Revision of the Task Force diagnostic criteria (TFC) for arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D), in 2010, has increased the sensitivity for the diagnosis of early and ...familial forms of the disease. Epsilon wave (EW) is a major diagnostic criterion in the context of ARVC/D, however, it remains unquantifiable and therefore, may leave room for substantial subjective interpretation, thus, explaining the existing high inter-observer variability in the assessment of EW. EW, when present, coexists with other disease characteristics, which are sufficient for ARVC/D diagnosis, making EW generally not required for ARVC/D diagnosis. Nevertheless, EW remains an important part of the electrocardiographic phenotype of ARVC/D that may be useful in planning diagnostic work-up, which needs to be recognized.
Arrhythmogenic 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.
The 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.
We 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:
in 41%,
in 13%,
in 7% and
in 3%. Reduced left ventricular ejection fraction (LVEF) ≤45% on cardiac MRI was more frequent among patients with
/
/
than
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
than
/
/
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
/
/
carriers. Male sex was a risk factor for both arrhythmias and reduced LVEF across all genotype groups (p<0.01).
In this large cohort of ARVC families with long-term follow-up, we found
genotype to be more arrhythmic than
/
2/
or gene-negative carrier status, whereas reduced LVEF was mostly seen among
/
2/
carriers. Male sex was associated with a more severe phenotype.
Recent studies in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients have drawn attention to atrial fibrillation (AF) as an arrhythmic manifestation of ARVC and as an indicator of atrial ...involvement in the disease progression. We aimed to assess the prevalence of AF in the Scandinavian cohort of ARVC patients and to evaluate its association with disease clinical manifestations.
Study sample comprised of 293 definite ARVC patients by 2010 Task Force criteria (TFC2010) and 141 genotype-positive family members (total n = 434, 43% females, median age at ARVC diagnosis 41 years interquartile range (IQR) 28–52 years). ARVC diagnostic score was calculated as the sum of major (2 points) and minor (1 point) criteria in all categories of the TFC2010.
AF was diagnosed in 42 patients (10%): in 41 patients with definite ARVC diagnosis (14%) vs in one genotype-positive family member (1%), p < 0.001. The median age at AF onset was 51 (IQR 38–58) years. The prevalence of AF was related to the ARVC diagnostic score: it significantly increased starting with the diagnostic score 4 (2% in those with score 3 vs 13% in those with score 4, p = 0.023) and increased further with increased diagnostic score (Somer's d value is 0.074, p < 0.001).
AF is seen in 14% of definite ARVC patients and is related to the severity of disease phenotype thus suggesting AF being an arrhythmic manifestation of this cardiomyopathy indicating atrial myocardial involvement in the disease progression.
•Atrial fibrillation is common in arrhythmogenic right ventricular cardiomyopathy.•Atrial fibrillation prevalence is related to the severity of disease phenotype.•Atrial fibrillation is associated with right ventricular structural abnormalities.
There is a paucity of data on heart transplantation (HTx) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), and specific recommendations on indications for listing ARVC ...patients for HTx are lacking. In order to delineate features pertinent to HTx assessment, we explored the pre-HTx characteristics and clinical history in a cohort of ARVC patients who received heart transplants.
Data from 31 ARVC/HTx patients enrolled in the Nordic ARVC Registry, transplanted between 1988 and 2014 at a median age of 46years (14–65), were compared with data from 152 non-transplanted probands with Definite ARVC according to 2010 Task Force Criteria from the same registry.
The HTx patients were younger at presentation, median 31 vs. 38years (p=0.001). There was no difference in arrhythmia-related events. The indication for HTx was heart failure in 28 patients (90%) and ventricular arrhythmias in 3 patients (10%). During median follow-up of 4.9years (0.04–28), there was one early death and two late deaths. Survival was 91% at 5years after HTx. Age at first symptoms under 35years independently predicted HTx in our cohort (OR=7.59, 95% CI 2.69–21.39, p<0.001).
