Diagnosis Of ARVC Research Articles

Improved diagnosis of arrhythmogenic right ventricular cardiomyopathy using electrocardiographic deep learning

BackgroundArrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare genetic heart disease associated with life-threatening ventricular arrhythmias. Diagnosis of ARVC is based on the 2010 Task Force Criteria (TFC), application of which often requires clinical expertise at specialized centers. ObjectiveThe purpose of this study was to develop and validate an electrocardiogram (ECG) deep learning (DL) tool for ARVC diagnosis. MethodsECGs of patients referred for ARVC evaluation were used to develop (n = 551 [80.1%]) and test (n = 137 [19.9%]) an ECG-DL model for prediction of TFC-defined ARVC diagnosis. The ARVC ECG-DL model was externally validated in a cohort of patients with pathogenic or likely pathogenic (P/LP) ARVC gene variants identified through the Geisinger MyCode Community Health Initiative (N = 167). ResultsOf 688 patients evaluated at Johns Hopkins Hospital (JHH) (57.3% male, mean age 40.2 years), 329 (47.8%) were diagnosed with ARVC. Although ARVC diagnosis made by referring cardiologist ECG interpretation was unreliable (c-statistic 0.53; confidence interval [CI] 0.52–0.53), ECG-DL discrimination in the hold-out testing cohort was excellent (0.87; 0.86–0.89) and compared favorably to that of ECG interpretation by an ARVC expert (0.85; 0.84–0.86). In the Geisinger cohort, prevalence of ARVC was lower (n = 17 [10.2%]), but ECG-DL–based identification of ARVC phenotype remained reliable (0.80; 0.77–0.83). Discrimination was further increased when ECG-DL predictions were combined with non–ECG-derived TFC in the JHH testing (c-statistic 0.940; 95% CI 0.933–0.948) and Geisinger validation (0.897; 95% CI 0.883–0.912) cohorts. ConclusionECG-DL augments diagnosis of ARVC to the level of an ARVC expert and can differentiate true ARVC diagnosis from phenotype-mimics and at-risk family members/genotype-positive individuals.

Arrhythmogenic right ventricular cardiomyopathy with sustained ventricular tachycardia: a case report

IntroductionArrhythmogenic right ventricular cardiomyopathy (ARVC) is an infrequent hereditary disorder distinguished by fibrofatty replacement of the myocardium in the right ventricular, which predisposes individuals to life-threatening arrhythmias. This case delineates an ARVC patient who suffered recurrent bouts of sustained ventricular tachycardia (VT). In this case, we mainly discuss the application of myocardial contrast echocardiography (MCE) in displaying myocardial fibrosis in patients with ARVC.Case presentationA 43-year-old male experienced three episodes of unexplained VT over an eight-year period, accompanied by symptoms of chest discomfort, palpitations and dizziness. Coronary angiography revealed no significant coronary stenosis. The electrocardiogram (ECG) results indicated characteristic epsilon waves in right precordial leads, and subsequent echocardiography identified right ventricular enlargement and right ventricular systolic dysfunction. MCE further disclosed regional myocardial ischemia at the epicardium of the left ventricular apex. Ultimately, cardiovascular magnetic resonance imaging (CMR) corroborated the ARVC diagnosis, highlighting linear intensification in the right ventricle during the delayed enhancement.ConclusionPrompt identification of ARVC is crucial for timely intervention and management. MCE may offer an effective and valuable technique for the detection of myocardial involvement in ARVC patient.

Use of 18F-fluorodeoxyglucose positron emission tomography in the differential diagnosis of arrhythmogenic right ventricular cardiomyopathy and cardiac sarcoidosis

