Clinical Characteristics and Follow-Up of Pediatric-Onset Arrhythmogenic Right Ventricular Cardiomyopathy

Background: The Defibrillator in Arrhythmogenic Right Ventricular Cardiomyopathy International (DARVIN) study was a multicenter investigation that enrolled patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) who received an implantable defibrillator (ICD) for either secondary or primary prevention of sudden death. Methods: In this DARVIN substudy, we examined whether programmed ventricular stimulation (PVS) is able to predict the arrhythmic risk in a large cohort of 201 ARVC patients (133 males, 68 females, aged 36 ± 12 years) who received an ICD. Implant indications were a history of cardiac arrest in 13 (6%) patients; sustained ventricular tachycardia (VT) in 82 (41%); syncope in 42 (21%); asymptomatic nonsustained VT in 40 (20%); and a family history of sudden death in 24 (12%). PVS prior to ICD implantation was carried out in 143 of 201 patients (71%). All antiarrhythmic drugs were discontinued ≥ 5 half-lives (≥ 6 weeks for amiodarone) before the study. PVS included a minimum of 2 drive cycles length and up to 3 ventricular extrastimuli while pacing from two right ventricular sites. Results: One hundred-nine patients (76%) were inducible to either sustained VT (patients 70; 64%), with a mean cycle length of 287 ± 66ms (range 220 to 410 ms), or ventricular fibrillation/flutter (VF) (patients 39; 36%). Of 109 patients who were inducible at PVS, 56 (52%) did not experience ICD therapy during a mean follow-up of 47 ± 22 months, whereas 11 of 34 (33%) noninducible patients had appropriate ICD interventions. Overall, the positive predictive value of PVS was 48%, the negative predictive value 67%, and the test accuracy 53%. The incidence of ICD discharges on VF, which in all likelihood would have been fatal in the absence of ICD therapy, did not differ between patients who were and were not inducible at PVS (26 of 109, 24% vs 7 of 34, 21%; p=0.87), regardless of clinical presentation. The type of ventricular arrhythmia inducible at PVS did not predict VF during the follow-up. Conclusions: The presence (or absence) of an inducible arrhythmia on PVS did not correlate with subsequent appropriate ICD interventions, suggesting a limited role for PVS in arrhythmic risk stratification of ARVC patient population. A negative PVS may not indicate better prognosis.

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372 Long term follow-up of patients with arrhythmogenic right ventricular cardiomyopathy and ventricular tachycardia treated by catheter ablation

EP Europace ◽

10.1016/eupace/7.supplement_1.78-a ◽

2005 ◽

Vol 7 (Supplement_1) ◽

pp. 78-78

Author(s):

E.K. Wlodarska ◽

L. Szumowski ◽

O. Wozniak ◽

P. Sanders ◽

M. Konka ◽

...

Keyword(s):

Ventricular Tachycardia ◽

Catheter Ablation ◽

Right Ventricular ◽

Arrhythmogenic Right Ventricular Cardiomyopathy ◽

Ventricular Cardiomyopathy ◽

Long Term Follow Up

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Clinical Findings and Diagnostic Yield of Arrhythmogenic Cardiomyopathy Through Genomic Screening of Pathogenic or Likely Pathogenic Desmosome Gene Variants

Circulation Genomic and Precision Medicine ◽

10.1161/circgen.120.003302 ◽

2021 ◽

Vol 14 (2) ◽

Author(s):

Eric D. Carruth ◽

Dominik Beer ◽

Amro Alsaid ◽

Marci L.B. Schwartz ◽

Megan McMinn ◽

...

