Mutation-positive arrhythmogenic right ventricular dysplasia/cardiomyopathy: the triangle of dysplasia displaced

Abstract

Introduction: The traditional description of the Triangle of Dysplasia in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) predates genetic testing and excludes biventricular phenotypes.

Methods and results: We analyzed Cardiac Magnetic Resonance (CMR) studies of 74 mutation-positive ARVD/C patients for regional abnormalities on a 5-segment RV and 17-segment LV model. The location of electroanatomic endo- and epicardial scar and site of successful VT ablation was recorded in 11 ARVD/C subjects. Among 54/74 (73%) subjects with abnormal CMR, the RV was abnormal in almost all (96%), and 52% had biventricular involvement. Isolated LV abnormalities were uncommon (4%). Dyskinetic basal inferior wall (94%) was the most prevalent RV abnormality, followed by basal anterior wall (87%) dyskinesis. Subepicardial fat infiltration in the posterolateral LV (80%) was the most frequent LV abnormality. Similar to CMR data, voltage maps revealed scar (<0.5 mV) in the RV basal inferior wall (100%), followed by the RV basal anterior wall (64%) and LV posterolateral wall (45%). All 16 RV VTs originated from the basal inferior wall (50%) or basal anterior wall (50%). Of 3 LV VTs, 2 localized to the posterolateral wall. In both modalities, RV apical involvement never occurred in isolation.

Conclusion: Mutation-positive ARVD/C exhibits a previously unrecognized characteristic pattern of disease involving the basal inferior and anterior RV, and the posterolateral LV. The RV apex is only involved in advanced ARVD/C, typically as a part of global RV involvement. These results displace the RV apex from the Triangle of Dysplasia, and provide insights into the pathophysiology of ARVD/C.

Keywords: arrhythmogenic right ventricular dysplasia/cardiomyopathy; electroanatomic mapping; genetics; implantable cardioverter defibrillator; magnetic resonance imaging; phenotype; ventricular tachcardia.

Figure 1. Representative CMR Examples of RV Involvement in ARVD/C

(A) Short axis bright blood image showing dyskinesis of the acute angle (arrow). (B) Horizontal long axis bright blood image showing subtricuspid bulging (arrow). Note subepicardial fat infiltration and wall thinning of the LV apicolateral region (arrowhead). (C) Short axis bright blood image showing a dilated RV with microaneurysms and dyskinesis of the inferior wall, acute angle, and anterior wall of the RV (arrows). (D) T1-weighted image reveals moderate subepicardial fat infiltration of the RV anterior wall, extending as “fingers” into the myocardium (arrow). Note fatty infiltration in the LV lateral wall (arrowhead). (E) RVOT bright blood image showing dyskinesis of the RVOT and RV inferior wall (arrows). (F) Horizontal long axis bright blood image showing dyskinesis of the subtricuspid region, RV anterior wall and RV apex (arrows). Abbreviations: ARVD/C: Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, CMR: cardiac magnetic resonance, RV: right ventricular, RVOT: right ventricular outflow tract.

Figure 2. LV Abnormalities in ARVD/C

(A) T1-weighted CMR image revealing subepicardial fat infiltration with myocardial wall thinning in the mid- to apical LV lateral wall (arrow). Also note subepicardial fat infiltration in the RV anterior wall (arrowhead). (B) Horizontal long axis bright blood CMR image showing subepicardial fat infiltration in the mid- to apical LV lateral wall (arrow). In addition, microaneurysms of the RV anterior wall are observed (arrowhead). (C) Late gadolinium enhanced short-axis CMR image showing delayed enhancement of the LV anterolateral wall, and a streak of intramyocardial delayed enhancement in the septal wall (arrows). (D) Left lateral electroanatomic voltage map revealing late potentials in the LV lateral wall surrounding an area of electroanatomic dense scar (<0.5 mV, colored red) (arrow). Abbreviations: ARVD/C: Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, CMR: cardiac magnetic resonance, LV: left ventricular, RV: right ventricular.

Figure 3. RV Regional Cardiac Involvement

Patients are stratified based on number of RV regions involved; numbers in the bars refer to number of patients with involvement of that specific region. A pattern of RV involvement is observed. In patients with limited disease (1 region affected), only the RV inferior wall, anterior wall, and/or acute angle are affected. In patients with moderate disease (2-3 regions affected), the RVOT and RV apex may also be affected, but abnormalities in these regions are infrequent. In patients with advanced disease (4-5 regions affected), a higher proportion of RVOT and RV apical involvement is observed. Abbreviations: RV: right ventricular, RVOT: right ventricular outflow tract.

Figure 4. Incremental Risk of Sustained Ventricular Arrhythmia with Increasing Severity of Structural Disease

Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy patients with more severe structural disease (i.e. more abnormal right ventricular regions) have a significantly higher arrhythmic propensity compared to patients with limited structural disease.

Figure 5. Electroanatomic Scar and Arrhythmic Substrate in ARVD/C

(A) RV involvement follows a pattern, as shown by representative epicardial electroanatomic voltage maps. Electroanatomic scar (<0.5 mV) is colored red; normal and low-voltage epicardium (≥0.5 mV) is colored purple. From left to right: patients with limited disease typically show scar in the subtricuspid region. In patients with moderate disease, an extension of scar along the inferior wall towards the RV apex, as well as to the basal anterior wall is observed. Advanced cases of ARVD/C show global RV involvement. Notably, RVOT and RV apical involvement were never observed as an isolated abnormality. (B) Sites of successful VT ablation in ARVD/C patients. All 19 induced VTs are shown, as well as corresponding sites of successful VT ablation. VTs are arranged and numbered based on bundle branch block morphology and axis. Overall, 16 VTs were mapped to and successfully ablated on the RV surface, clustering to two regions: VTs 1 and 3-9 were mapped to the basal anterior wall below the RVOT, VTs 10-16 were mapped to the subtricuspid region extending along the inferior wall. VT 17 was mapped to the RV inferior wall close to the interventricular groove. Overall, 3 VTs were mapped to and successfully ablated on the LV surface: VT 2 (anterior wall close to the interventricular septum), VT 18 (lateral wall), and VT 19 (posterolateral wall). Overall, 18 VTs came from the epicardial surface; only VT 12 was successfully ablated on the endocardium. Abbreviations: ARVD/C: Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, LV: left ventricular, RV: right ventricular, RVOT: right ventricular outflow tract, VT: ventricular tachycardia.