Abstract Introduction Arrhythmogenic Cardiomyopathy (ACM) is defined as an arrhythmogenic heart muscle disorder not explained by ischemic, hypertensive, or valvular heart disease, which ranges from a systemic immunologic disorder such as cardiac sarcoidosis (CS), to a genetically determined one (arrhythmogenic right ventricular cardiomyopathy=ARVC). The aim of this study was to assess the utility of 18F-fluordeoxyglucose positron emission tomography /computer tomography (18F-FDG-PET/CT) in the differential diagnosis of ACM. Methods This study included 45 patients with a definite diagnosis of ARVC, in whom 18F-FDG-PET/CT was performed to screen for CS. Following a positive PET, diagnosis of CS was pursued according to the 2014 HRS consensus document. The patients were divided into two cohorts: the ARVC Cohort (ARVC-C) and the Cardiac Sarcoidosis Cohort (CS-C). Results All 45 patients received an 18F-FDG-PET/CT, of these 5 had a positive PET showing myocardial hypermetabolism. All 5 patients with a positive PET had a final diagnosis of histologically confirmed CS, as such the 18F-FDG-PET/CT had a negative predictive value (NPV) of 100%. All 45 patients also received genetic testing (cardiomyopathy panel). In the ARVC-C, 23 (58%) patients harbored a pathogenic (P)/likely pathogenic (LP) variant (40% in PKP2). In the CS-C, 1 (20%) patient with histologically confirmed CS harbored a LP DSG2 variant. Nine (23%) subjects in the ARVC-C presented with atrioventricular block (AVB) (grade I) and 7 (18%) with QRS fragmentation, whereas 5 (100%) patients in the CS-C presented with AVB (grade I and higher) and 4 (80%) with QRS fragmentation. On TTE, left ventricular (LV) involvement was less frequent in the ARVC-C (LVEF 52.2 +/- 8.7%; wall motion abnormalities in 19 patients (48%)), while LV-involvement in the CS-C was more frequent (LVEF 44.0 +/- 16.2%; wall motion abnormalities in 3 (60%). On cardiac magnetic resonance imaging (cMRI), late gadolinium enhancement was present in the ARVC-C in 14 (35%) in the RV and 15 (38%) in the LV, while it was present in 3 (60%) patients in the RV and 3 (60%) in the LV in the CS-C. Conclusions CS is an underdiagnosed clinical entity, which can be challenging to differentiate from ARVC. 18F-FDG-PET/CT has a high NPV to exclude CS in patients fulfilling definite ARVC criteria. Hence, we recommend to offer 18F-FDG-PET/CT to patients fulfilling definite ARVC criteria who present with AVB, QRS fragmentation, or biventricular involvement to screen for CS, especially to those who do not have an LP/P variant in the PKP2 gene.

Detection of gene mutation in the prognosis of a patient with arrhythmogenic right ventricular cardiomyopathy: a case report

BackgroundArrhythmogenic right ventricular cardiomyopathy (ARVC), or more recently known as arrhythmogenic cardiomyopathy (ACM), is an heritable disorder of the myocardium characterized by progressive fibrofatty replacement the heart muscle and risk of ventricular arrhythmias and sudden cardiac death (SCD). We report a case study to demonstrate the role of gene mutation detection in risk stratification for primary prevention of SCD in a young patient diagnosed with ARVC.Case presentationA 15-year-old Asian (Vietnamese) male patient with no history of documented tachyarrhythmia or syncope and a family history of potential SCD was admitted due to palpitations. Clinical findings and work-up including cardiac magnetic resonance imaging (MRI) were highly suggestive of ARVC. Gene sequencing was performed for SCD risk stratification, during which PKP2 gene mutation was found. Based on the individualized risk stratification, an ICD was implanted for primary prevention of SCD. At 6 months post ICD implantation, the device detected and successfully delivered an appropriate shock to terminate an episode of potentially fatal ventricular arrhythmia. ICD implantation was therefore proven to be appropriate in this patient.ConclusionsWhile gene mutations are known to be an important factor in the diagnosis of ARVC according to the 2010 Task Force Criteria and recent clinical guidelines, their role in risk stratification of SCD remains controversial. Our case demonstrated that when used with other clinical factors and family history, this information could be helpful in identifying appropriate indication for ICD implantation.

Kiosk 3R-FB-08 - Diagnostic Accuracy of LV 'Fat-bite' Pattern on Cardiac MR in ARVC Diagnosis

Kiosk 3R-FB-08 - Diagnostic Accuracy of LV 'Fat-bite' Pattern on Cardiac MR in ARVC Diagnosis

Characterization of right ventricular low voltage areas in patients with arrhythmogenic right ventricular cardiomyopathy

Abstract Funding Acknowledgements Type of funding sources: None. Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by fibrofatty replacement in the myocardium progressing from the epicardium towards the endocardium and affecting primarily the right ventricle (RV). Little data is available on the distribution of RV electrical abnormalities at the era of epicardial and high-resolution mapping. Purpose To evaluate the extent and distribution of RV epicardial and endocardial low voltage areas and their relationship with ECG abnormalities in ARVC patients. Methods Patients with a definite ARVC diagnosis according to the 2020 Task Force Criteria, who underwent ventricular tachycardia ablation between 2016 and 2022 with a high-density RV 3-dimensional electroanatomic mapping, were included. A custom RV segmentation dividing the RV into 10 segments from endocardial maps was used: anterior and lateral right ventricular outflow tract (RVOT); basal and mid inferior wall; apex; septum; basal anterolateral, basal inferolateral, mid anterolateral and mid inferolateral RV free wall (Figure). A standard definition of electrical scar was used (bipolar voltage ≤0.5 mV), and scar areas were manually delineated. Percentage of scar was defined by the ratio between scar area and the total segment area. ECG abnormal findings, such as epsilon wave and T-wave inversion in precordial leads, were measured before ablation procedure. Results Twenty-nine consecutive definite ARVC patients were included, among whose 24 had epicardial mapping in addition to endocardial mapping. When considering all segments, the epicardial scar (median:70%, interquartile range [IQR] 37-97%) was larger (p<0.0001) than the endocardial scar (9% [IQR] 0-32%). The higher percentage of epicardial scar was found in the basal inferolateral (100% [IQR] 73-100%), basal anterolateral (94% [IQR] 67-100%), RV free wall and lateral RVOT (89% [IQR] 48-100%) segments (Table). Transmural scar was observed mostly in basal inferolateral RV free wall (10 patients, 41%) and basal inferior wall (8 patients, 33%). Patients with major depolarization criteria had a higher percentage of epicardial and endocardial scar as compared to those with no or minor depolarization criteria (respectively 93% [IQR] 59-100% versus 62% [IQR] 28-89%, p<0.0001 and 17% [IQR] 0-42% versus 4% [IQR] 0-23%, p=0.001). There was no significant difference of the percentage of epicardial or endocardial scar in patients with and without major repolarization criteria (respectively 90% [IQR] 49-98% versus 84% [IQR] 43-100%, p=0.91 and 14% [IQR] 11-35% versus 16% [IQR] 0-41%, p=0.73). Conclusion In ARVC, the electrical abnormalities predominate in the basal epicardium. Patients with major depolarization criteria had a higher extent of epicardial and endocardial scar, but there was an association between scar extent and repolarization abnormalities.