HTx in patients with ARVC is performed predominantly due to heart failure. This suggests that current 2016 International Society for Heart and Lung Transplantation heart transplant listing recommendations for other cardiomyopathies could be applicable in many cases when taking into account the haemodynamic consequences of right ventricular failure in conjunction with ventricular arrhythmia.
The genetic basis of arrhythmogenic right ventricular cardiomyopathy (ARVC) is complex. Mutations in genes encoding components of the cardiac desmosomes have been implicated as being causally related ...to ARVC. Next-generation sequencing allows parallel sequencing and duplication/deletion analysis of many genes simultaneously, which is appropriate for screening of mutations in disorders with heterogeneous genetic backgrounds. We designed and validated a next-generation sequencing test panel for ARVC using HaloPlex. We used SureDesign to prepare a HaloPlex enrichment system for sequencing of DES, DSC2, DSG2, DSP, JUP, PKP2, RYR2, TGFB3, TMEM43 , and TTN from patients with ARVC using a MiSeq instrument. Performance characteristics were determined by comparison with Sanger, as the gold standard, and TruSeq Custom Amplicon sequencing of DSC2, DSG2, DSP, JUP , and PKP2 . All the samples were successfully sequenced after HaloPlex capture, with >99% of targeted nucleotides covered by >20×. The sequences were of high quality, although one problematic area due to a presumptive context-specific sequencing error–causing motif located in exon 1 of the DSP gene was detected. The mutations found by Sanger sequencing were also found using the HaloPlex technique. Depending on the bioinformatics pipeline, sensitivity varied from 99.3% to 100%, and specificity varied from 99.9% to 100%. Three variant positions found by Sanger and HaloPlex sequencing were missed by TruSeq Custom Amplicon owing to loss of coverage.
Background
Sudden cardiac death (SCD) is a global public health issue, accounting for 10–20% of deaths in industrialized countries. Identification of modifiable risk factors may reduce SCD incidence.
...Methods
This umbrella review systematically evaluates published meta-analyses of observational and randomized controlled trials (RCT) for the association of modifiable risk and protective factors of SCD.
Results
Fifty-five meta-analyses were included in the final analysis, of which 31 analyzed observational studies and 24 analyzed RCTs. Five associations of meta-analyses of observational studies presented convincing evidence, including three risk factors diabetes mellitus (DM), smoking, and early repolarization pattern (ERP) and two protective factors implanted cardiac defibrillator (ICD) and physical activity. Meta-analyses of RCTs identified five protective factors with a high level of evidence: ICDs, mineralocorticoid receptor antagonist (MRA), beta-blockers, and sodium-glucose cotransporter-2 (SGLT-2) inhibitors in patients with HF. On the contrary, other established, significant protective agents i.e., amiodarone and statins along with angiotensin-converting enzyme (ACE) inhibitors in heart failure (HF), did not show credibility. Likewise, risk factors as left ventricular ejection fraction in HF, and left ventricular hypertrophy, non-sustain ventricular tachycardia, history of syncope or aborted SCD in pediatric patients with hypertrophic cardiomyopathy, presented weak or no evidence.
Conclusions
Lifestyle risk factors (physical activity, smoking), comorbidities like DM, and electrocardiographic features like ERP constitute modifiable risk factors of SCD. Alternatively, the use of MRA, beta-blockers, SGLT-2 inhibitors, and ICD in patients with HF are credible protective factors. Further investigation targeted in specific populations will be important for reducing the burden of SCD.
Systematic Review Registration
https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020216363
, PROSPERO CRD42020216363.
