Diagnosis Of Arrhythmogenic Right Ventricular Cardiomyopathy Research Articles

Electroanatomical voltage mapping with a force-sensing technology catheter for diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Invasive three-dimensional electroanatomical mapping (EAM) can be helpful to diagnose arrhythmogenic right ventricular cardiomyopathy (ARVC). Contact force sensing catheters (CFSC) represent the gold standard to verify adequate tissue contact during EAM. However, normal reference values for right ventricular (RV) EAM as well as substrate characterization in patients with ARVC using CFSC have not been systematically investigated, which was the aim of this prospective study. Methods EAM of the RV during sinus rhythm was performed with the Thermocool SmartTouch catheter via a long sheath in the CARTO3 system in 11 patients with definite ARVC and 5 age- and gender-matched control subjects without structural heart disease. Only points with a mean contact force of ≥4G were analyzed. To account for differences due to RV anatomy, it was divided into 5 segments: RV outflow tract (RVOT), septum, free wall, sub-tricuspid region and apex. Endocardial bipolar and unipolar voltages, signal characteristics and signal duration were analyzed. The impact of catheter orientation on endocardial signals was also assessed. Results A median of 227 (IQR:120-364) endocardial RV points were analyzed. Median bipolar voltage in healthy controls was 3.8mV (range 3.6-4.6, IQR 2.7-5.4), with lower values in the RVOT and higher values in the RV septum. ARVC patients showed significantly lower bipolar voltages as compared to controls (repeated measures ANOVA; between-subjects effect: F=6.443,p=0.024), showing significantly lower bipolar voltage values in the sub-tricuspid region (1.8±1.9vs.4.6±2.9mV,p=0.031) and in the RV apex (2.9±1.4vs.7.2±5.2mV,p=0.024), Figure 1c. Bipolar voltage values in all RV regions yielded a high sensitivity and specificity for ARVC diagnosis (AUC62-78%,p<0.001 for all), with the highest performance for the sub-tricuspid region (AUC78%,95%CI0.75-0.81,p<0.001). A bipolar voltage value <1.5mV in the sub-tricuspid region yielded a sensitivity of 98% and a specificity of 53% for ARVC diagnosis (Figure 1a-b, showing the typical RV free wall "C-scar" in ARVC and normal values for the RV apex in less advanced disease stages). A positive correlation between bipolar voltage values and an orthogonal catheter orientation (46°-90°: r=0.106,p<0.001) as well as a higher catheter contact force (r=0.054,p=0.008), and a negative correlation between bipolar voltage values and QRS duration (r=-0.370,p<0.001) was found. Conclusions For the first time a systematic analysis of RV endocardial low voltage areas in ARVC patients as compared to controls by using CFSC was performed, and confirmed that RV voltages are generally lower in ARVC as compared to controls, with the sub-tricuspid area showing the lowest values and highest discriminatory power vs controls.

PO-05-135 SIGNAL-AVERAGED ECG IN THE NORDIC ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY REGISTRY: ASSOCIATION WITH PREVALENT LIFE-THREATENING ARRHYTHMIAS AND ASCERTAINMENT OF CLINICAL DIAGNOSIS.

In arrhythmogenic right ventricular cardiomyopathy (ARVC), minor depolarization criteria by TFC2010 include ventricular late potentials (LP) assessed using signal-averaged ECG (SAECG) and terminal activation duration (TAD). TAD is measured from a standard V1 lead, which favors its use in clinical practice, however its ability to fully replace LP in ARVC workup is not clear. 1. To assess the association between TAD and LP and the prevalence of life-threatening ventricular arrhythmias in patients with ARVC. 2. To assess diagnostic impact of SAECG by characterizing the subgroup of patients, who would not have received definite ARVC diagnosis if LP were not considered. Patients with definite ARVC or genotype-positive family members who underwent SAECG were included (n=358, 47% women, age 41±16 years, 43% probands, 67% definite ARVC). LP and TAD were defined according to TFC2010 criteria. TFC score was calculated by assigning 2 points for major and 1 for minor criterium. Ventricular tachycardia (VT) was defined as sustained VT, aborted cardiac arrest or appropriate ICD shock. Logistic regression adjusted for clinical covariates was used to test association of TAD and LP with prevalent VT. In a subgroup of patients with TFC score 4, i.e. minimally required for diagnosis, patients who would be reclassified into borderline category if LP not considered (LP-dependent, n=38) were compared with those who had TFC score 4 regardless of LP (LP-independent, n=30) in terms of proband status, prevalence of imaging criteria and VT. LP were found in 209 patients (58%); TAD in 65 (18%); 90 patients had prevalent VT (25%). LP was associated with prevalent VT (OR=2.5 95%CI 1.2-5.3; Sensitivity 84%, Specificity 50%) while TAD was not (OR=1.6 95%CI 0.7-3.6; Sensitivity 32%, Specificity 87%). In the LP-dependent group, 9 of 14 (64 %) probands had prevalent VT, 7 (50%) survived cardiac arrest and 4 (29%) were genotype-positive. Clinical characteristics did not demonstrate significant differences between LP-dependent and LP-independent subgroups. LP is independently associated with VT and is more sensitive than TAD in identification of patients with prevalent VT. LP were critical for ascertainment of ARVC diagnosis required for initiation of family screening in 9% probands. Although the diagnostic impact of LP varies depending on SAECG availability, our data support its use as a sensitive non-invasive diagnostic tool.