Reentrant atrial tachycardia in a patient with arrhythmogenic right ventricular cardiomyopathy

A 59-year-old man with a diagnosis of definite ARVC without overt left ventricular involvement presented with recurrent palpitations. The surface 12-lead electrocardiogram raised the suspicion of atrial tachycardia.

1102 ARRYTHMOGENIC CARDIOMYOPATHY: LESSONS FROM A LARGE FAMILY

Abstract Background Arrhythmogenic cardiomyopathy is a genetically-inherited cardiomyopathy. PKP2 mutations are the most common cause of the disease, associated with conventional ARVC phenotype. Case presentation We presented a 14 years old sportswoman admitted to our emergency department for cardiac arrest-related to ventricular fibrillation. The patient was asymptomatic leading up to cardiac arrest. At admission, she met the diagnosis of AC with bi-ventricular involvement (T negative waves in V1-V6 and inferior leads; severe biventricular dysfunction with fibrofatty replacement involving both ventricles). Family history revealed that her cousin, a 15 years competitive athlete, received a recent diagnosis of ARVC, wherein pathogenetic variant p.Tyr857_Lys859 in heterozygosity in the PKP2 gene was found. As expected, the index case presented the same mutations in PKP2 gene, and no other mutations were found. Implanted cardioverter defibrillator (ICD) and strength follow-up, including heart failure management, was performed. Cascade screening of family members allowed us to identify 19 mutations carriers. Of these, 5 patients were identified to have disease expression. The first to be studied was her 9 years old sister, who involved in high level of sport activities. She presented abnormal ECG with negative T waves in V2-V4, significance burden of premature ventricular complex (PVC >500/24 h) with mild right ventricle dilatation. Of others family members, four patients presented early signs of myocardial disease and significant arrhythmias burden. Except for one patient, all these members were involved in amateur sport activities. Two members had signs of left ventricle (LV) involvement (inverted T waves in leads V4–V6 and inferior leads, LV wall motion abnormalities and late enhancement), whereas one patient (P3) showed a fulfilled ARVD. Three patients presented significant PVC on 24-hour ambulatory ECG monitoring (PVC >500/24 h) (P2, P3 and P5). The arrhythmic burden was more pronounced in two young patients having a sports activity (P2 and P3). This trend was also confirmed at exercise testing. Except for one patient, these findings appear to be related to sport activity, even if this is no high-intensity activity. Among other carriers of pathogenic mutation, three patients showed ECG abnormalities in infero-lateral leads and significance PVC at 24-hour ECG monitoring in absence of other findings related-cardiomyopathy. All family members carried PKP2 mutation were restricted in sports activities, and, in patients presented early disease and arrhythmogenic burden, treatment with beta-blockers was started. Conclusion In this family presenting PKP2 mutation, heterogenicity of disease expression and a close relationship with sport activity was found. This large family case encourages future ACM studies to better understand disease expression and their relationship with sports activity across the entire ACM phenotypic spectrum and ages. Also, this case underscores the importance of early familiar screening, including children involved high-level of sports activity.