Myocarditis most often affects otherwise healthy athletes and is one of the leading causes of sudden death in children and young adults. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a ...genetically determined heart muscle disorder with increased risk for paroxysmal ventricular arrhythmias and sudden cardiac death. The clinical picture of myocarditis and ARVC may overlap during the early stages of cardiomyopathy, which may lead to misdiagnosis. In the literature, we found several cases that presented with episodes of myocarditis and ended up with a diagnosis of arrhythmogenic cardiomyopathy, mostly of the left predominant type. The aim of this case presentation is to shed light upon a possible link between myocarditis, a desmoplakin (DSP) gene variant, and ARVC by describing a case of male monozygotic twins who presented with symptoms and signs of myocarditis at 17 and 18 years of age, respectively. One of them also had a recurrent episode of myocarditis. The twins and their family were extensively examined including electrocardiograms (ECG), biochemistry, multimodal cardiac imaging, myocardial biopsy, genetic analysis, repeated cardiac magnetic resonance (CMR) and echocardiography over time. Both twins presented with chest pain, ECG with slight ST‐T elevation, and increased troponin T levels. CMR demonstrated an affected left ventricle with comprehensive inflammatory, subepicardial changes consistent with myocarditis. The right ventricle did not appear to have any abnormalities. Genotype analysis revealed a nonsense heterozygous variant in the desmoplakin (DSP) gene NM_004415.2:c.2521_2522del (p.Gln841Aspfs*9) that is considered likely pathogenic and presumably ARVC related. There was no previous family history of heart disease. There might be a common pathophysiology of ARVC, associated with desmosomal dysfunction, and myocarditis. In our case, both twins have an affected left ventricle without any right ventricular involvement, and they are carriers of a novel DSP variant that is likely associated with ARVC. The extensive inflammation of the LV that was apparent in the CMR may or may not be the primary event of ARVC. Nevertheless, our data suggest that irrespective of a possible link here to ARVC, genetic testing for arrhythmogenic cardiomyopathy might be advisable for patients with recurrent myocarditis associated with a family history of myocarditis.
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) carries a risk of sudden death. We aimed to assess whether vectorcardiographic (VCG) parameters directed toward the right heart and ...a measured angle of the S-wave would help differentiate ARVD/C with otherwise normal electrocardiograms from controls.
Task Force 2010 definite ARVD/C criteria were met for all patients. Those who did not fulfill Task Force depolarization or repolarization criteria (-ECG) were compared with age and gender-matched control subjects. Electrocardiogram measures of a 3-dimentional spatial QRS-T angle, a right-precordial-directed orthogonal QRS-T (RPD) angle, a root mean square of the right sided depolarizing forces (RtRMS-QRS), QRS duration (QRSd) and the corrected QT interval (QTc), and a measured angle including the upslope and downslope of the S-wave (S-wave angle) were assessed.
Definite ARVD/C was present in 155 patients by 2010 Task Force criteria (41.7 ± 17.6 years, 65.2% male). -ECG ARVD/C patients (66 patients) were compared to 66 control patients (41.7 ± 17.6 years, 65.2% male). All parameters tested except the QRSd and QTc significantly differentiated -ECG ARVD/C from control patients (p < 0.004 to p < 0.001). The RPD angle and RtRMS-QRS best differentiated the groups. Combined, the 2 novel criteria gave 81.8% sensitivity, 90.9% specificity and odds ratio of 45.0 (95% confidence interval 15.8 to 128.2).
ARVD/C disease process may lead to development of subtle ECG abnormalities that can be distinguishable using right-sided VCG or measured angle markers better than the spatial QRS-T angle, the QRSd or QTc, in the absence of Taskforce ECG criteria.
Background: Atrial arrhythmias are present in up to 20% of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). Catheter ablation (CA) is an effective treatment for atrial ...arrhythmias in the general population. Data regarding CA for atrial arrhythmias in ARVC are scarce. Objective: To assess the safety and efficacy of CA for atrial arrhythmias in patients with ARVC. Methods: In this international collaborative effort, all patients with a definite diagnosis of ARVC undergoing CA for atrial fibrillation (AF), focal atrial tachycardia (AT), or cavotricuspid isthmus (CTI)-dependent atrial flutter (AFl) were extracted from twelve ARVC registries. Demographic, periprocedural, and long-term arrhythmic outcome data were collected. Results: Thirty-seven patients were enrolled in the study (age 50.2 ± 16.6 years, male 84%, CHA2DS2VASc 1 (1,2), HAS-BLED 0 (0–2)). The arrhythmia leading to CA was AF in 23 (62%), focal left AT in 5 (14%), and CTI-dependent AFl in 9 (24%). Acute procedural success was achieved in all procedures but one (n = 1 focal left AT; 97% acute success). The median follow-up period was 27 (13–67) months, and 96%, 74%, and 61% of patients undergoing AF ablation were free from any atrial arrhythmia recurrence after a single procedure at 6 months, 12 months, and last follow-up, respectively. After focal AT ablation, freedom from atrial arrhythmia recurrence was 80%, 80%, and 60% at 6 months, 12 months, and last follow-up, respectively. All patients undergoing CTI ablation were free from atrial arrhythmia recurrences at 6 months, with 89% single-procedural arrhythmic freedom at last follow-up. One major complication (2.7%; PV stenosis requiring PV stenting) occurred. Conclusions: CA is safe and effective in managing atrial arrhythmias in patients with ARVC, with success rates comparable to the general population.