PO-02-228 ASSOCIATION BETWEEN SIGNAL-AVERAGED ECG INDICES AND RV STRUCTURAL ABNORMALITIES IN PATIENTS WITH ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY: INSIGHTS FROM NORDIC ARVC REGISTER

The value of signal-averaged ECG (SAECG) derived ventricular late potentials (LP) as a minor depolarization criterion of arrhythmogenic right ventricular cardiomyopathy (ARVC) has been debated. Another criterion from the same category, terminal activation duration (TAD>55 ms), is obtained from standard V1 ECG lead, which makes it easier for use. However little data exist regarding the relationship between structural right ventricular (RV) ARVC substrate, LP and TAD. We aimed to explore the association between structural and functional RV abnormalities assessed using cardiac magnetic resonance (CMR), SAECG parameters, and abnormal TAD. Patients with definite ARVC diagnosis or genotype-positive family members who were recruited in the Nordic ARVC Registry with SAECG and CMR were included (n=268, mean age 42±16 years, female 46%, probands 49%). RV end-diastolic volume index (RVEDVI), RV ejection fraction (RVEF), and late gadolinium enhancement (LGE) presence were assessed. RV was defined as enlarged if RVEDVI > 100 ml/m2 for men and 90 ml/m2 for women. RVEF was considered reduced if lower than 45%. SAECG components were assessed using TFC2010 definitions: filtered QRS duration (fQRSd)>114 ms, duration of terminal low-amplitude QRS signal below 40 μV (LAS40)> 38 ms and root-mean-square voltage of the terminal 40 ms (RMS40)< 20 μV. An abnormal value of any one or more of these indexes was considered as the presence of LP. We assessed sensitivity and specificity of the SAECG indexes and TAD for association with abnormal RVEF, LGE and/or RVEDVI. C-statistics was used to assess the association between each of SAECG parameters as continuous variables and RV abnormalities. All 3 SAECG indexes were significantly associated with RV structural abnormalities using c-statistics (Table), each of them characterized by higher specificity and lower sensitivity than LP. TAD demonstrated high specificity but poor sensitivity in prediction of RV structural abnormalities. LP had lower specificity, but much higher sensitivity for association with RV structural and functional abnormalities than TAD. In a large cohort of patients with definite ARVC or genotype-positive family members SAECG indexes appear to have lower specificity for detection of structural and functional RV abnormalities compared to TAD, however its sensitivity far exceeds the one of the TAD and supports SAECG value as an ECG indicator of RV substrate.

CE-452779-3 RANDOMIZED PLACEBO-CONTROLLED TRIAL OF FLECAINIDE IN PATIENTS WITH ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is an inherited arrhythmia disorder with a high risk of ventricular tachycardia (VT) or ventricular fibrillation (VF), and implantable cardioverter defibrillators (ICD) remain the palliative therapy of choice. We conducted an NIH-funded pilot clinical trial hypothesizing flecainide administration is more effective than placebo in reducing the burden of ventricular premature beats (VPBs) in ARVC patients. The study was designed as a randomized double-blinded placebo-controlled crossover trial in ARVC patients with administration of 100 mg bid of flecainide or matching placebo for 4 weeks each with a washout period. The primary specific aim was to determine whether flecainide administration is associated with a significant reduction of number of VPBs in comparison to placebo, measured on 7-day Zio-Patch ECG monitoring. Inclusion criteria required ARVC diagnosis with the 2010 ARVC Task Force Criteria at the age of at least 18 years, implanted ICD, and over 500 VPBs on a diagnostic 24-hour Holter recording. Patients were required to be treated with beta-blockers. Patients on other antiarrhythmic treatment required washout with reconfirmation of over 500 VPBs per 24 hour off antiarrhythmic medication. The effect of flecainide on log2(VPB rate) was analyzed using a weighted linear mixed effects analysis of variance model with fixed effects for treatment and period and a random effect for subject, with wights proportional to teh Zio-Patch monitoring time. There were 22 patients with ARVC and an ICD enrolled with a mean age 45+/-13 years, including 12 females. There were 19 patients with at least one Zio-Patch recording and 17 with both recordings. The Table includes details of arrhythmias on placebo and on flecainide. The mean and median number of VPBs/day was significantly lower on flecainide than placebo. At least 50% reduction in VPBs/day was observed in 79% and at least 75% reduction in 53% of patients. The primary analysis showed that flecainide reduced the VPB rate by 72% (p < 0.0001, 95% CI: 56-82%), adjusted for the period effect. There were 2 subjects with pro-arrhythmic response, but flecainide was safe for most of study patients. This is the first randomized clinical trial testing antiarrhythmic management in ARVC patients. Flecainide signficantly reduced the VPB rate and NSVT/VT/VF rate supporting clinical use of this medication in ARVC patients.

