Genetic architecture of acute myocarditis and the overlap with inherited cardiomyopathy

Lota, Amrit S., Hazebroek, Mark R., Theotokis, Pantazis, Wassall, Rebecca, Salmi, Sara, Halliday, Brian P., Tayal, Upasana, Verdonschot, Job, Meena, Devendra, Owen, Ruth, de Marvao, Antonio, Iacob, Alma, Yazdani, Momina, Hammersley, Daniel J., Jones, Richard E., Wage, Riccardo, Buchan, Rachel, Vivian, Fredrik, Hafouda, Yakeen, Noseda, Michela, Gregson, John, Mittal, Tarun, Wong, Joyce, Robertus, Jan Lukas, Baksi, A. John, Vassiliou, Vassilios S. ORCID:, Tzoulaki, Ioanna, Pantazis, Antonis A., Cleland, John G. F., Barton, Paul J. R., Cook, Stuart A., Pennell, Dudley J., Garcia-Pavia, Pablo, Cooper Jr, Leslie T., Heymans, Stephane, Ware, James S. and Prasad, Sanjay K. (2022) Genetic architecture of acute myocarditis and the overlap with inherited cardiomyopathy. Circulation, 146 (15). 1123–1134. ISSN 0009-7322

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Background: Acute myocarditis is an inflammatory condition that may herald the onset of dilated cardiomyopathy (DCM) or arrhythmogenic cardiomyopathy (ACM). We investigated the frequency and clinical consequences of DCM and ACM genetic variants in a population-based cohort of patients with acute myocarditis. Methods: This was a population-based cohort of 336 consecutive patients with acute myocarditis enrolled in London and Maastricht. All participants underwent targeted DNA sequencing for well-characterized cardiomyopathy-associated genes with comparison to healthy controls (n=1053) sequenced on the same platform. Case ascertainment in England was assessed against national hospital admission data. The primary outcome was all-cause mortality. Results: Variants that would be considered pathogenic if found in a patient with DCM or ACM were identified in 8% of myocarditis cases compared with <1% of healthy controls (P=0.0097). In the London cohort (n=230; median age, 33 years; 84% men), patients were representative of national myocarditis admissions (median age, 32 years; 71% men; 66% case ascertainment), and there was enrichment of rare truncating variants (tv) in ACM-associated genes (3.1% of cases versus 0.4% of controls; odds ratio, 8.2; P=0.001). This was driven predominantly by DSP-tv in patients with normal LV ejection fraction and ventricular arrhythmia. In Maastricht (n=106; median age, 54 years; 61% men), there was enrichment of rare truncating variants in DCM-associated genes, particularly TTN-tv, found in 7% (all with left ventricular ejection fraction<50%) compared with 1% in controls (odds ratio, 3.6; P=0.0116). Across both cohorts over a median of 5.0 years (interquartile range, 3.9–7.8 years), all-cause mortality was 5.4%. Two-thirds of deaths were cardiovascular, attributable to worsening heart failure (92%) or sudden cardiac death (8%). The 5-year mortality risk was 3.3% in genotype-negative patients versus 11.1% for genotype-positive patients (Padjusted=0.08). Conclusions: We identified DCM- or ACM-associated genetic variants in 8% of patients with acute myocarditis. This was dominated by the identification of DSP-tv in those with normal left ventricular ejection fraction and TTN-tv in those with reduced left ventricular ejection fraction. Despite differences between cohorts, these variants have clinical implications for treatment, risk stratification, and family screening. Genetic counseling and testing should be considered in patients with acute myocarditis to help reassure the majority while improving the management of those with an underlying genetic variant.

Item Type: Article
Additional Information: Funding: The study was funded and supported by Alexander Jansons Myocarditis UK, British Heart Foundation (FS/17/21/32712 awarded to Drs Lota and Prasad; RE/18/4/34215; FS/ICRF/21/26019 awarded to Dr Halliday), Cardiovascular Research Centre at the Royal Brompton and Harefield Hospitals, Medical Research Council (UK), National Institute for Health Research Royal Brompton Cardiovascular Biomedical Research Unit, National Institute for Health Research Imperial College Biomedical Research Centre, National Heart and Lung Institute Foundation, Royston Centre for Cardiomyopathy Research, the Wellcome Trust, Foundation Leducq, and the Instituto de Salud Carlos III. Dr Prasad has received research grant funding from the Alexander Jansons Foundation, Rosetree Trust, British Heart Foundation, Medical Research Council, and Coronary Artery Disease Research Association. Dr Hazebroek has received funding from the Kootstra Talented Post-Doc Fellowship. Dr Heymans acknowledges support from the Netherlands Cardiovascular Research Initiative, an initiative with support of the Dutch Heart Foundation; Dutch Cardiovascular Alliance; CVON Arena-PRIME, 2017-18 for gene sequencing; and Double Dosis 2020-B005 for patient inclusion. The Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by the Instituto de Salud Carlos III, Ministerio de Ciencia, the Pro-CNIC Foundation, and the Severo Ochoa Centers of Excellence program (CEX2020-001041-S).
Uncontrolled Keywords: arrhythmogenic right ventricular dysplasia,cardiomyopathy, dilated,connectin,death, sudden, cardiac,desmoplakins,heart failure,myocarditis,cardiology and cardiovascular medicine,physiology (medical) ,/dk/atira/pure/subjectarea/asjc/2700/2705
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Groups > Cardiovascular and Metabolic Health
Faculty of Science > Research Groups > Norwich Epidemiology Centre
Faculty of Medicine and Health Sciences > Research Groups > Norwich Epidemiology Centre
Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
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Depositing User: LivePure Connector
Date Deposited: 20 Jul 2022 16:30
Last Modified: 19 Oct 2023 03:23
DOI: 10.1161/CIRCULATIONAHA.121.058457


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