State of the Art Review on Genetics and Precision Medicine in Arrhythmogenic Cardiomyopathy

Figures

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  Figure 1. Explanted heart images showing pathological features of different phenotypes in ACM, adapted from Calkins (2013) [10], Thiene et al. (2016) [11], Corrado et al. (2020) [12]. (A) Gross specimen shows dilated thin RV, fatty replacement of entire RV free wall epicardium and thin fibrotic endocardium (white arrow). (B) Gross specimen shows little evidence of RV involvement, however subepicardial grey band of fibrotic tissue (black arrow) is seen in the posterolateral section of the LV. (C) Gross specimen shows fibro-fatty biventricular involvement (black arrows). (D) Histology image shows fat replacement extending from epicardium to endocardium. (E) Histology image with trichrome staining identifies fibrous scars within fat tissue. LV = left ventricle; RV = right ventricle.

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  Figure 2. Spectrum of clinical presentations of right ventricular disease, left ventricular disease, and dilated cardiomyopathy. (A) ACM and ALVC show overlapping phenotypes with ARVC, but the pathology is seen primarily in the left ventricle (although right ventricle is also usually affected). (B) Timeline showing the clinical features of ACM. Hypokinetic non-dilated cardiomyopathy and isolated-ischaemic scar pertain to the pathology where there is marked ventricular scarring as identified by cardiac MRI. Modified from Elliott et al. (2019) [22] and Pinto et al. (2016) [24]. ACM = arrhythmogenic cardiomyopathy; aDCM = arrhythmogenic dilated cardiomyopathy; ALVC = arrhythmogenic left ventricular cardiomyopathy; ARVC = arrhythmogenic right ventricular cardiomyopathy; BiV = biventricular; BivACM = biventricular arrhythmogenic cardiomyopathy; CMP = cardiomyopathy; DCM = dilated cardiomyopathy; LV = left ventricle; PVC = premature ventricular contraction; RV = right ventricle; RWMA = regional wall motion abnormality; SCD = sudden cardiac death.

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  Figure 3. Genetic mutations associated with arrhythmogenic cardiomyopathy. Overlapping genetic determinant implicated in ACM identified from our clinical experience. ACM = arrhythmogenic cardiomyopathy; ALVC = arrhythmogenic left ventricular cardiomyopathy; ARVC = arrhythmogenic right ventricular cardiomyopathy; DCM = dilated cardiomyopathy.

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  Figure 4. Exemplar MRI and ECG finding found in ACM patients with PKP2 mutations. (A) CMR of a patient with PKP2 c1664del T mutation reveals moderate enlargement of the right ventricle; (B) yellow arrow shows apical fibrosis in LGE mode;.(C) 12-Lead ECG of same patient showing ventricular tachycardia with left bundle branch block morphology and inferior axis; (D) resting 12-Lead ECG upon admission to our hospital showing sinus rhythm, and T-wave inversion is present in V1-V4. Reproduced with permission from Trenkwalder et al. (2015) [34].

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  Figure 5. Exemplar MRI and ECG finding found in ACM patients with DSG2 mutations. (A) CMR of a patient with DSG2 p.Leu237Ter mutation showing dilation of both ventricles; (B) a representative ECG of the same patient showing T wave inversion in V1-V3. Reproduced with permission from Chen et al. (2020) [35].

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  Figure 6. Exemplar MRI and ECG finding found in ACM patients with DSP mutations. (A) CMR of a patient with DSP mutation showing left ventricular lateral wall fatty infiltration (red arrow); (B) LGE MRI of the same patient showing fibrosis/scaring of both left ventricular lateral wall and septum; (C) 12-lead ECG showing T-wave inversion in V5-V6 (anterolateral leads). Reproduced with permission from Mattesi et al. (2020) [36].

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  Figure 7. Exemplar MRI and ECG finding found in ACM patients with DSC2 mutations. (A,B) CMR of a patient with DSC2 p.Arg49His mutation showing biventricular involvement in the LGE mode (red arrows); (C) 12-lead ECG showing a reduction of R waves amplitude in left precordial leads (left involvement) and inverted T waves in V1-V6 (RV strain pattern); together they indicate biventricular involvement. Reproduced with permission from Gaido et al. (2017) [37].

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  Figure 8. Exemplar MRI and ECG finding found in ACM patients with JUP mutations. (A,B) CMR of a patient with JUP mutation showing LGE of the RV free wall, secondary to fibrosis (white arrow); (C) ECG findings in a different patient with JUP mutation at 3 different times (separated by two vertical lines into 1. right panel = sinus rhythm with T waves inversion in V1–V6, and 2. middle and 3.left panels = ventricular tachycardia). (A,B) were reproduced with permission from Mavrogeni et al. (2012) [38]; (C) was reproduced with permission from Protonotarios et al. (1986) [27].

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  Figure 9. Exemplar MRI and ECG finding found in ACM patients with TTN mutations. (A) CMR of a patient with TTN mutation, the white arrows show mid-wall scars in the inferior septum and inferior wall; (B) ECG of a different patient with TTN Thr2896Ile mutation showing epsilon waves. (A) was reproduced from Augusto et al. (2019) [39]; (B) from Taylor et al. (2011) [40] with permissions.

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  Figure 10. Exemplar MRI and ECG finding found in ACM patients with LMNA mutations. (A) CMR of a patient with LMNA mutation showing a mid-wall (LGE) scar in the septum and inferior RV; (B) 12-lead ECG of a different patient with a p.Gly382Val LMNA mutation, which shows sinus bradycardia, poor R-wave progression, T-wave inversion in V1–V3 leads. (A) reproduced with permission from Augusto et al. (2019) [39]; and (B) reproduced with permission from Quarta et al. (2012) [41].

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  Figure 11. Exemplar MRI and ECG finding found in ACM patients with DES mutations. (A) CMR of a patient with DES mutation (deletion of guanine at position 735) showing extensive mid-wall fibrosis (LGE short-axis view); (B) 12-lead ECG of a different patient with p.Gly382Val mutation of the LMNA gene showing sinus tachycardia, inverted T waves in V1–V3 ad poor R wave progression. Reproduced from Koitka et al. (2017) with permission [42].

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  Figure 12. Exemplar MRI and ECG finding found in ACM patients with FLNC mutations. (A,B) CMR of a patient with p.Arg991X (nonsense) mutation of the FLNC gene; the arrows show basal lateral subepicardial fibrosis in the LGE mode (white arrows); (C) 12-lead ECG of the same patient showing T-wave inversion in III and aVF (inferior leads). Reproduced with permission from Hall et al. (2020) [43].