PO-05-120 CLINICAL SIGNIFICANCE OF POST-ABLATION PREMATURE VENTRICULAR COMPLEXES BURDEN IN PATIENTS WITH ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY UNDERWENT ABLATION FOR VENTRICULAR TACHYCARDIA

A high burden of premature ventricular contractions (PVCs) at disease diagnosis has been associated with an overall higher risk of ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy (ARVC). Data regarding PVC burden after catheter ablation for ARVC patients with ventricular tachycardia (VT) at follow-up with ICD recording and its impact on recurrence are scarce. To describe changes in the PVC burden and to assess whether elimination of PVC during substrate modification is associated with recurrence during follow-up in patients with ARVC. In this cohort study, patients with a definite ARVC diagnosis, VT, and ICD underwent ablation were enrolled. The variables retrieved at ICD recording before and after ablation, baseline characteristics, and electrophysiological parameters were extracted for analysis. The association between the parameter and recurrent sustained VA after ablation was assessed using a multivariate logistical model. A total of 38 patients and 65 procedures were enrolled for this study. The VT/VF burden was suppressed after ablation. Recurrence of sustained VA were recorded in 26 procedures. The high mean PVC burden and the presence of NSVT in the ICD recording (3 months post-ablation) was the only parameter associated with recurrence. After multivariate analysis, the PVC burden more than 920 beats/day (obtained from ROC curve) was the only independent predictors for recurrence (HR: 4.314 (95% CI =2.087-9.920), p<0.001). Despite successful ablation in the patients with ARVC, the post-ablation PVC burden could predict the VT/VF recurrence. Aggressive strategy with PVC elimination in addition to substrate modification might be considered.

QI-452785-2 INDIVIDUALIZED FAMILY SCREENING FOR ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a clinically heterogeneous disease for which guidelines recommend a one-size-fits-all screening approach to monitor at-risk relatives. Prioritizing relatives on their predicted probability of definite ARVC development could ensure that low-risk people are not unnecessarily followed-up, while resources can be allocated to more frequently monitor high-risk relatives. Determine the probability of definite ARVC diagnosis, identify predictors of new TFC development, and describe the incidence of ventricular arrhythmias (VA) among at-risk relatives of ARVC probands. We included all relatives without definite ARVC diagnosis by 2010 Task Force Criteria (TFC) referred to our center for family screening. Demographics, symptoms and multi-generation pedigrees were ascertained. Relatives underwent electrocardiogram, Holter monitor, and cardiac imaging at baseline and follow-up. Subjects were divided by baseline clinical phenotype: “possible ARVC” (only genetic/familial predisposition) or “borderline ARVC” (one minor TFC criterion plus genetic/familial predisposition). A multi-state model was used to determine probability of definite ARVC development. VA (defined as sustained ventricular tachycardia, ICD therapy or aborted sudden cardiac death) was ascertained by record review. Overall, 78 relatives (50% male, age 22.2 (interquartile range (IQR) 14.8-40.9)) without definite ARVC diagnosis were included. At baseline, 54 (69%) had possible ARVC and 24 (31%) borderline ARVC. During 7.9 (IQR 4.2-10.8) years of follow-up, 42 (54%) relatives developed a new TFC criterion and 27 (35%) progressed towards definite ARVC. Siblings of the proband were at higher hazard of new TFC criterion development (hazard ratio 2.37, p=0.042), while having symptoms was associated with definite ARVC diagnosis (hazard ratio 2.87, p=0.009)(Table 1). Those with borderline ARVC had >10-fold higher probability of progressing to definite ARVC compared to those with possible ARVC (p<0.01)(Figure 1). Two relatives had a VA >9 years after definite ARVC diagnosis; no VA occurred in relatives without definite ARVC diagnosis. Symptomatic patients, siblings, and those with borderline ARVC have higher probability of developing definite ARVC. These patients will benefit from more frequent follow-up, while others may be monitored less often. VAs are rare among relatives without definite ARVC diagnosis.

Clinical Features, Genetic Findings, and Risk Stratification in Arrhythmogenic Right Ventricular Cardiomyopathy: Data From a Brazilian Cohort.