NT-proBNP is superior to novel plasma biomarkers for predicting adverse outcome in arrhythmogenic right ventricular cardiomyopathy

Abstract Background/Introduction Arrhythmogenic right ventricular cardiomyopathy is a heritable heart muscle disease characterized by progressive substitution of the myocardium with fibrous and fatty tissue, which is the substrate for ventricular arrhythmia, systolic dysfunction and heart failure. Determining the optimal time for heart transplantation is challenging and, therefore, finding risk factors for disease progression is needed. Purpose The purpose of the study was to evaluate the role of markers of myocardial fibrosis sST2, Gal-3, MMP-2 and MMP-9, as well as NT-proBNP and hsTnT, in predicting major adverse outcomes in ARVC. Moreover, we aimed to identify other risk factors for developing end-stage heart failure. Methods We included 91 patients with the definite diagnosis of ARVC according to the 2010 Task Force Criteria (59 males, mean age of 47±16 years). Patients were interviewed for their medical history, electrocardiography and echocardiography were performed and plasma levels of selected biomarkers were measured. Thereafter, subjects were followed for the occurrence of the composite endpoint of death or heart transplantation (HTx) and major arrhythmic events defined as ventricular fibrillation, sustained ventricular tachycardia or appropriate implantable cardioverter-defibrillator intervention. Results During the median follow-up of 36,4 months [29,8–41,2], 13 subjects (14%) reached the composite endpoint of death or HTx and 27 subjects (30%) experienced major arrhythmic event. Among the studied biomarkers, significantly higher levels of sST2, MMP-2, NT-proBNP and hsTnT were found in patients who achieved the composite endpoint. The remaining prognostic factors are shown in Table 1. In the multivariate analysis, three factors turned out to be significant: higher NT-proBNP levels (the cut-off point ≥890.3 pg/m), greater right ventricular end-diastolic area (the cut-off point ≥39.0 cm2) and history of atrial tachycardia. Kaplan-Meyer survival analysis depending on the number of predictors is presented in Figure 1. None of the biomarkers predicted major arrhythmic events. Conclusions NT-proBNP ≥890.3 pg/ml, RV area ≥39.0 cm2 and history of atrial tachycardia are independent risk factors for death or HTx in ARVC. Among the studied biomarkers, higher levels of sST2, MMP-2, NT-proBNP and hsTnT were observed in patients who reached the composite endpoint. Biomarkers had no value in predicting ventricular arrhythmias. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): National Institute of Cardiology, Warsaw, Poland

Different underlying aetiologies in patients presenting with ventricular tachycardia fulfilling task force criteria for ARVC: initial suspicion based on the 12-lead electrocardiogram

Abstract Background The Task Force Criteria (TFC) for ARVC are highly sensitive, but lack specificity. Patients with atypical RV-involvement (aRVi) may have different underlying aetiologies and prognosis, requiring specific therapeutic interventions. Purpose We aimed to evaluate the role of the baseline ECG for initial suspicion of aRVi. Methods From the Netherlands Heart Institute Arrhythmogenic Cardiomyopathy (NHI-ACM) registry, patients were selected who 1) fulfilled TFC for definite ARVC, 2) presented with sustained VT, 3) underwent genetic testing. The first available ECG after VT was evaluated for AV-conduction and the presence and surface area (SA) of an R'-wave in V1-V3. ECGs with AV-conduction disturbances or an R'-wave with SA ≥1.65 mm2 were classified as suspicious for `atypical RV-involvement' (aRVi-ECG). Patients with ARVC-related pathogenic/likely pathogenic variant (P/LP+) were classified as “typical ARVC”. Data of patients without an ARVC-related pathogenic/likely pathogenic variant (P/LP−) were reviewed by an expert panel and classified as either “typical ARVC” or “suggestive for another aetiology” based on consensus. Results In total 124 P/LP+ patients and 35 P/LP− patients were included. Nineteen patients had an aRVi-ECG, which appeared significantly more predominant in the P/LP− group (11 (9%) P/LP+ vs. 8 (22%) P/LP−, p=0.019). Of the P/LP− patients, seventeen (49%) were classified as “suggestive for another aetiology” (e.g. myocarditis, ischemia, sarcoid), including all 8 patients with an aRVI-ECG. Among P/LP+ patients with an aRVi-ECG, 46% carried the Arg14del phospolamban variant and 64% died, versus 15% and 18% of P/LP+ patients without aRVi-ECG, respectively (Table 1). Conclusion For patients presenting with sustained VT and fulfilling the TFC for ARVC diagnosis, a baseline ECG suggestive for atypical RV-involvement should raise suspicion for a different underlying aetiology in patients without an ARVC-related P/LP variant. In P/LP+ patients, an aRVi-ECG may identify those with poor outcome. Funding Acknowledgement Type of funding sources: None.

