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 ( 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.

Recent highlights on myocarditis, cardiovascular complications of COVID-19, and cardiomyopathies from the International Journal of Cardiology: Heart & Vasculature

“…Patients with dilated cardiomyopathy and a pathogenic TTN variant can also develop fulminant myocarditis as an initial presentation, as described in a case report in the Journal [24] . This finding was further confirmed by a large cohort that identified pathogenic TTN truncating variants in 7% of all patients presenting with myocarditis complicated by left ventricular systolic dysfunction [19] .…”

“…Perhaps the most relevant news in the field of myocarditis are that we could collect reports related to myocarditis with a clear genetic background [18] , [19] , myocarditis associated with COVID-19 infection [20] , [21] , and myocarditis in conjunction with COVID-19 vaccination [22] , [23] .…”

A Novel Nonsense Pathogenic TTN Variant Identified in a Patient with Severe Dilated Cardiomyopathy

“…Patients with a genetic predisposition may remain phenotypically silent until an environmental trigger occurs. The TTN tv clinical phenotype is also particularly susceptible to environmental factors, which can favor the onset of the disease [ 45 , 46 , 47 ]. At first sight, the present case could be classified as an acquired form of DCM.…”

Innate Immunity in Cardiovascular Diseases – Identification of Novel Molecular Players and Targets

“…Recent clinical studies employing highly advanced but clinical practice-ready genetic diagnostics [4,[22][23][24] have revealed significant direct impact of myocardial inflammation upon the induction of life-threatening arrhythmias. These studies investigated patients with well-defined genetic anomalies identified by large-scale mutation scanning.…”