Stephane Heymans1, James S Ware2,3,4, Sanjay K Prasad2,4, Amrit S Lota2,4, Mark R Hazebroek1, Pantazis Theotokis2,4, Rebecca Wassall2,4, Sara Salmi2,4, Brian P Halliday2,4, Upasana Tayal2,4, Job Verdonschot1, Devendra Meena5, Ruth Owen6, Antonio de Marvao2,4, Alma Iacob2,4, Momina Yazdani2,4, Daniel J Hammersley2,4, Richard E Jones2,4, Riccardo Wage2,4, Rachel Buchan2,4, Fredrik Vivian4, Yakeen Hafouda4, Michela Noseda2, John Gregson6, Tarun Mittal4, Joyce Wong4, Jan Lukas Robertus2,4, A John Baksi4, Vassilios Vassiliou7, Ioanna Tzoulaki5, Antonis Pantazis2,4, John G F Cleland2,8, Paul J R Barton2,3,4, Stuart A Cook3,9, Dudley J Pennell2,4, Pablo Garcia-Pavia10,11,12, Leslie T Cooper13. 1. Centre for Heart Failure Research, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, the Netherlands (M.R.H., J.V., S.H.). 2. National Heart & Lung Institute (A.S.L., P.T., R.W., S.S., B.P.H., U.T., A.d.M., A.I., M.Y., M.J.H., R.E.J., R.W., R.B., M.N., J.L.R., A.P., J.G.F.C., P.J.R.B., D.J.P., J.S.W., S.K.P.), Imperial College London, UK. 3. MRC London Institute of Medical Sciences (P.J.R.B., S.A.C., J.S.W.), Imperial College London, UK. 4. Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK (A.S.L., P.T., R.W., S.S., B.P.H., U.T., A.d.M., A.I., M.Y., M.J.H., R.E.J., R.W., R.B., F.V., Y.H., T.M., J.W., J.L.R., A.J.B., A.P., P.J.R.B., D.J.P., J.S.W., S.K.P.). 5. Epidemiology and Biostatistics, School of Public Health (D.M., I.T.), Imperial College London, UK. 6. London School of Hygiene and Tropical Medicine, UK (R.O., J.G.). 7. Norfolk and Norwich University Hospital and University of East Anglia, Norwich, UK (V.V.). 8. Robertson Centre for Biostatistics, University of Glasgow, UK (J.G.F.C.). 9. National Heart Centre Singapore and Duke-National University of Singapore (S.A.C.). 10. Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, CIBERCV, Madrid, Spain (P.G.-P.). 11. Universidad Francisco de Vitoria, Pozuelo de Alarcon, Spain (P.G.-P.). 12. Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (P.G.-P.). 13. Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, FL (L.T.C.).
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.
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.
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