P21 AGE–RELATED DIFFERENCES AND ASSOCIATED OUTCOMES OF S–ICD: INSIGHTS FROM A LARGE, EUROPEAN, MULTICENTER REGISTRY

Abstract Background The subcutaneous implantable cardioverter defibrillator (S–ICD) has become an alternative to transvenous ICDs (TV–ICD) in patients who do not need pacing. To date, there is little evidence directly comparing the rates of inappropriate shocks (IAS) in young vs old S–ICD recipients. Purpose Aim of our study was to assess differences in device–related complications and inappropriate shocks (IS) between teenagers/young adults and adult recipients of a subcutabeous implantable cardioverter defibrillator (S–ICD) device. Methods Two propensity–matched cohorts of teenagers + young adults (≤ 30–year–old) and adults (> 30–year–old) were retrieved from the ELISIR registry. The primary outcome was the comparison of the inappropriate shock (IAS) rate; complications, freedom from sustained ventricular arrhythmic events, overall and cardiovascular mortality were deemed secondary outcomes. Results A total of 1491 patients were extracted from the ELISIR project. Teenagers + young adults represented 11.0% of the entire cohort. Two propensity–matched groups of 161 patients each were used for the analysis (Figure 1); median follow–up was 23.1 [13.2–40.5] months. 15.2% patients experienced inappropriate S–ICD shocks and 9.3% device related complications were observed with no age–related differences in IAS (16.1% vs 14.3%; p = 0.642) and complication rates (9.9% vs 8.7%; p = 0.701); Figure 2 shows a survival analysis from inappropriate shocks in the teen–ager/young adult cohort (red) and in the adult cohort (blue). At univariate analysis, young age was not associated with increased rates of IAS (HR 1.204 [0.675–2.148]: p = 0.529). At multivariate analysis (Figure 3), the use of SMART pass algorithm was associated to a strong reduction in IAS (aHR 0.292 [0.161–0.525]; p < 0.001), while ARVC was associated with higher rates of IAS (aHR 2.380 [1.205–4.697]; p = 0.012). Conclusion In a large multicentered European registry of patients with S–ICD, 11.0% of all recipients were teenagers or young adults. The use of S–ICD in teenagers/young adults resulted safe and effective, and the rates of complications and IAS between teenagers/young adults and adults were not significantly different. The only predictor of increased IAS was a diagnosis of ARVC.

Whole-Exome Sequencing Identifies a Novel Variant (c.1538T > C) of TNNI3K in Arrhythmogenic Right Ventricular Cardiomyopathy.

BackgroundsArrhythmic right ventricular cardiomyopathy (ARVC) is a cardiomyopathy with a genetic predisposition that can lead to a sudden cardiac death and heart failure. According to the 2010 Task Force Criteria, genetic diagnosis is one of the most important methods, but, so far, only a few genes related to ARVC have been identified.MethodsIn this study, the pathogenic gene of a patient with ARVC was examined using whole-exome sequencing. The plasmids of TNNI3K were constructed, and the effects of the TNNI3K variant was investigated by a real-time polymerase chain reaction (PCR) and western blot.ResultsA novel variant (c.1538T > C) of TNNI3K was identified, with phenotypes of dominant right ventricular (RV) disease preliminarily fulfilling the diagnosis of ARVC. A comprehensive assessment revealed that the variant was pathogenic. We found that this variant would lead to a decrease in the level of TNNI3K mRNA and protein, as well as a decrease in the expression of the RYR2 gene, which further proves that TNNI3K plays an important role in cardiomyopathy and expands the spectrum of the TNNI3K variants.ConclusionIn this study, we reported a TNNI3K variant in ARVC for the first time, and the results not only contribute to the diagnosis of ARVC, but also provide a reference for genetic counseling and promote the understanding of the genetic mechanism of cardiomyopathy.

423 Prevalence and prognostic significance of atrial arrhythmias in arrhythmogenic cardiomyopathy

Abstract Aims Limited data are available concerning atrial arrhythmias (AA) role in arrhythmogenic cardiomyopathy (AC). The aim of the present study was to assess the prevalence and incidence of AA in a large cohort of AC patients and to evaluate its association with clinical outcomes. Methods and results We retrospectively analysed 115 patients with definite diagnosis of ARVC, according to 2010 Task Force Criteria, enrolled in the Trieste Heart Muscle Disease Registry. Subjects were further classified into two phenotypic variants, based on ventricular involvement: right-dominant and biventricular form. Uni- and multivariable, extended Kaplan-Meier and cumulative incidence function analysis were performed, as appropriate, for the primary composite endpoint of death and heart transplant (HTx) and for the two distinct secondary endpoints of: (i) death, HTx and first heart failure (HF) hospitalization; (ii) first major ventricular arrhythmias (MVA). Mean age of patients at the time of enrollment was 39 ± 16 years and 80% were male. 73 patients (63%) had a right-dominant form, while 42 (37%) presented a biventricular involvement. AA occurred in the 26% of our study population at baseline or during a median follow-up of 214 months (IQR: 105–311), with a non-significant trend in higher cumulative incidence of AA in patients with biventricular form. At baseline, patients experiencing AA were older (44 ± 18 vs. 37 ± 15 years, P = 0.044) and had larger atrial dimensions, in particular of the right atrium (RA) (23, IQR: 19–27 vs. 18, IQR: 15–25 cm2, P < 0.007). AA emerged as independently associated to death/HTx (HR 2.68, 95% CI: 1.02–7.05, P = 0.046) along with NYHA class >2 (HR: 7.08, 95% CI: 2.50–20.1, P < 0.001) and RA area (HR: 1.05, 95% CI: 1.01–1.09, P = 0.011). Consistently, AA were also independently associated with the secondary endpoint of death/HTx/HF hospitalization (HR: 2.50, 95% CI: 1.06–5.88, P = 0.036), together with NYHA >2, the presence of biventricular involvement, higher RA and left atrium area. Finally, AA did not emerge as independently correlated to MVA during follow-up. Conclusions This observational long-term study suggests that AA were common in patients with AC and were independently associated with poor outcomes, mostly related to HF events. A prompt identification throughout the follow-up of AA appears relevant in improving the clinical management of AC patients.

