Genetic Landscape of Patients With Dilated Cardiomyopathy and a Systemic Immune-Mediated Disease
Sophie L.V.M. Stroeks, Michiel T.H.M. Henkens, Fernándo Domínguez, Marco Merlo, Debby M.E.I. Hellebrekers, Esther Gonzalez-Lopez, Matteo Dal Ferro, Juan Pablo Ochoa, Francesco Venturelli, Godelieve R.F. Claes, Max F.G.H.M. Venner, Ingrid P.C. Krapels, Els K. Vanhoutte, Pieter van Paassen, Arthur van den Wijngaard, Maurits A. Sikking, Rick van Leeuwen, Myrurgia Abdul Hamid, Xiaofei Li, Han G. Brunner, Gianfranco Sinagra, Pablo García‐Pavía, Stéphane Heymans, Job A.J. Verdonschot
Abstract
BACKGROUND: Systemic immune-mediated diseases (SIDs) are a well-known cause of dilated cardiomyopathy (DCM), a cardiac phenotype influenced by genetic predispositions and environmental factors. OBJECTIVES: This study sought to examine if an underlying genetic predisposition is present in patients with DCM and SID. METHODS: Genotyped DCM-SID patients (n = 183) were enrolled at 3 European centers. Genetic variants were compared with healthy control subjects (n = 20,917), DCM patients without SID (n = 560), and individuals with a suspicion of an SID (n = 1,333). Clinical outcomes included all-cause mortality, heart failure hospitalization, and life-threatening arrhythmias. RESULTS: The SID diagnosis preceded the DCM diagnosis by 4.8 months (Q1-Q3: -68.4 to +2.4 months). The prevalence of pathogenic/likely pathogenic (P/LP) variants in DCM patients with an SID from the Maastricht cohort was 17.1%, compared with 1.9% in healthy control subjects (P < 0.001). In the Madrid/Trieste cohort, the prevalence was 20.5% (P < 0.001). Truncating variants showed the strongest enrichment (10.7% [OR: 24.5] (Maastricht) and 16% [OR: 116.6 (Madrid/Trieste); both P < 0.001), with truncating TTN (titin) variant (TTNtv) being the most prevalent. Left ventricular ejection fraction at presentation was reduced in TTNtv-SID patients compared with DCM patients with SID without a P/LP (P = 0.016). The presence of a P/LP variant in DCM-SID had no impact on clinical outcomes over a median follow-up of 8.4 years (Q1-Q3: 4.9-12.1 years). CONCLUSIONS: One in 6 DCM patients with an SID has an underlying P/LP variant in a DCM-associated gene. This highlights the role of genetic testing in those patients with immune-mediated DCM, and supports the concept that autoimmunity may play a role in unveiling a DCM phenotype in genotype-positive individuals.