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Genetic Landscape of Patients With Dilated Cardiomyopathy and a Systemic Immune-Mediated Disease

Sophie L V M Stroeks1, Michiel T H M Henkens2, Fernando Dominguez3

  • 1Cardiovascular Research Institute Maastricht, Department of Cardiology, Maastricht University, Maastricht, the Netherlands; Cardiovascular Sciences, KU Leuven, Leuven, Belgium; European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), Amsterdam, the Netherlands; Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands.

JACC. Heart Failure
|October 19, 2024
PubMed

Insights

Genetic testing reveals that approximately 1 in 6 patients with dilated cardiomyopathy and systemic immune-mediated disease (DCM-SID) carry a pathogenic variant. This finding underscores the importance of genetic screening for DCM-SID, suggesting autoimmunity may trigger DCM in genetically predisposed individuals.

Area of Science:

  • Cardiology
  • Genetics
  • Immunology

Background:

  • Systemic immune-mediated diseases (SIDs) are recognized causes of dilated cardiomyopathy (DCM).
  • DCM is a cardiac condition influenced by both genetic predispositions and environmental factors.
  • The interplay between genetic factors and SIDs in DCM development requires further investigation.

Purpose of the Study:

  • To investigate the presence of an underlying genetic predisposition in patients diagnosed with both DCM and SID.
  • To compare genetic variant prevalence between DCM-SID patients, healthy controls, DCM-only patients, and individuals with suspected SID.

Main Methods:

  • Genotyping was performed on 183 DCM-SID patients across three European centers.
  • Genetic variants were compared against a large cohort of 20,917 healthy controls, 560 DCM patients without SID, and 1,333 individuals with suspected SID.
  • Clinical outcomes, including mortality, heart failure hospitalizations, and arrhythmias, were tracked.

Main Results:

  • A significant prevalence of pathogenic/likely pathogenic (P/LP) variants was found in DCM-SID patients (17.1% in Maastricht, 20.5% in Madrid/Trieste), compared to healthy controls (1.9%).
  • Truncating variants, particularly truncating TTN (titin) variants (TTNtv), were highly enriched in DCM-SID patients.
  • While P/LP variants were common, their presence did not significantly impact long-term clinical outcomes in DCM-SID patients.

Conclusions:

  • Approximately 1 in 6 patients with DCM and SID harbors a P/LP variant in a DCM-associated gene.
  • Genetic testing is recommended for patients with immune-mediated DCM to identify underlying genetic predispositions.
  • These findings support the hypothesis that autoimmunity may unmask DCM in individuals with a genetic susceptibility.
Abstract

Keywords:
autoimmunitydilated cardiomyopathygeneticsheart failuresystemic immune-mediated diseasetitin

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