A Novel Diagnostic Score Integrating Atrial Dimensions to Differentiate between the Athlete’s Heart and Arrhythmogenic Right Ventricular Cardiomyopathy

Objective: The 2010 Task Force Criteria (TFC) have not been tested to differentiate ARVC from the athlete’s heart. Moreover, some criteria are not available (myocardial biopsy, genetic testing, morphology of ventricular tachycardia) or subject to interobserver variability (right ventricular regional wall motion abnormalities) in clinical practice. We hypothesized that atrial dimensions are useful and robust to differentiate between both entities and proposed a new diagnostic score based upon readily available parameters including echocardiographic atrial dimensions. Methods: In this observational study, 21 patients with definite ARVC were matched for age, gender and body mass index to 42 athletes. Based on ROC analysis, the following parameters were included in the score: indexed right/left atrial volumes ratio (RAVI/LAVI ratio), NT-proBNP, RVOT measurements (PLAX and PSAX BSA-corrected), tricuspid annular motion (TAM), precordial TWI and depolarization abnormalities according to TFC. Results: ARVC patients had a higher RAVI/LAVI ratio (1.76 ± 1.5 vs. 0.87 ± 0.2, p < 0.001), lower right ventricular function (fac: 29 ± 10.1 vs. 42.2 ± 5%, p < 0.001; TAM: 19.8 ± 5.4 vs. 23.8 ± 3.8 mm, p = 0.001) and higher serum NT-proBNP levels (345 ± 612 vs. 48 ± 57 ng/L, p < 0.001). Our score showed a good performance, which is comparable to the 2010 TFC using those parameters, which are available in routine clinical practice (AUC93%, p < 0.001 (95%CI 0.874–0.995) vs. AUC97%, p < 0.001 (95%CI 0.93–1.00). A score of 6/12 points yielded a specificity of 91% and an improved sensitivity of 67% for ARVC diagnosis as compared to a sensitivity of 41% for the abovementioned readily available 2010 TFC. Conclusions: ARVC patients present with significantly larger RA compared to athletes, resulting in a greater RAVI/LAVI ratio. Our novel diagnostic score includes readily available clinical parameters and has a high diagnostic accuracy to differentiate between ARVC and the athlete’s heart.

QRS dispersion detected in ARVC patients and healthy gene carriers using 252-leads body surface mapping: an explorative study of a potential diagnostic tool for arrhythmogenic right ventricular cardiomyopathy.

The diagnosis of ARVC remains complex requiring both imaging and electrocardiographic (ECG) techniques. The purpose was therefore to investigate whether QRS dispersion assessed by body surface mapping (BSM) could be used to detect early signs of ARVC, particularly in gene carriers. ARVC patients, gene carriers without a history of arrhythmias or structural cardiac changes and healthy controls underwent 12-lead resting ECG, signal-averaged ECG, echocardiographic examination, 24-hours Holter monitoring, and BSM with electrocardiographic imaging. All 252-leads BSM recordings and 12-leads ECG recordings were manually analyzed for QRS durations and QRS dispersion. Eight controls, 12 ARVC patients with definite ARVC and 20 healthy gene carriers were included. The ECG-QRS dispersion was significantly greater in ARVC patients (42 vs. 25 ms, p<.05), but failed to fully differentiate them from controls. The BSM-derived QRS dispersion was also significantly greater in ARVC patients versus controls (65 vs. 29 ms, p<.05) and distinguished 11/12 cases from controls using the cut-off 40msec. The BSM derived QRS dispersion was abnormal (>40 ms) in 4/20 healthy gene carriers without signs of ARVC, which may indicate early depolarization changes. QRS dispersion, when assessed by BSM versus 12-lead ECG, seem to better distinguish ARVC patients from controls, and could potentially be used to detect early ARVC in gene carriers. Further studies are required to confirm the value of BSM-QRS dispersion in this respect.