Keyword(s):

Family History ◽

Right Ventricular ◽

Arrhythmogenic Right Ventricular Cardiomyopathy ◽

Diagnostic Testing ◽

Great Promise ◽

Arrhythmogenic Cardiomyopathy ◽

Ventricular Cardiomyopathy ◽

Patient Reported ◽

Genomic Screening

Background: Genomic screening holds great promise for presymptomatic identification of hidden disease, and prevention of dramatic events, including sudden cardiac death associated with arrhythmogenic cardiomyopathy (ACM). Herein, we present findings from clinical follow-up of carriers of ACM-associated pathogenic/likely pathogenic desmosome variants ascertained through genomic screening. Methods: Of 64 548 eligible participants in Geisinger MyCode Genomic Screening and Counseling program (2015–present), 92 individuals (0.14%) identified with pathogenic/likely pathogenic desmosome variants by clinical laboratory testing were referred for evaluation. We reviewed preresult medical history, patient-reported family history, and diagnostic testing results to assess both arrhythmogenic right ventricular cardiomyopathy and left-dominant ACM. Results: One carrier had a prior diagnosis of dilated cardiomyopathy with arrhythmia; no other related diagnoses or diagnostic family history criteria were reported. Fifty-nine carriers (64%) had diagnostic testing in follow-up. Excluding the variant, 21/59 carriers satisfied at least one arrhythmogenic right ventricular cardiomyopathy task force criterion, 11 (52%) of whom harbored DSP variants, but only 5 exhibited multiple criteria. Six (10%) carriers demonstrated evidence of left-dominant ACM, including high rates of atypical late gadolinium enhancement by magnetic resonance imaging and nonsustained ventricular tachycardia. Two individuals received new cardiomyopathy diagnoses and received defibrillators for primary prevention. Conclusions: Genomic screening for pathogenic/likely pathogenic variants in desmosome genes can uncover both left- and right-dominant ACM. Findings of overt cardiomyopathy were limited but were most common in DSP -variant carriers and notably absent in PKP2 -variant carriers. Consideration of the pathogenic/likely pathogenic variant as a major criterion for diagnosis is inappropriate in the setting of genomic screening.

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Sudden Cardiac Death Prediction in Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC): A Multinational Collaboration

Circulation Arrhythmia and Electrophysiology ◽

10.1161/circep.120.008509 ◽

2020 ◽

Author(s):

Julia Cadrin-Tourigny ◽

Laurens P. Bosman ◽

Weijia Wang ◽

Rafik Tadros ◽

Aditya Bhonsale ◽

...

Keyword(s):

Sudden Cardiac Death ◽

Right Ventricular ◽

Cardiac Death ◽

Cox Regression ◽

Arrhythmogenic Right Ventricular Cardiomyopathy ◽

Right Ventricular Ejection Fraction ◽

Ventricular Cardiomyopathy ◽

Clinical Predictors ◽

Ventricular Ejection Fraction

Background - Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is associated with ventricular arrhythmias (VA) and sudden cardiac death (SCD). A model was recently developed to predict incident sustained VA in ARVC patients. However, since this outcome may overestimate the risk for SCD, we aimed to specifically predict life-threatening VA (LTVA) as a closer surrogate for SCD. Methods - We assembled a retrospective cohort of definite ARVC cases from 15 centers in North America and Europe. Association of 8 pre-specified clinical predictors with LTVA (SCD, aborted SCD, sustained or ICD treated VT>250 bpm) in follow-up was assessed by Cox regression with backward selection. Candidate variables included age, sex, prior sustained VA (≥30s, hemodynamically unstable or ICD treated VT; or aborted SCD), syncope, 24-hour premature ventricular complexes (PVC) count, the number of anterior and inferior leads with T-wave inversion (TWI), left and right ventricular ejection fraction. The resulting model was internally validated using bootstrapping. Results - A total of 864 definite ARVC patients (40±16 years; 53% male) were included. Over 5.75 years [IQR 2.77, 10.58] of follow-up, 93 (10.8%) patients experienced LTVA including 15 with SCD/aborted SCD (1.7%). Of the 8 pre-specified clinical predictors, only 4 (younger age, male sex, PVC count and number of leads with TWI) were associated with LTVA. Notably, prior sustained VA did not predict subsequent LTVA (p=0.850). A model including only these 4 predictors had an optimism-corrected C-index of 0.74 (95% CI:0.69-0.80) and calibration slope of 0.95 (95% CI:0.94-0.98) indicating minimal over-optimism. Conclusions - LTVA events in patients with ARVC can be predicted by a novel simple prediction model using only 4 clinical predictors. Prior sustained VA and the extent of functional heart disease are not associated with subsequent LTVA events.

