Rare and potential pathogenic mutations of LMNA and LAMA4 associated with familial arrhythmogenic right ventricular cardiomyopathy/dysplasia with right ventricular heart failure, cerebral thromboembolism and hereditary electrocardiogram abnormality.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is associated with ventricular arrhythmia, heart failure (HF), and sudden death. Thromboembolism is also an important and serious complication of ARVC/D. However, the etiology of ARVC/D and thromboembolism and their association with genetic mutations are unclear. METHODS: Genomic DNA samples of peripheral blood were conducted for whole-exome sequencing (WES) and Sanger sequencing in the ARVC/D family. Then, we performed bioinformatics analysis for genes susceptible to cardiomyopathies and arrhythmias. Further, we analyzed how the potential pathogenic mutations were affecting the hydrophobicity and phosphorylation of amino acids and their joint pathogenicity by ProtScale, NetPhos and ORVAL algorisms. RESULTS: We discovered a Chinese Han family of ARVC/D with right ventricular HF (RVHF), cerebral thromboembolism, arrhythmias (atrial fibrillation, atrial standstill, multifocal ventricular premature, complete right bundle block and third-degree atrioventricular block) and sudden death. Based on the WES data, the variants of LMNA p.A242V, LAMA4 p.A225P and RYR2 p.T858M are highly conserved and predicated as "deleterious" by SIFT and MetaSVM algorithms. Their CADD predicting scores are 33, 27.4 and 25.8, respectively. These variants increase the hydrophobicity of their corresponding amino acid residues and their nearby sequences by 0.378, 0.266 and 0.289, respectively. The LAMA4 and RYR2 variants lead to changes in protein phosphorylation at or near their corresponding amino acid sites. There were high risks of joint pathogenicity for cardiomyopathy among these three variants. Cosegregation analysis indicated that LMNA p.A242V might be an important risk factor for ARVC/D, electrocardiogram abnormality and cerebral thromboembolism, while LAMA4 p.A225P may be a pathogenic etiology of ARVC/D and hereditary electrocardiogram abnormality. CONCLUSIONS: The LMNA p.A242V may participate in the pathogenesis of familial ARVC/D with RVHF and cerebral thromboembolism, while LAMA4 p.A225P may be associated with ARVC/D and hereditary electrocardiogram abnormality.

Safety and efficacy of flecainide associated with beta-blockers in arrhythmogenic right ventricular cardiomyopathy.

AIMS: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy associated with a high risk of ventricular arrhythmia (VA). Current guidelines recommend beta-blockers as first-line medical therapy and if ineffective, sotalol or amiodarone. We describe our experience, as a tertiary centre for ARVC, with the effectiveness and tolerance of flecainide in addition to beta-blockers to prevent VA in ARVC. METHODS AND RESULTS: We retrospectively included 100 consecutive ARVC patients who received flecainide with beta-blockers between May 1999 and November 2017. Treatment persistence and related side effects were assessed, as was VA-free survival on treatment, 24-h Holter monitoring and programmed ventricular stimulation (PVS) off- and on-treatment. Tolerance was good, with 10% flecainide discontinuations (lack of efficacy in six, atrial fibrillation in one, and side effects in three). No Brugada-induced electrocardiography pattern on flecainide or haemodynamic impairment was reported. Premature ventricular contraction burden at 24-h Holter monitoring was significantly decreased under treatment [median 415 (interquartile range, IQR 97-730) vs. 2370 (1572-3400) at baseline, P < 0.0001, n = 46]. Among the 33 patients with PVS under treatment, PVS was positive in 40% on-treatment vs. 94% off-treatment (P < 0.001). During a median follow-up of 47 months (IQR 23-73), 22 patients presented sustained VA on treatment, corresponding to an event rate of 5% [95% confidence interval (CI) (0.6-9)] at 1 year and 25% [95% CI (14-35)] at 5 years under treatment. No patient died. CONCLUSION: This study suggests that flecainide and beta-blockers association is complementary to implantable cardioverter-defibrillator and catheter ablation and is safe for treating persistent symptomatic VA in patients with ARVC.

Revisiting the Newly Modified Criteria for Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia (ARVC/D) and Reporting Newly Identified Genes.