Sudden cardiac death due to ARVC in the young: molecular autopsy by whole exome sequencing of DNA from dried blood spots (DBS) collected at birth

Abstract Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): Uppsala University Hospital (ALF) and Marcus Börgström Foundation Background The post-mortem investigation of cases with sudden cardiac death (SCD) is critical for risk stratification and adequate care of surviving relatives. Genetic testing is limited by access to DNA from the proband, as blood samples are not routinely collected at the time of death, or DNA of poor quality obtained from formalin-fixed paraffin-embedded (FFPE) tissues. Whole exome sequencing (WES) on minute amounts of DNA has opened up for the possibility to use DNA from Dried Blood Spots (DBS). Purpose To evaluate the feasibility of WES on DNA from archived DBS collected at the time of newborn screening in cases of SCD. Methods Through National Health Databases and Registries, we identified all cases of SCD in the young (&amp;lt;35 y.o.a.) in Sweden with a post-mortem diagnosis of ARVC between 2000 and 2010 (n = 22). Clinical records, medical and family histories, and autopsy findings were collected. Surviving parents were invited to participate. DNA was extracted from samples in National Biobanks such as DBS collected at birth (n = 19), formalin-fixed paraffin-embedded (FFPE) heart tissues (n = 8) from autopsies, and frozen blood samples (n = 3). Patient and parental DNA samples (when available) underwent WES. DNA- and sequencing-quality check (QC) metrics were compared between two different sequencing platforms and specimen types. We analysed 392 cardiomyopathy and arrhythmia genes and variants were classified as pathogenic or likely pathogenic according to the criteria from the American College of Medical Genetics. Results A higher quality but a lower yield of DNA (7.3 – 140 ng) was obtained from DBS when compared to FFPE samples (515 – 3065 ng). However, 100% of DBS vs. 62,5% of FFPE samples passed QC before sequencing. The average mean target depth for DBS samples (160X) was similar to that in blood samples (155X) and higher than FFPE (82X). Furthermore, &amp;gt;97% of target regions were covered with read depths &amp;gt;30X in DNA from DBS and blood compared to 88% for FFPE samples (Min 63%; Max 97%). Analysis of WES data uncovered clinically relevant variants in 12 out of 19 families (63%), of which four were located in ARVC genes. In six cases, the molecular autopsy identified another arrhythmogenic syndrome. Additionally, we identified one SCD with hemochromatosis and one with myotonic dystrophy as a possible contributing cause. In two additional families, variants of unknown significance fulfilled criteria for further segregation analysis. The concordance of positive results between different tissue samples was 100%. Conclusions DNA obtained from DBS has a quality comparable to that of blood and is a reliable source for WES-based molecular autopsy that may improve the diagnostic yield in cases of SCD. In a proportion of cases diagnosed post-mortem with ARVC, our molecular autopsy analysis pointed to a different diagnosis, highlighting its importance for the correct medical care of surviving relatives.

Diagnosing arrhythmogenic ventricular cardiomyopathy: a re-appraisal of the role and normal range of the signal-averaged ECG

Abstract Funding Acknowledgements Type of funding sources: None. Introduction The 2010 Task Force Criteria (TFC) for the diagnosis of arrhythmogenic right ventricular cardiomyopathy (A(R)VC) in 1st degree relatives includes an abnormality in a single parameter of the signal averaged ECG (SAECG). SAECG normal ranges were derived predominately from ischaemic heart disease patients, so may not be applicable in an A(R)VC population. There remain concerns that the SAECG is not specific enough and its role in the diagnosis of A(R)VC is under scrutiny. Purpose to improve the diagnostic utility of the SAECG Methods Patients with an A(R)VC diagnosis and 1st degree family members (FM) under follow-up at a single inherited cardiac conditions (ICC) centre were included. All cases were independently reviewed by 3 cardiologists experienced in the diagnosis and management of A(R)VC. All SAECGs included were free from artefact. TFC clinical variables and genetic status were recorded for each patient. Where tests had been repeated the most recent values were used. Because of concerns about the use of a single abnormal SAECG parameter in making a clinical diagnosis we required ≥2 abnormal SAECG parameters, or a confirmed genetic mutation to make a diagnosis. A diagnosis of false positive SAECG was made with ≥2 abnormalities when the individual was known not to carry the familial pathogenic mutation. Results A study population of 160 patients (male 103 (64%), age 46yrs (range 18-85yrs); 41 pro-bands and 119 FM. 62(52%) FM had a clinical diagnosis of AVC, with ARVC the pre-dominant phenotype 51(82%). A pathogenic genetic variant was identified in 24(47%) of FM with ARVC. The SAECG data is presented graphically for each parameter. A clinical diagnosis of ARVC was made on the basis of an affected 1st degree FM and an abnormal SAECG in 24(47%) of FM. Of these, 16(67%) had three abnormal SAECG parameters, 6(25%) two and 2(8%) a single abnormal parameter. Both patients with only one abnormal SAECG parameter carry a pathogenic variant. In total 88% of FM with ARVC, and 32% of FM without AVC had an abnormal SAECG as per current TFC. False positive values were mainly in fQRS duration (17/18), but also LAS40 (5/18), and RMS40 (2/18). By redefining an abnormal fQRS duration to be ≥118ms, false positives are reduced from 17 to 4. In addition, if there is a requirement for a 2nd abnormality then the false positives are reduced to 2 (4%). By adjusting the diagnostic criteria to fQRS duration ≥118ms, with a 2nd abnormal parameter or known pathogenic gene carrier status none of the 24 FM with a clinical diagnosis on abnormal SAECG alone would change diagnostic classification. Conclusion The SAECG is useful in family screening as it is frequently the only test to show an abnormality. However, the current TFC reference values lack specificity. By redefining an abnormal fQRS as ≥118ms with the requirement of a 2nd abnormal parameter, specificity is increased to 96%, with no significant change in sensitivity. Abstract Figure. SAECG Parameters in Family Members