Introduction: ARVC (Arrhythmogenic Right Ventricular Cardiomyopathy) is a heritable rare disease of the heart muscle, primarily affecting the right ventricle, that may cause arrhythmias and heart ...failure. Aim: The overall aim of this thesis was to study various aspects of genetic information and electrocardiography (ECG), for their use in diagnosis and risk evaluation in ARVC. Material and methods: Paper I: The genotype-phenotype correlations in four unrelated families with a plakophilin 2 gene variant (PKP2 c.2146-1C>G) were studied, to determine 1) to what extent family members fulfil diagnostic criteria and 2) to assess whether these gene carriers had any specific clinical characteristics in common. Paper II: Patients with definite ARVC but one group with and one without diagnostic ECG criteria were compared to each other and a healthy control group. Vectorcardiographic parameters were assessed alongside QRS duration, corrected QT interval and an angle measuring the upslope and downslope of the S wave (S-wave angle). Paper III: Combined Annotation Dependent Depletion (CADD, a bioinformatic tool) scores were calculated for all pathogenic and likely pathogenic variants in PKP2 found in patients from two ARVC Registries, and the scores association with arrhythmic events and age at definite ARVC diagnosis were assessed. Paper IV: Digital ECGs (n=6871) from 353 patients with definite ARVC were analysed using Glasgow algorithm to describe the longitudinal development of different ECG characteristics, but also to assess the relationship between the ECG parameters and 1) structural abnormalities and 2) sustained ventricular tachycardia (VT) during a 10-year follow-up. Results: Paper I: In 41 family members evaluated, 23 were mutation carriers, and seven of them fulfilled diagnostic criteria. The clinical presentation was variable, and no specific genotype-phenotype correlation was found. Paper II: The vectorcardiographic parameters significantly differentiated the ARVC patients with normal ECGs from controls (p>0.004 to p<0.001). Paper III: In total, 33 unique genetic variants were reported in 179 patients. CADD score was neither associated with age at cardiac events (HR 1.002, 95% CI: 0.953-1.054, p=0.933) nor with age at definite ARVC diagnosis (HR 0.992, 95% CI: 0.947-1.039, p=0.731). Paper IV: Progressive changes in depolarisation and repolarisation parameters before as well as after the diagnosis was established confirming the progressive nature of ARVC developing over the course of decades, possibly in parallel with structural changes in the ventricles. The presence of T wave inversion in leads V3 or aVF at first ECG was significantly associated with ventricular tachycardia during 10 years follow-up (for lead V3 HRadj 2.11, 95%CI 1.28-3.49, p=0.003, lead aVF HRadj 1.68, 95%CI 1.02-2.77, p=.041 both adjusted for age, sex and proband status). Conclusions: Our studies confirms previous results that, with our current knowledge, genetic variants in desmosomal genes are useful for diagnosis and cascade screening in family members but not for detailed risk stratification or prediction of diagnosis. Progressive changes in depolarisation and repolarisation ECG parameters before as well as after the diagnosis were established, confirming the progressive nature of ARVC developing over the course of decades, possibly in parallel with structural changes in the ventricles. Novel vectorcardiographic markers may aid in early detection of disease progression, possibly with biggest potential in cascade screening.
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