Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterised by fibrofatty replacement of predominantly the right ventricle and high risk of ventricular ...arrhythmias and sudden cardiac death (SCD). Early diagnosis and accurate risk assessment are challenging yet essential for SCD prevention. This manuscript summarises the current state of the art on ARVC diagnosis and risk stratification. Improving the 2010 diagnostic criteria is an ongoing discussion. Several studies suggest that early diagnosis may be facilitated by including deformation imaging ('strain') for objective assessment of wall motion abnormalities, which was shown to have high sensitivity for preclinical disease. Adding fibrofatty replacement detected by late gadolinium enhancement or T1 mapping in cardiac MRI as criterion for diagnosis is increasingly suggested but requires more supporting evidence from consecutive patient cohorts. In addition to the traditional right-dominant ARVC, standard criteria for arrhythmogenic cardiomyopathy (ACM) and arrhythmogenic left ventricular cardiomyopathy (ALVC) are on the horizon. After diagnosis confirmation, the primary management goal is SCD prevention, for which an implantable cardioverter-defibrillator is the only proven therapy. Prior studies determined that younger age, male sex, previous (non-) sustained ventricular tachycardia, syncope, extent of T-wave inversion, frequent premature ectopic beats and lower biventricular ejection fraction are risk factors for subsequent events. Previous implantable cardioverter-defibrillator indication guidelines were however limited to three expert-opinion flow charts stratifying patients in risk groups. Now, two multivariable risk prediction models (arvcrisk.com) combine the abovementioned risk factors to estimate individual risks. Of note, both the flow charts and prediction models require clinical validation studies to determine which should be recommended.
Objectives The aim of this study was to identify the incremental value and optimal role of cardiac magnetic resonance (CMR) imaging in arrhythmic risk stratification of arrhythmogenic right ...ventricular dysplasia/cardiomyopathy (ARVD/C)–associated desmosomal mutation carriers without histories of sustained ventricular arrhythmia. Background Risk stratification of ARVD/C mutation carriers is challenging. Methods Sixty-nine patients (mean age 27.0 ± 15.3 years, 42% men) harboring ARVD/C-associated pathogenic mutations (83% plakophilin 2) without prior sustained ventricular arrhythmias were included. Electrocardiographic and 24-h Holter monitoring findings closest to presentation were analyzed for electrical abnormalities per revised task force criteria. CMR studies were done to identify abnormal cardiac structure and function according to the revised task force criteria. Results Overall, 42 patients (61%) presented with electrical abnormalities on the basis of electrocardiography and Holter monitoring, of whom 20 (48%) had abnormal results on CMR. Only 1 of 27 patients (4%) without electrical abnormalities at initial evaluation had abnormal CMR results. Over a mean follow-up period of 5.8 ± 4.4 years, 11 patients (16%) experienced sustained ventricular arrhythmias, exclusively in patients with both electrical abnormalities (electrocardiography and/or Holter monitoring) and abnormal CMR results. Conclusions These results suggest that electrical abnormalities on electrocardiography and Holter monitoring precede detectable structural abnormalities in ARVD/C mutation carriers. Therefore, evaluation of cardiac structure and function using CMR is probably not necessary in the absence of baseline electrical abnormalities. Among ARVD/C mutation carriers, the presence of both electrical and CMR abnormalities identifies patients at high risk for events and thus patients who might benefit from prophylactic implantable cardioverter-defibrillator placement.
Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is one of the most arrhythmogenic forms of inherited cardiomyopathy and a frequent cause of sudden death in the young. Affected individuals ...typically present between the second and fourth decade of life with arrhythmias coming from the right ventricle. Pathogenic mutations in genes encoding the cardiac desmosome can be found in approximately 60% of index patients, leading to our current perception of ARVC as a desmosomal disease. Although ARVC is known to preferentially affect the right ventricle, early and/or predominant left ventricular involvement is increasingly recognized. Diagnosis is made by combining multiple sources of diagnostic information as prescribed by the "Task Force" criteria. Recent research suggests that electrical abnormalities precede structural changes in ARVC. Cardiovascular Magnetic Resonance (CMR) is an ideal technique in ARVC workup, as it provides comprehensive information on cardiac morphology, function, and tissue characterization in a single investigation. Prevention of sudden cardiac death using implantable cardioverter-defibrillators is the most important management consideration. This purpose of this paper is to provide an updated review of our understanding of the genetics, diagnosis, current state-of-the-art CMR acquisition and analysis, and management of patients with ARVC.
Abstract Background Incomplete penetrance and variable expressivity of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) complicate family screening. Objectives The objective of the ...present study was to determine the optimal approach to longitudinal follow-up regarding: 1) screening interval; and 2) testing strategy in at-risk relatives of ARVD/C patients. Methods We included 117 relatives (45% male, age 33.3 ± 16.3 years) from 64 families who were at risk of developing ARVD/C by virtue of their familial predisposition (72% mutation carriers 92% plakophilin-2; 28% first-degree relatives of a mutation-negative proband). Subjects were evaluated by electrocardiography (ECG), Holter monitoring, signal-averaged ECG, and cardiac magnetic resonance (CMR). Disease progression was defined as the development of a new criterion by the 2010 Task Force Criteria (not the “Hamid criteria”) at last follow-up that was absent at enrollment. Results At first evaluation, 43 subjects (37%) fulfilled an ARVD/C diagnosis according to the 2010 Task Force Criteria. Among the remaining 74 subjects (63%), 11 of 37 (30%) with complete re-evaluation experienced disease progression during 4.1 ± 2.3 years of follow-up. Electrical progression (n = 10 27%, including by ECG 14%, Holter monitoring 11%, or signal-averaged ECG 14%) was more frequently observed than structural progression (n = 1 3% on CMR). All 5 patients (14%) with clinical ARVD/C diagnosis at last follow-up had an abnormal ECG or Holter monitor recording, and the only patient with an abnormal CMR already had an abnormal ECG at enrollment. Conclusions Over a mean follow-up of 4 years, our study showed that: 1) almost one-third of at-risk relatives have electrical progression; 2) structural progression is rare; and 3) electrical abnormalities precede detectable structural changes. This information could be valuable in determining family screening protocols.
Left ventricular (LV) fibrofatty infiltration in arrhythmogenic right ventricular (RV) dysplasia/cardiomyopathy (ARVD/C) has been reported, however, detailed cardiovascular magnetic resonance (CMR) ...characteristics and association with outcomes are uncertain. We aim to describe LV findings on CMR in ARVD/C patients and their relationship with arrhythmic outcomes.
CMR of 73 subjects with ARVD/C according to the 2010 Task Force Criteria (TFC) were analyzed for LV involvement, defined as ≥ 1 of the following features: LV wall motion abnormality, LV late gadolinium enhancement (LGE), LV fat infiltration, or LV ejection fraction (LVEF) < 50%. Ventricular volumes and function, regional wall motion abnormalities, and the presence of ventricular fat or fibrosis were recorded. Findings on CMR were correlated with arrhythmic outcomes.
Of the 73 subjects, 50.7% had CMR evidence for LV involvement. Proband status and advanced RV dysfunction were independently associated with LV abnormalities. The most common pattern of LV involvement was focal fatty infiltration in the sub-epicardium of the apicolateral LV with a "bite-like" pattern. LGE in the LV was found in the same distribution and most often had a linear appearance. LV involvement was more common with non-PKP2 genetic mutation variants, regardless of proband status. Only RV structural disease on CMR (HR 3.47, 95% CI 1.13-10.70) and prior arrhythmia (HR 2.85, 95% CI 1.33-6.10) were independently associated with arrhythmic events.