Arrhythmogenic right ventricular cardiomyopathy (ARVC), a rare inherited disease, causes ventricular tachycardia, sudden cardiac death, and heart failure (HF). We investigated ARVC clinical features, genetic findings, natural history, and the occurrence of life-threatening arrhythmic events (LTAEs), HF death, or heart transplantation (HF-death/HTx) to identify risk factors. The clinical course of 111 consecutive patients with definite ARVC, predictors of LTAE, HF-death/HTx, and combined events were analyzed in the entire cohort and in a subgroup of 40 patients without sustained ventricular arrhythmia before diagnosis. The 5-year cumulative probability of LTAE was 30% and HF-death/HTx was 10%. Predictors of HF-death/HTx were reduced right ventricle ejection fraction (HR: 0.93; P=0.010), HF symptoms (HR: 4.37; P=0.010), epsilon wave (HR: 4.99; P=0.015), and number of leads with low QRS voltage (HR: 1.28; P=0.001). Each additional lead with low QRS voltage increased the risk of HF-death/HTx by 28%. Predictors of LTAE were prior syncope (HR: 1.81; P=0.040), number of leads with T wave inversion (HR: 1.17; P=0.039), low QRS voltage (HR: 1.12; P=0.021), younger age (HR: 0.97; P=0.006), and prior ventricular arrhythmia/ventricular fibrillation (HR: 2.45; P=0.012). Each additional lead with low QRS voltage increased the risk of LTAE by 17%. In patients without ventricular arrhythmia before clinical diagnosis of ARVC, the number of leads with low QRS voltage (HR: 1.68; P=0.023) was independently associated with HF-death/HTx. Our study demonstrated the characteristics of a specific cohort with a high prevalence of arrhythmic burden at presentation, male predominance, younger age and HF severe outcomes. Our main results suggest that the presence and extension of low QRS voltage can be a risk predictor for HF-death/HTx in ARVC patients, regardless of the arrhythmic risk. This study can contribute to the global ARVC risk stratification, adding new insights to the international current scientific knowledge.

Characterisation of patients referred to a tertiary-level inherited cardiac condition clinic with suspected arrhythmogenic right ventricular cardiomyopathy (ARVC)

BackgroundArrhythmogenic right ventricular cardiomyopathy (ARVC) or arrhythmogenic cardiomyopathy is a rare inherited disease with incomplete penetrance and an environmental component. Although a rare disease, ARVC is a common cause of sudden cardiac death in young adults. Data on the different stages of ARVC remains scarce. The purpose of this study is to describe the initial presentation and cardiac phenotype of definite and non-definite ARVC for patients seen at a tertiary service.MethodsThis is a single centre, observational cohort study of patients with definite and non-definite ARVC seen at the Inherited Cardiac Conditions services at University Hospital Birmingham (UHB) in the period 2010–2021. Patients were identified by interrogation of digital health records, medical history, imaging and by examining 12-lead electrocardiograms (ECG).ResultThe records of 1451 patients were reviewed; of those, 165 patients were at risk of ARVC (mean age 41 ± 17 years, 56% male). 60 patients fulfilled task force criteria for definite ARVC diagnosis (n = 40, 67% males), and 38 (72%) of them carried a known pathogenic variant. The remaining 105 patients (50% males) were non-definite, and of these 45 (62%) carried a known pathogenic variant. Patients in the definite group were more symptomatic, with palpitations (57% vs. 17%), syncope (35% vs. 6%) and shortness of breath (28% vs. 5%, p < 0.001). T-wave inversion in V1-V3 and epsilon waves were observed only in the definite group. Both PR interval and QRS duration were longer in the definite (170 ± 34 ms and 100 ± 19 ms, p < 0.001) compared to (149 ± 25 and 91 ± 14 ms, p = 0.005). Patients with definite ARVC had significantly larger RV end diastolic areas and significantly reduced biventricular function (RVEDA = 27 ± 10 cm2, RVFAC = 37 ± 11% and EF = 56 ± 12%) compared to the non-definite group (RVEDA = 18 ± 4 cm2, RVFAC 49 ± 6% and LVEF 64 ± 7%, p < 0.001). Sustained ventricular tachycardia (VT) occurred more frequently in the definite group compared to the non-definite group (27% vs. 2%, p < 0.001). Ventricular fibrillation was observed in the definite group only (8 of 60 patients, 13%).ConclusionOur study showed differences between definite and non-definite ARVC patients in terms of clinical, electrophysiological and imaging features. Major adverse cardiac events occurred more commonly in the definite group, but also were observed in non-definite ARVC. This single centre observational cohort study forms a basis for further prospective multicentre interventional studies.

Correlations Between Endocardial Voltage Mapping, Diagnosis, and Genetics in Patients With Arrhythmogenic Right Ventricular Cardiomyopathy