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Genotype–phenotype correlation in arrhythmogenic right ventricular cardiomyopathy—risk of arrhythmias and heart failure

Journal of Medical Genetics ◽

10.1136/jmedgenet-2021-107911 ◽

2021 ◽

pp. jmedgenet-2021-107911

Author(s):

Alex Hørby Christensen ◽

Pyotr G Platonov ◽

Henrik Kjærulf Jensen ◽

Monica Chivulescu ◽

Anneli Svensson ◽

...

Keyword(s):

Right Ventricular ◽

Arrhythmogenic Right Ventricular Cardiomyopathy ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Carrier Status ◽

Ventricular Cardiomyopathy ◽

Ventricular Ejection Fraction ◽

Male Sex ◽

The Impact

BackgroundArrhythmogenic right ventricular cardiomyopathy (ARVC) is predominantly caused by desmosomal genetic variants, and clinical hallmarks include arrhythmias and systolic dysfunction. We aimed at studying the impact of the implicated gene(s) on the disease course.MethodsThe Nordic ARVC Registry holds data on a multinational cohort of ARVC families. The effects of genotype on electrocardiographic features, imaging findings and clinical events were analysed.ResultsWe evaluated 419 patients (55% men), with a mean follow-up of 11.2±7.4 years. A pathogenic desmosomal variant was identified in 62% of the 230 families: PKP2 in 41%, DSG2 in 13%, DSP in 7% and DSC2 in 3%. Reduced left ventricular ejection fraction (LVEF) ≤45% on cardiac MRI was more frequent among patients with DSC2/DSG2/DSP than PKP2 ARVC (27% vs 4%, p<0.01). In contrast, in Cox regression modelling of patients with definite ARVC, we found a higher risk of arrhythmias among PKP2 than DSC2/DSG2/DSP carriers: HR 0.25 (0.10–0.68, p<0.01) for atrial fibrillation/flutter, HR 0.67 (0.44–1.0, p=0.06) for ventricular arrhythmias and HR 0.63 (0.42–0.95, p<0.05) for any arrhythmia. Gene-negative patients had an intermediate risk (16%) of LVEF ≤45% and a risk of the combined arrhythmic endpoint comparable with DSC2/DSG2/DSP carriers. Male sex was a risk factor for both arrhythmias and reduced LVEF across all genotype groups (p<0.01).ConclusionIn this large cohort of ARVC families with long-term follow-up, we found PKP2 genotype to be more arrhythmic than DSC2/DSG2/DSP or gene-negative carrier status, whereas reduced LVEF was mostly seen among DSC2/DSG2/DSP carriers. Male sex was associated with a more severe phenotype.

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Abstract 11990: LMNA Cardiomyopathy Mimicking Arrhythmogenic Right Ventricular Cardiomyopathy

Circulation ◽

10.1161/circ.130.suppl_2.11990 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Koichi Kato ◽

Seiko Ohno ◽

Takeru Makiyama ◽

Minoru Horie

Keyword(s):

