Genetic Architecture of Acute Myocarditis and the Overlap With Inherited Cardiomyopathy
Authors: 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 , Tzoulaki Ioanna , Pantazis Antonis , Cleland John G.F. , Barton Paul J.R. , Cook Stuart A. , Pennell Dudley J. , Garcia-Pavia Pablo , Cooper Leslie T. , Heymans Stephane , Ware James S. , Prasad Sanjay K. 
Published: September 2022

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 (
P
adjusted
=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.