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) Probably Caused by DSG2 p.Val149Ile Mutation as Genetic Background When Carrying with Heterozygous PRRT2 p.Arg217ProfsTer8 Mutation: A Case Report

BackgroundARVC is a rare genetic-related disease characterized by fibrous fat replacement in the ventricular myocardium, caused by mutations in genes encoding for the desmosomal proteins, such as the desmoglein-2 gene (DSG2). It is reported in the literature that other genetic factors may play a role in disease penetrance. Herein, we report a Chinese proband with ARVC, which was probably caused by DSG2 p.Val149Ile mutation as genetic background when carrying heterozygous PRRT2 p.Arg217ProfsTer8 mutation.Case PresentationA 17-year-old male with a history of paroxysmal kinesigenic dyskinesia (PKD) presented to the hospital for syncope induced by ventricular tachycardia. According to relevant clinical data and the diagnostic criteria of ARVC, a precise positive diagnosis of ARVC was finally made. Gene testing revealed that the patient carried a DSG2 heterozygous missense mutation (NM_001943: exon5: c.445G>A, p.Val149Ile) as well as frameshift mutation of PRRT2 (NM_001256442: exon2: p. Arg217Profs Ter8).ConclusionThis is the first time to report a Chinese proband with ARVC and a history of PKD carrying both DSG2 p. val149ile mutation and PRRT2 p. Arg217ProfsTer8 mutation, which can provide a new direction for gene screening of patients with ARVC and further supplements for its diagnostic criteria.

Implantable cardiac defibrillator events in patients with arrhythmogenic right ventricular cardiomyopathy

ObjectiveArrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with a risk of sudden cardiac death. Optimal risk stratification is still under debate. The main purpose of this long-term, single-centre observation was...

The repolarization pattern of ARVC patients, healthy gene carriers and controls as analyzed with a 252-leads Body Surface Mapping Vest

Abstract Background Repolarization abnormalities have a central role on the diagnosis of ARVC according to recent HRS consensus document from 2019 stating that T wave inversion in the right precordial leads is a major criteria if it appears in V1-V3 or a minor criteria if it appears in only V1-V2. Purpose The aim of our study was to investigate whether repolarization patterns as recorded by a Body Surface Mapping (BSM) system consisting of a vest with 252 ECG leads, could differentiate ARVC patients and even gene carriers from normal individuals. Our hypothesis is that the method can potentially identify repolarization disturbances earlier or better than conventional 12-lead ECG. Method 12 definite ARVC patients, 20 healthy gene carriers and 8 family members who tested negative for the family mutation (controls) were included. All patients underwent 12-lead ECG, including right precordial leads (V4R) and BSM recordings. Repolarization (T-wave polarity and concordance with QRS complex vector) was analyzed qualitatively in all BSM recordings, the results of which were displayed on a color code map (fig.1). Results The mean age was 49.6, 43.6 and 38.8 years in ARVC patients, healthy gene carriers and controls, respectively. The number of males in the three groups were 8/12, 8/20 and 5/8, respectively. All 8 controls had similar repolarization patterns with negative and concordant T waves on the right back panel, and T waves that successively changed from negative concordant (green) to positive disconcordant (red) and finally positive concordant (blue) on the left front panel (pattern 1). All 12 ARVC patients had different repolarization patterns as compared to the controls. Two of these patients had no apparent repolarization changes on conventional 12 lead ECG. The pattern type 2 repolarization, as defined by same pattern as the controls at the right back panel but different pattern at the front left panel was seen in 3/12 ARVC patients. The remaining 9 ARVC patients had different repolarization patterns both on the front and on the back panel (pattern 3). Among gene carriers, 15 had a normal repolarization pattern (pattern 1) and 5 demonstrated an abnormal repolarization pattern (4 had pattern type 2 and one pattern 3) despite normal surface ECG. Conclusions Using BSM recordings, abnormal repolarization patterns can be detected in all ARVC patients, even in those without repolarization changes on conventional surface ECG. The observation that 25% of gene carriers had divergent repolarization patterns, may indicate an early stage of the disease, and be used as an early diagnostic marker of the disease. Further and larger studies are warranted to confirm these observations. Repolarisation patterns recorded by BSM Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Selanders Stiftelse