The relations between endocardial voltage mapping and the genetic background of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) have not been investigated so far. A total of 97 patients with proved or suspected ARVC who underwent 3-dimensional endocardial mapping and genetic testing have been retrospectively included. Presence, localization, and size of scar areas were correlated to ARVC diagnosis and the presence of a pathogenic variant. A total of 78 patients (80%) presented with some bipolar or unipolar scar on endocardial voltage mapping, whereas 43 carried pathogenic variants (44%). Significant associations were observed between presence of endocardial scars on voltage mapping and previous or inducible ventricular tachycardia, right ventricular function and dimensions, or electrocardiogram features of ARVC. A total of 60 of the 78 patients (77%) with an endocardial scar fulfilled the criteria for a definitive arrhythmogenic right ventricular dysplasia diagnosis versus 8 of 19 patients (42%) without scar (p=0.003). Patients with a definitive diagnosis of ARVC had more scars from any location and the scars were larger in patients with ARVC. In the 68 patients with a definitive diagnosis of ARVC, the presence of any endocardial scar was similar whether an ARVC-causal mutation was present or not. Only scar extent was significantly greater in patients with pathogenic variants. There was no difference in the presence and characteristics of scars in PKP2 mutated versus other mutated patients. The 3-dimensional endocardial mapping could have an important role for refining ARVC diagnosis and may be able to detect minor forms with otherwise insufficient criteria for diagnosis. The trend for larger scar extent were observed in mutated patients, without any difference according to the mutated genes.

Longitudinal Prediction of Ventricular Arrhythmic Risk in Patients With Arrhythmogenic Right Ventricular Cardiomyopathy.

The arrhythmogenic right ventricular cardiomyopathy (ARVC) risk calculator stratifies risk for incident sustained ventricular arrhythmias (VA) at the time of ARVC diagnosis. However, included risk factors change over time, and how well the ARVC risk calculator performs at follow-up is unknown. This was a retrospective analysis of patients with definite ARVC and without prior sustained VA. Risk factors for VA including age, nonsustained ventricular tachycardia, premature ventricular complex burden, T-wave inversions on electrocardiogram, cardiac syncope, right ventricular function, therapeutic medication use, and exercise intensity were assessed at the time of 2010 Task Force Criteria based ARVC diagnosis and upon repeat evaluations. Changes in these risk factors were analyzed over 5-year follow-up. The 5-year risk of VA was predicted longitudinally using (1) the baseline ARVC risk calculator prediction, (2) the ARVC risk prediction calculated using updated risk factors, and (3) time-varying Cox regression. Discrimination and calibration were assessed in comparison to observed VA event rates. Four hundred eight patients with ARVC experiencing 132 primary VA events were included. Matched comparison of risk factors at baseline versus at 5 years of follow-up revealed decreased burdens of premature ventricular complexes (-1200/day) and nonsustained ventricular tachycardia (-14%). Presence of significant right ventricular dysfunction and number of T-wave inversions on electrocardiogram were unchanged. Observed risk for VA decreased by 13% by 5 years follow-up. The baseline ARVC risk calculator's ability to predict 5-year VA risk worsened during follow-up (C statistics, 0.83 at diagnosis versus 0.68 at 5 years). Both the updated ARVC risk calculator (C statistics of 0.77) and time-varying Cox regression model (C statistics, 0.77) had strong discrimination. The updated ARVC risk calculator overestimated 5-year VA risk by an average of +6%. Risk factors for VA in ARVC are dynamic, and overall risk for incident sustained VA decreases during follow-up. Up-to-date risk factor assessment improves VA risk stratification.

Arrhythmogenic Right Ventricular Cardiomyopathy Accompanied by Chronic Myocarditis.

Patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) classically present with ventricular arrhythmias and less commonly heart failure. ARVC is an inherited cardiomyopathy and generally based on a variant of desmosomal genes. Recently, the association between myocardial inflammation and ARVC has been a matter of great concern. We encountered a patient with ARVC who had a desmoglein-2 mutation with advanced right ventricular failure accompanying a preserved left ventricular function. Concomitant right ventricular myocarditis was detected four years after the diagnosis of ARVC. ARVC and myocarditis might have a deep pathophysiological association, at least in some cases.

Programmed Ventricular Stimulation as an Additional Primary Prevention Risk Stratification Tool in Arrhythmogenic Right Ventricular Cardiomyopathy: A Multinational Study.

A novel risk calculator based on clinical characteristics and noninvasive tests that predicts the onset of clinical sustained ventricular arrhythmias (VA) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) has been proposed and validated by recent studies. It remains unknown whether programmed ventricular stimulation (PVS) provides additional prognostic value. All patients with a definite ARVC diagnosis, no history of sustained VAs at diagnosis, and PVS performed at baseline were extracted from 6 international ARVC registries. The calculator-predicted risk for sustained VA (sustained or implantable cardioverter defibrillator treated ventricular tachycardia [VT] or fibrillation, [aborted] sudden cardiac arrest) was assessed in all patients. Independent and combined performance of the risk calculator and PVS on sustained VA were assessed during a 5-year follow-up period. Two hundred eighty-eight patients (41.0±14.5 years, 55.9% male, right ventricular ejection fraction 42.5±11.1%) were enrolled. At PVS, 137 (47.6%) patients had inducible ventricular tachycardia. During a median of 5.31 [2.89-10.17] years of follow-up, 83 (60.6%) patients with a positive PVS and 37 (24.5%) with a negative PVS experienced sustained VA (P<0.001). Inducible ventricular tachycardia predicted clinical sustained VA during the 5-year follow-up and remained an independent predictor after accounting for the calculator-predicted risk (HR, 2.52 [1.58-4.02]; P<0.001). Compared with ARVC risk calculator predictions in isolation (C-statistic 0.72), addition of PVS inducibility showed improved prediction of VA events (C-statistic 0.75; log-likelihood ratio for nested models, P<0.001). PVS inducibility had a 76% [67-84] sensitivity and 68% [61-74] specificity, corresponding to log-likelihood ratios of 2.3 and 0.36 for inducible (likelihood ratio+) and noninducible (likelihood ratio-) patients, respectively. In patients with a ARVC risk calculator-predicted risk of clinical VA events <25% during 5 years (ie, low/intermediate subgroup), PVS had a 92.6% negative predictive value. PVS significantly improved risk stratification above and beyond the calculator-predicted risk of VA in a primary prevention cohort of patients with ARVC, mainly for patients considered to be at low and intermediate risk by the clinical risk calculator.

