Familial screening in case of acute myocarditis reveals inherited arrhythmogenic left ventricular cardiomyopathies

Abstract

Aims: Several data suggest that acute myocarditis could be related to genetic variants involved in familial cardiomyopathies, particularly arrhythmogenic cardiomyopathy, but the management of patients with acute myocarditis and their families regarding their risk for having an associated inherited cardiomyopathy is unclear.

Methods and results: Families with at least one individual with a documented episode of acute myocarditis and at least one individual with a cardiomyopathy or a history of sudden death were included in the study. Comprehensive pedigree, including genetic testing, and history of these families were analysed. Six families were included. Genetic analysis revealed a variant in desmosomal proteins genes in all the probands [five in desmoplakin (DSP) gene and one in desmoglein 2 gene]. In the five families identified with a DSP variant, genetic testing was triggered by the association of an acute myocarditis with a single case of apparently isolated dilated cardiomyopathy or sudden death. Familial screening identified 28 DSP variant carriers; 39% had an arrhythmogenic left ventricular (LV) cardiomyopathy phenotype. Familial histories of sudden death were frequent, and a remarkable phenotype of isolated LV late gadolinium enhancement on contrast-enhanced cardiac magnetic resonance without any other structural abnormality was found in 38% of asymptomatic mutation carriers. None of the DSP variant carriers had imaging characteristics of right ventricle involvement meeting current Task Force criteria for arrhythmogenic right ventricular cardiomyopathy.

Conclusions: Comprehensive familial screening including genetic testing in case of acute myocarditis associated with a family history of cardiomyopathy or sudden death revealed unknown or misdiagnosed arrhythmogenic variant carriers with left-dominant phenotypes that frequently evade arrhythmogenic right ventricular cardiomyopathy Task Force criteria. In view of our results, acute myocarditis should be considered as an additional criterion for arrhythmogenic cardiomyopathy, and genetic testing should be advised in patients who experience acute myocarditis and have a family history of cardiomyopathy or sudden death.

Keywords: Arrhythmogenic cardiomyopathy; Genetics; Myocarditis.

Figure 1

Pedigrees of the six families.

Figure 2

Different DSP‐related ALVC phenotypes observed in a family. (A) Family 1 pedigree. The red circle indicates the subject who had an acute myocarditis, blue squares outline individuals with a DCM or HNDCM phenotype, red squares for individuals with a history of sudden cardiac death, and green squares for individuals with isolated LGE on CMR without any other structural or functional abnormality. Red arrows indicate individuals with frequent PVC. (B) Twelve‐lead ECG showing T‐waves inversion in V4 to V6 and low QRS voltage in the index patient (IV.8) of the family with a phenotype mimicking HNDCM. (C) CMR findings showing focal myocardial oedema (a) and LGE (b) outlined by blue arrows in subject V.1 at the time of acute myocarditis, oedema regression (c), and persistent LGE (d) at follow‐up. Similar LGE pattern in subjects IV.9 (e) and V.2 (f) without any other structural abnormality. ALVC, arrhythmogenic left ventricular cardiomyopathy; CMR, cardiac magnetic resonance; DCM, dilated cardiomyopathy; DSP, desmoplakin; ECG, electrocardiogram; HNDCM, hypokinetic non‐dilated cardiomyopathy; LGE, late gadolinium enhancement; LGE, late gadolinium enhancement; PVC, premature ventricular complex.

Figure 3

CMR findings in subject II.4 from Family 2. (A) Short‐axis slice T2‐weighted images at the time of acute myocarditis showing focal hypersignals on the left ventricle in favour of myocardial oedema (blue arrows). (B) LGE sequences at the same time showing a circumferential midwall and sub‐epicardial ring‐like LGE pattern. (C) Follow‐up CMR 3 months after acute myocarditis showing persistent LGE at the site of initial T2 signals. At this time, there was no LV T2 hypersignal and LVEF dropped. CMR, cardiac magnetic resonance; LGE, late gadolinium enhancement; LVEF, left ventricular ejection fraction.

Figure 4

CMR findings in subjects II.4 (A–C) and I.2 (D) from Family 3. (A) and (B) respectively show T2 hypersignals and LGE of LV inferior and inferoseptal walls at the time of acute myocarditis in subject II.4. (C) Persistence of LGE at the same sites despite no residual T2 hypersignals at 2 years' follow‐up. (D) Similar LGE lesions in her mother (subject I.2) with a DCM phenotype and similar genetic status. CMR, cardiac magnetic resonance; DCM, dilated cardiomyopathy; LGE, late gadolinium enhancement; LV, left ventricular.