Right Ventricular ◽

Genetic Screening ◽

Clinical Characteristics ◽

Age Of Onset ◽

Arrhythmogenic Right Ventricular Cardiomyopathy ◽

Study Cohort ◽

Inherited Disease ◽

Ventricular Cardiomyopathy ◽

Lmna Mutation ◽

Mutation Carriers

Background and Objectives: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disease characterized by RV dilatation and ventricular arrhythmias. Desmosomal gene mutations are the major cause of ARVC. LMNA mutations have been known to lead dilated cardiomyopathy, other systemic diseases, and more recently, ARVC. In this study, we performed extensive genetic screening for LMNA in ARVC patients and assessed the clinical characteristics of patients with LMNA mutations. Methods: Study cohort consisted of 57 ARVC probands (definite; 45). Coding exons of LMNA, 4 desmosomal protein genes (PKP2, DSP, DSG2, DSC), and also 3 long QT syndrome related genes (KCNQ1, KCNH2, SCN5A) were amplified and sequenced by using illumina next generation sequencer. Clinical characteristics of LMNA mutation carriers and those of desmosomal mutation carriers were compared by using student t test. Results: Among 57 clinically-diagnosed ARVC probands, we identified desmosomal mutations in 32 probands (56.1%) and two LMNA mutations in two probands. The first LMNA mutation, p.M1K was detected in 62-year-old male, and the second one, p.W514X was in 70-year-old male. Both patients showed RV dilatation, non-sustained ventricular tachycardia, and complete atrioventricular block. His younger brother also died from ARVC. The proband’s daughter and son, who are currently in their 30s, have the same M1K mutation, however, have not had any signs of ARVC yet. In the family member with W514X mutant, the proband’s father suddenly died in his 40s and 45-year-old daughter who had the same W514X mutation, showed RV dilatation and brady-AF. In probands with LMNA mutations compared to those with desmosomal mutations, the age of onset was significantly older (38.6±18.1 vs 60.0±2.8), and their heart rate was significantly slower (61.1±12.5 vs 47±1.4). Both probands with LMNA mutations underwent pacemaker therapy, which is rare in patients with desmosomal mutations (2/2 vs 1/32 ). In family members with LMNA mutations, none of mutation carriers had showed ARVC until their 50s. Conclusion: Our patients with LMNA mutations developed ARVC with bradyarrhythmia after age of 50. Genetic screening for LMNA gene is important for ARVC, especially in cases with bradycardia.

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Abstract 13646: Clinical Profile and Ablation Outcomes in Patients With Arrhythmogenic Right Ventricular Cardiomyopathy and Biventricular Involvement

Circulation ◽

10.1161/circ.142.suppl_3.13646 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Lishui Shen ◽

Lihui Zheng ◽

Yan Yao

Keyword(s):

Catheter Ablation ◽

Heart Transplantation ◽

Right Ventricular ◽

Arrhythmogenic Right Ventricular Cardiomyopathy ◽

Clinical Profile ◽

Ventricular Cardiomyopathy ◽

Free Survival ◽

Younger Age ◽

Procedural Success

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a progressive disease which can involve both ventricles. This study aimed to elucidate the clinical profile and ablation efficacy in Chinese ARVC patients with biventricular (BiV) involvement. Methods and Results: Based on cardiovascular magnetic resonance findings, 255 ARVC patients were divided into two groups: the BiV involved group (n=137) and the isolated right ventricular (RV) involved group (n=118). Patients with BiV involvement were more likely to suffer from heart failure (28.5% vs. 8.5%; P <0.001) and recurrent syncope (32.8% vs. 21.2%; P =0.038), and presented with lower heart transplantation-free survival and composed endpoint (death or heart transplantation)-free survival (all P <0.05). Of the 255 subjects, 52 BiV involved patients and 77 isolated RV involved patients underwent catheter ablation for ventricular tachycardia (VT). After 5 years’ follow-up, the outcomes including VT recurrence and all-cause mortality in 2 groups showed no difference (all P >0.05). The age, amount of induced VT during electrophysiology study and non-acute procedural success (partial success, defined as inducing the same VT with cycle length 30% longer after ablation; substrate modification only) were independent predictors of VT recurrence in BiV involved patients (all P <0.05). Conclusion: BiV involvement in ARVC indicated worse symptoms and poor prognosis. Nonetheless, catheter ablation remained effective for VT control in this population. The younger age, more induced VTs and non-acute procedural success were associated with VT recurrence after ablation.

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