Correlations between endocardial voltage mapping, diagnosis and genetic in patients with arrhythmogenic right ventricular cardiomyopathy

Abstract Background The relations between voltage mapping and diagnosis or genetic background of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) have not been investigated so far. Objective To investigate if diagnosis or genetic background were linked to voltage mapping in ARVC. Method 97 patients with proved or suspected ARVC undergoing 3D endocardial mapping and genetic testing have been retrospectively included. Presence, localisation and extension of low voltage areas were correlated to ARVC diagnosis and presence of a culprit mutation. Results 68 patients (70%) fulfilled ARVC diagnosis according to the Task Force criteria and 43 (44%) had ARVC-causal mutations. 78 (80%) presented with some bipolar or unipolar endocardial scar. 60/ 78 patients with endocardial scar (77%) fulfilled the criteria for a definitive ARVC diagnosis versus 8/19 patients without scar (42%) (p=0.003). In the 68 patients with a definitive diagnosis of ARVC, the presence of endocardial scar was similar whether an ARVC-causal mutation was present or not (35/40 vs 25/28, p=ns). While there was slightly more infero-lateral scars in patients carrying a pathogenic genetic variant (34/40 vs 18/28, p=0.04), there was no difference for right ventricular outflow tract (24/40 vs 17/28) and apical scars (12/40 vs 11/28) or for multiple scars (26/35 vs 14/25 patients with scars). Scar extension was greater in patients with pathogenic variants (bipolar 12±10 vs 6±10%, p=0.02, and unipolar 22±13 vs 12±15%, p=0.01). Conclusion 3D endocardial mapping could have an important role for refining ARVC diagnosis. Trends for larger and more infero-lateral scars were observed in mutated patients, without difference according to the mutated genes. Funding Acknowledgement Type of funding sources: None.

Arrhythmogenic right ventricular cardiomyopathy – evolution of electrocardiographic markers during long-term follow-up prior to ascertainment of diagnosis

Abstract Background Depolarization and repolarization abnormalities are part of the diagnostic Task Force Criteria of 2010 (TFC2010) for arrhythmogenic right ventricular cardiomyopathy (ARVC). These abnormalities are thought to be progressive but have also been described as dynamic and sometimes reversible. Evolution of ECG abnormalities prior to clinical ARVC diagnosis is poorly studied. Objective To assess the evolution of ECG depolarization and repolarization characteristics in patients with ARVC prior to diagnosis and to identify markers of disease progression at a preclinical stage. Methods 353 patients with definite ARVC from Sweden, Denmark, the Netherlands and Canada with at least one 12-lead digital ECG (65% males, 67% probands, 56% mutation carriers, median age at diagnosis 42 [IQR 29–53] years and median age at first ECG 44 [30–55] years) were included. Digital ECGs were extracted from regional ECG archives. ECGs with left bundle branch block, ventricular pacing or recorded either prior to 15 years of age or after heart transplantation were excluded. Remaining 6,871 ECGs were digitally processed and automatically analysed using the Glasgow algorithm. Median values for overall QRS duration, terminal activation delay (TAD) in lead V1 as well as amplitudes of QRS-T-components in precordial leads per patient per year were used for analyses and graphically represented using Lowess smoothing with cubic splines (Figure 1). Blue lines indicate smoothed conditional mean with 95% confidence interval (shadow). Time “0” (red line) indicates the time when TFC2010 were fulfilled for definite diagnosis. A database of 18,564 anonymized digital ECGs (58% males, median age at latest ECG 41 years [IQR 32–52]) who were in contact with health care during 2020–2021 was processed using the same exclusion criteria and signal-processing methodology as in the ARVC group and used as a reference (black line). Results TAD in lead V1 and overall QRS duration demonstrated a significant increase years before ARVC diagnosis, and significant reductions were seen in QRS-T voltages measured as R wave amplitude, QRS amplitude (the absolute sum of R wave and S wave), and T wave amplitude (Table 1 and Figure 1). The changes were seen in all precordial leads, not only the right-sided, and visually diverging from the controls. Conclusion Development of the ARVC ECG phenotype started several years before diagnosis and continued afterwards. QRS duration and TAD increased, QRS voltages decrease, and T wave amplitude decreased eventually leading to T wave inversion. These changes might be visually assessed but also measured with available ECG software. These findings may be clinically useful in the screening and follow-up of ARVC relatives. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Governmental funding of clinical research (ALF), Region Ostergotland, Sweden.The Swedish Heart-Lung Foundation.