Among patients with 2010 TFC for ARVD/C, CMR evidence for LV abnormalities are seen in half of patients and typically manifest as fibrofatty infiltration in the subepicardium of the apicolateral wall and are not associated with arrhythmic outcomes.
Regional right ventricular (RV) dysfunction is the hallmark of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C), but is currently only qualitatively evaluated in the clinical ...setting. Feature Tracking Cardiovascular Magnetic Resonance (FT-CMR) is a novel quantitative method that uses cine CMR to calculate strain values. However, most prior FT-CMR studies in ARVD/C have focused on global RV strain using different software methods, complicating implementation of FT-CMR in clinical practice. We aimed to assess the clinical value of global and regional strain using FT-CMR in ARVD/C and to determine differences between commercially available FT-CMR software packages.
We analyzed cine CMR images of 110 subjects (39 overt ARVD/C mutation+/phenotype+, 40 preclinical ARVD/C mutation+/phenotype- and 31 control) for global and regional (subtricuspid, anterior, apical) RV strain in the horizontal longitudinal axis using four FT-CMR software methods (Multimodality Tissue Tracking, TomTec, Medis and Circle Cardiovascular Imaging). Intersoftware agreement was assessed using Bland Altman plots.
For global strain, all methods showed reduced strain in overt ARVD/C patients compared to control subjects (p < 0.041), whereas none distinguished preclinical from control subjects (p > 0.275). For regional strain, overt ARVD/C patients showed reduced strain compared to control subjects in all segments which reached statistical significance in the subtricuspid region for all software methods (p < 0.037), in the anterior wall for two methods (p < 0.005) and in the apex for one method (p = 0.012). Preclinical subjects showed abnormal subtricuspid strain compared to control subjects using one of the software methods (p = 0.009). Agreement between software methods for absolute strain values was low (Intraclass Correlation Coefficient = 0.373).
Despite large intersoftware variability of FT-CMR derived strain values, all four software methods distinguished overt ARVD/C patients from control subjects by both global and subtricuspid strain values. In the subtricuspid region, one software package distinguished preclinical from control subjects, suggesting the potential to identify early ARVD/C prior to overt disease expression.
ARVD/C: The Triangle of Dysplasia Displaced
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.
Background
Exercise is associated with age‐related penetrance and arrhythmic risk in carriers of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C)‐associated desmosomal mutations; ...however, its role in patients without desmosomal mutations (gene‐elusive) is uncertain. This study investigates whether exercise is (1) associated with onset of gene‐elusive ARVD/C and (2) has a differential impact in desmosomal and gene‐elusive patients.
Methods and Results
Eighty‐two ARVD/C patients (39 desmosomal, all probands) were interviewed about regular physical activity from age 10. Participation in endurance athletics, duration (hours/year), and intensity (MET‐Hours/year) of exercise prior to clinical presentation were compared between patients with desmosomal and gene‐elusive ARVD/C. All gene‐elusive patients were endurance athletes. Gene‐elusive patients were more likely to be endurance athletes (P<0.001) and had done significantly more intense (MET‐Hrs/year) exercise prior to presentation (P<0.001), particularly among cases presenting < age 25 (P=0.027). Family history was less prevalent among gene‐elusive patients (9% versus 40% desmosomal, P<0.001), suggesting a greater environmental influence. Gene‐elusive patients without family history did considerably more intense exercise than other ARVD/C patients (P=0.004). Gene‐elusive patients who had done the most intense (top quartile MET‐Hrs/year) exercise prior to presentation had a younger age of presentation (P=0.025), greater likelihood of meeting ARVD/C structural Task Force Criteria (100% versus 43%, P=0.02), and shorter survival free from a ventricular arrhythmia in follow‐up (P=0.002).
Conclusions
Gene‐elusive, non‐familial ARVD/C is associated with very high intensity exercise suggesting exercise has a disproportionate role in the pathogenesis of these cases. As exercise negatively modifies cardiac structure and promotes arrhythmias, exercise restriction is warranted.
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