@article{3c0e8a7308614b64825c8cefd6dd2c19,
title = "Genetic Architecture of Acute Myocarditis and the Overlap with Inherited Cardiomyopathy",
abstract = "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.",
author = "Lota, {Amrit S} and Hazebroek, {Mark R} and Pantazis Theotokis and Rebecca Wassall and Sara Salmi and Halliday, {Brian P} and Upasana Tayal and Job Verdonschot and Devendra Meena and Ruth Owen and {de Marvao}, Antonio and Alma Iacob and Momina Yazdani and Hammersley, {Daniel J} and Jones, {Richard E} and Ricardo Wage and Rachel Buchan and Fredrik Vivian and Yakeen Hafouda and Michela Noseda and John Gregson and Tarun Mittal and Joyce Wong and Robertus, {Jan Lukas} and Baksi, {A John} and Vassiliou, {Vassilios S} and Ioanna Tzoulaki and Antonis Pantazis and Cleland, {John G F} and Barton, {Paul J R} and Cook, {Stuart A} and Pennell, {Dudley J} and Pablo Garcia-Pavia and Cooper, {Leslie T} and Stephane Heymans and Ware, {James S} and Prasad, {Sanjay K}",
note = "Funding Information: 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). Funding Information: Dr Prasad has received honoraria from Bayer Schering and travel support from Circle 42, outside the submitted work. Dr Ware has received personal fees from Myokardia and Foresite Labs, outside the submitted work. Dr Heymans receives personal fees for scientific advice to AstraZeneca, Cellprothera, and CSL Behring and an unrestricted research grant from Pfizer. Dr Pennell has received research support from Siemens and Bayer and personal fees from Bayer and Chiesi, outside the submitted work. The other authors report no conflicts. Publisher Copyright: {\textcopyright} 2022 Lippincott Williams and Wilkins. All rights reserved.",
year = "2022",
month = oct,
day = "11",
doi = "10.1161/CIRCULATIONAHA.121.058457",
language = "English",
volume = "146",
pages = "1123--1134",
journal = "Circulation",
issn = "0009-7322",
publisher = "LIPPINCOTT WILLIAMS & WILKINS",
number = "15",
}