Value of 3D echocardiography in the diagnosis of arrhythmogenic right ventricular cardiomyopathy.

The 2010 Task Force Criteria (TFC) require that both right ventricular (RV) regional wall-motion abnormalities (WMA) and specific RV size cut-offs be met in order to fulfil one of the major criterion for arrhythmogenic right ventricular cardiomyopathy (ARVC) diagnosis. Currently, 2D echocardiography (2DE) and cardiovascular magnetic resonance imaging (cMRI) are used to determine if these criteria are met. Little is known about the diagnostic value of 3D echocardiography (3DE) in ARVC. The aim of this study was to determine whether a combination of 2DE-3DE is non-inferior to the currently used 2DE-cMRI combination in the diagnosis of patients with ARVC. Thirty-nine individuals (47±15 years) with suspected ARVC underwent evaluation of the RV with cMRI, 2DE, and 3DE. 3DE and cMRI were independently used to obtain RV volumes, ejection fraction (EF) and determine the presence of segmental RV WMA. Studies were blindly classified as meeting criteria for ARVC in accordance with the 2010 TFC. Kappa statistics were used to test the concordance between 2DE-cMRI and 2DE-3DE approaches. Using the 2DE-cMRI approach, 3/39 were not affected, 5/39 possible, 8/39 borderline, and 23/39 definite ARVC. The proposed 2DE-3DE approach yielded 5/39 not affected, 7/39 possible, 8/39 borderline, and 19/39 definite diagnoses. The two approaches were highly concordant (k = 0.71; 95% confidence interval: 0.44-0.84). Although 3DE underestimated RV volumes in comparison with cMRI, interfering, in some instances with the fulfilment of a major criterion, it was able to identify more RV WMA (28/39) than 2DE (11/39), with a detection-rate comparable to cMRI (33/39) highlighting a unique advantage. The combination of 2DE-3DE for ARVC diagnosis is comparable to the conventional 2DE-cMRI approach. 3DE should be performed in all suspected ARVC patients to aide in the detection of WMA.

Highly malignant disease in childhood-onset arrhythmogenic right ventricular cardiomyopathy.

This study aimed to explore the incidence of severe cardiac events in paediatric arrhythmogenic right ventricular cardiomyopathy (ARVC) patients and ARVC penetrance in paediatric relatives. Furthermore, the phenotype in childhood-onset ARVC was described. Consecutive ARVC paediatric patients and genotype positive relatives ≤18 years of age were followed with electrocardiographic, structural, and arrhythmic characteristics according to the 2010 revised Task Force Criteria. Penetrance of ARVC disease was defined as fulfilling definite ARVC criteria and severe cardiac events were defined as cardiac death, heart transplantation (HTx) or severe ventricular arrhythmias. Childhood-onset disease was defined as meeting definite ARVC criteria ≤12 years of age. Among 62 individuals [age 9.8 (5.0-14.0) years, 11 probands], 20 (32%) fulfilled definite ARVC diagnosis, of which 8 (40%) had childhood-onset disease. The incidence of severe cardiac events was 23% (n = 14) by last follow-up and half of them occurred in patients ≤12 years of age. Among the eight patients with childhood-onset disease, five had biventricular involvement needing HTx and three had severe arrhythmic events. Among the 51 relatives, 6% (n = 3) met definite ARVC criteria at time of genetic diagnosis, increasing to 18% (n = 9) at end of follow-up. In a paediatric ARVC cohort, there was a high incidence of severe cardiac events and half of them occurred in children ≤12 years of age. The ARVC penetrance in genotype positive paediatric relatives was 18%. These findings of a high-malignant phenotype in childhood-onset ARVC indicate a need for ARVC family screening at younger age than currently recommended.

Family History and Warning Symptoms Precede Sudden Cardiac Death in Arrhythmogenic Right Ventricular Cardiomyopathy (from a Nationwide Study in Sweden)

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease explaining about 4% of sudden cardiac death (SCD) cases in the young in Sweden. This study aimed to describe the circumstances preceding SCD in all victims &lt;35 years of age who received an autopsy-confirmed diagnosis of ARVC from January 1, 2000, to December 31, 2010, in Sweden (n=22). Data on demographics, medical and family history, circumstances of death, and anatomopathological findings were collected from several compulsory national health registries, clinical records, family interviews, and autopsy reports. Registry-based data were compared with age-matched, gender-matched, and geographically-matched population controls. During the 6 months preceding SCD, 15 cases (68%) had experienced symptoms of cardiac origin, mainly syncope or presyncope (54%) and chest discomfort (27%). A total of 8 cases (36%) had sought medical care because of cardiac symptoms. The occurrence of hospital visits was significantly increased in cases compared with controls (odds ratio 4.62 [1.35 to 15.8]). A total of 10 cases (45%) had a family history of SCD. The most common activity at the time of death was exercise (41%). A complete cardiac investigation was seldom performed; only 1 case was diagnosed with ARVC before death. In conclusion, in this nationwide study, we observed a high prevalence of symptoms of cardiac origin, healthcare use, and family history of SCD preceding SCD in the young caused by ARVC. Increased awareness of these warning signals in younger patients is critical to improving risk stratification and early disease detection.

