife and was associated with a high burden of AF and ventricular arrhythmias, which often preceded DCM diagnosis. Furthermore, LVRR occurred in a high proportion of patients and was a strong negative predictor of the composite outcome. Female sex was positively associated with occurrence of LVRR and longer event-free survival.

  • heart failure
  • arrhythmias
  • cardiac
  • cardiomyopathies
  • genetics
  • medical
  • phenotype

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

https://doi.org/10.1136/jmedgenet-2020-107178

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    Data availability statement

    All data relevant to the study are included in the article or uploaded as supplementary information.

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    Footnotes

    • Twitter @ulvedreng

    • Contributors Concept and design: AHC, HB and CRV. Acquisition of data: CRV, TBR, AMD, MSO, LNP, MJ and AHC. Statistical analyses and interpretation of data: CRV, HB and AHC. Drafting of manuscript and critical revision of the article: CRV, TBR, AMD, MSO, LNP, MJ, HB and AHC.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • 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.