Genetic Overlap of Acute Myocarditis and Inherited Cardiomyopathy

Abstract

Background: Acute myocarditis is a complex inflammatory disease increasingly associated with dilated cardiomyopathy (DCM) and arrhythmogenic ventricular cardiomyopathy (ACM), but its underlying genetic basis is unknown. We sought to determine if there is a genetic overlap between myocarditis and inherited forms of cardiomyopathy. Methods: Population-based cohort of 336 consecutive patients with acute myocarditis enrolled in London and Maastricht. All participants underwent targeted DNA-sequencing for well-characterised cardiomyopathy-associated genes with comparison to healthy controls (n=1053). Case ascertainment was assessed against national admission data. Findings: Variants of known or likely pathogenicity were identified in 6% of cases compared to <1% of controls (∆+5%; p=0.0097). In London (n=230; median age 33years; 84% men), which was representative of national myocarditis admissions (median age 32years; 71% men; 66% case ascertainment), 4.8% of cases carried rare truncating variants (tv), particularly within ACM genes (3% cases vs 0% controls; odds ratio 8.2; p=0.001). This was predominantly driven by desmoplakin ( DSP )-tv in patients with normal LVEF and ventricular arrhythmia. In Maastricht (n=106; median age 54years; 61% men), there was enrichment of rare tv in DCM genes, particularly TTN -tv found in 7% (all with LVEF<50%) compared to 1% in controls (OR 3.6; p=0.0116). DCM variants occurred in patients with LV dysfunction (median LVEF 39% vs 60%; p<0.0001). During a median follow-up of 1.9years, all-cause mortality was greatest with a DCM variant (18% vs 4% with no variant; OR 5.0; p=0.004). Interpretation: One in 20 myocarditis cases had a DCM- or ACM-associated genetic variant that would potentially inform clinical management and need for family screening. This was dominated by DSP -tv in those with normal LVEF, and TTN -tv in those with reduced LVEF. Routine genetic testing may be beneficial in acute myocarditis. Funding: British Heart Foundation, Alexander Jansons Foundation, Royal Brompton Hospital, Imperial College London, Wellcome Trust, Medical Research Council and Rosetrees Trust. Declaration of Interest: SKP has received honoraria from Bayer Schering and travel support from Circle 42, outside the submitted work. JSW has received personal fees from Myokardia, outside the submitted work. JSW also has a patent (US 62383189—Methods, systems and apparatus for identifying pathogenic gene variants) issued. DJP has received research support from Siemens and Bayer, and personal fees from Bayer and Chiesi, outside the submitted work. All other authors declare no competing interests. Ethical Approval: All participants in cohorts 1, 2 and 3 provided written informed consent as approved by the 23 National Research Ethics Service [references 09/H0504/104+5 and 09/H0707/69] or Medical Ethical Committee of Maastricht University.