Age-related differences and associated mid-term outcomes of subcutaneous implantable cardioverter-defibrillators: A propensity-matched analysis from a multicenter European registry.

A few limited case series have shown that the subcutaneous implantable cardioverter-defibrillator (S-ICD) system is safe for teenagers and young adults, but a large-scale analysis currently is lacking. The purpose of this study was to compare mid-term device-associated outcomes in a large real-world cohort of S-ICD patients,stratified by age at implantation. Two propensity-matched cohorts of teenagers + young adults (≤30 years old) and adults (>30 years old) were retrieved from the ELISIR Registry. The primary outcome was the comparison of inappropriate shock rate. Complications, freedom from sustained ventricular arrhythmias, and overall and cardiovascular mortality were deemed secondary outcomes. Teenagers + young adults represented 11.0% of the entire cohort. Two propensity-matched groups of 161 patients each were used for the analysis. Median follow-up was 23.1 (13.2-40.5) months. In total, 15.2% patients experienced inappropriate shocks, and 9.3% device-related complications were observed, with no age-related differences in inappropriate shocks (16.1% vs 14.3%; P = .642) and complication rates (9.9% vs 8.7%; P = .701). At univariate analysis, young age was not associated with increased rates of inappropriate shocks (hazard ratio [HR] 1.204 [0.675-2.148]: P = .529). At multivariate analysis, use of the SMART Pass algorithm was associated with a strong reduction in inappropriate shocks (adjusted HR 0.292 [0.161-0.525]; P <.001), whereas arrhythmogenic right ventricular cardiomyopathy (ARVC) was associated with higher rates of inappropriate shocks (adjusted HR 2.380 [1.205-4.697]; P = .012). In a large multicenter registry of propensity-matched patients, use of the S-ICD in teenagers/young adults was safe and effective. The rates of inappropriate shocks and complications between cohorts were not significantly different. The only predictor of increased inappropriate shocks was a diagnosis of ARVC.

Arrhythmogenic Right Ventricular Cardiomyopathy - A Case Report

Arrhythmogenic right ventricular cardiomyopathy (ARVC), formerly called "arrhythmogenic right ventricular dysplasia/cardiomyopathy" (ARVD/ARVC), is a myocardial structural abnormality disease with clinical presentation of cardiac arrhythmia. It is characterized by the replacement of the myocardium with fibrofatty tissue. In 2010, Marcus et al. proposed revised criteria based on the original Task Force Criteria 1994. We present a case of a young African American male who met two major criteria for definite diagnosis of ARVC: Electrocardiogram (EKG) major criteria and Magnetic Resonance Imaging (MRI) major criteria. The patient had early transition inverted t waves in lead V1-V4, and MRI showed Right Ventricle (RV) dyskinesia with RV Ejection Fraction (EF) &lt; 40%, both satisfying the two major criteria required for definitive diagnosis of ARVC

Importance of genotype for risk stratification in arrhythmogenic right ventricular cardiomyopathy using the 2019 ARVC risk calculator.

AimsTo study the impact of genotype on the performance of the 2019 risk model for arrhythmogenic right ventricular cardiomyopathy (ARVC).Methods and resultsThe study cohort comprised 554 patients with a definite diagnosis of ARVC and no history of sustained ventricular arrhythmia (VA). During a median follow-up of 6.0 (3.1,12.5) years, 100 patients (18%) experienced the primary VA outcome (sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator intervention, aborted sudden cardiac arrest, or sudden cardiac death) corresponding to an annual event rate of 2.6% [95% confidence interval (CI) 1.9–3.3]. Risk estimates for VA using the 2019 ARVC risk model showed reasonable discriminative ability but with overestimation of risk. The ARVC risk model was compared in four gene groups: PKP2 (n = 118, 21%); desmoplakin (DSP) (n = 79, 14%); other desmosomal (n = 59, 11%); and gene elusive (n = 160, 29%). Discrimination and calibration were highest for PKP2 and lowest for the gene-elusive group. Univariable analyses revealed the variable performance of individual clinical risk markers in the different gene groups, e.g. right ventricular dimensions and systolic function are significant risk markers in PKP2 but not in DSP patients and the opposite is true for left ventricular systolic function.ConclusionThe 2019 ARVC risk model performs reasonably well in gene-positive ARVC (particularly for PKP2) but is more limited in gene-elusive patients. Genotype should be included in future risk models for ARVC.