Predicted deleterious cardiomyopathy genes prognosticate myocarditis: Insights from population-wide genome sequencing

Background Myocarditis is a heterogenous inflammatory cardiac disorder classified by histology, etiology and clinical presentation. Recent case-control studies suggest that genetic causes of dilated (DCM), hypertrophic (HCM) and arrhythmogenic (ACM) cardiomyopathies may alter the susceptibility to and outcomes following myocarditis. These associations have not been studied in the general population; findings may have significant implications for risk-prediction at an individual level, and for the development of clinical pathways. Purpose To investigate the impact of pathogenic/likely pathogenic (P/LP) variants in cardiomyopathy genes on the development and prognosis of myocarditis at a population level. Methods From the UK Biobank and the National Institutes of Health All of Us (AoU) Research Program, 884,495 participants with whole exome sequencing were dichotomized into carrier (G+) and non-carrier (G-) cohorts for P/LP variants in ClinGen ACM-, DCM- and HCM-associated genes with at least moderate evidence of disease causality. Outcomes included myocarditis and the composite cardiovascular (CV) endpoint of heart failure (HF), cardiomyopathy, ventricular arrhythmia (VA) and death from any cause. Cox proportional hazards regression and Kaplan-Meier survival analysis modelled associations between carrier status, myocarditis diagnosis and outcomes. Results Overall, 875 (0.1%) participants had myocarditis of whom 30 (3.4%) were G+ (Figure 1). 30/12,603 (0.24%) G+ versus 845/871,892 (0.10%) G- developed myocarditis (HR 2.40 [1.66–3.48]) (Figure 2). In comparison to 1,639/12,573 (13.0%) G+ without myocarditis and 446/845 (52.8%) G- with myocarditis, almost 2 in 3 G+ with myocarditis reached the composite CV endpoint (HR 3.46 [2.13-5.60] and HR 1.29 [0.79-2.11], respectively). Myocarditis in G+ was associated with subsequent cardiomyopathy (HR 5.54 [3.23-9.50]), HF (HR 5.33 [3.17-8.96]) and VA (HR 4.79 [2.34-9.80]) events (Figure 1). G+ status in myocarditis was associated with subsequent cardiomyopathy (HR 1.74 [1.01-3.01]) and HF (HR 1.70 [1.00-2.88]) events (Figure 1). There were no differences in death rates across groups (P > 0.05). Conclusion Our unselected population level study highlights an increased association between P/LP cardiomyopathy-associated gene variants, risk of myocarditis and poorer outcomes. Genetic testing should be considered in index myocarditis cases to refine risk prediction for amongst others, cardiomyopathy and HF.Figure 1Figure 2