Background: Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia is an inherited cardiomyopathy, characterized by replacement of the RV muscle wall with fibrofatty tissue. The diagnosis is challenging, due to the absence of a unique presentation and a lack of specific reproducible diagnostic criteria. Materials and methods: Slides and additional clinical information including follow up from 16 cases were reviewed. Pediatric criteria of >30% of muscle replacement was used, instead of >40% as used in adults. Results: All 16 cases were confirmed by genetic testing and show ARVC/D. Applying the adult criteria, 7 cases would not have been categorized as ARVC/D. Conclusion: The modified pediatric criteria for ARVC/D should be used for pediatric patients. Better detection will aid in genetic counseling in order to identify those additional family members susceptible to sudden cardiac deaths so they can be followed optimally.

The prevalence of left and right bundle branch block morphology ventricular tachycardia amongst patients with arrhythmogenic cardiomyopathy and sustained ventricular tachycardia: insights from the European Survey on Arrhythmogenic Cardiomyopathy.

AIMS: In arrhythmogenic cardiomyopathy (ACM), sustained ventricular tachycardia (VT) typically displays a left bundle branch block (LBBB) morphology while a right bundle branch block (RBBB) morphology is rare. The present study assesses the VT morphology in ACM patients with sustained VT and their clinical and genetic characteristics. METHODS AND RESULTS: Twenty-six centres from 11 European countries provided information on 954 ACM patients who had ≥1 episode of sustained VT spontaneously documented during patients' clinical course. Arrhythmogenic cardiomyopathy was defined according to the 2010 Task Force Criteria, and VT morphology according to the QRS pattern in V1. Overall, 882 (92.5%) patients displayed LBBB-VT alone and 72 (7.5%) RBBB-VT [alone in 42 (4.4%) or in combination with LBBB-VT in 30 (3.1%)]. Male sex prevalence was 79.3%, 88.1%, and 56.7% in the LBBB-VT, RBBB-VT, and LBBB + RBBB-VT groups, respectively (P = 0.007). First RBBB-VT occurred 5 years after the first LBBB-VT (46.5 ± 14.4 vs 41.1 ± 15.8 years, P = 0.011). An implanted cardioverter-defibrillator was more frequently implanted in the RBBB-VT (92.9%) and the LBBB + RBBB-VT groups (90%) than in the LBBB-VT group (68.1%) (P < 0.001). Mutations in PKP2 predominated in the LBBB-VT (65.2%) and the LBBB + RBBB-VT (41.7%) groups while DSP mutations predominated in the RBBB-VT group (45.5%). By multivariable analysis, female sex was associated with LBBB + RBBB-VT (P = 0.011) while DSP mutations were associated with RBBB-VT (P < 0.001). After a median follow-up of 103 (51-185) months, death occurred in 106 (11.1%) patients with no intergroup difference (P = 0.176). CONCLUSION: RBBB-VT accounts for a significant proportion of sustained VTs in ACM. Sex and type of pathogenic mutations were associated with VT type, female sex with LBBB + RBBB-VT, and DSP mutation with RBBB-VT.

Epsilon Waves as an Extreme Form of Depolarization Delay: Focusing on the Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia.

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.

Sex Differences in Right Ventricular Dysfunction: Insights From the Bench to Bedside.

There are inherent distinctions in right ventricular (RV) performance based on sex as females have better RV function than males. These differences are magnified and have very important prognostic implications in two RV-centric diseases, pulmonary hypertension (PH), and arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). In both PH and ARVC/D, RV dysfunction results in poor patient outcomes. However, there are no currently approved therapies specifically targeting the failing RV, an important unmet need for these two life-threatening disorders. In this review, we highlight human data demonstrating divergent RV phenotypes in healthy, PH, and ARVC/D patients based on sex. Furthermore, we discuss the links between estrogen (the female predominant sex hormone), testosterone (the male predominant sex hormone), and dehydroepiandrosterone (a precursor hormone for multiple sex hormones in males and females) and RV function in both disorders. To provide potential mechanistic insights into sex differences in RV function, we review data that investigate how sex hormones combat or contribute to pathophysiological changes in the RV. Finally, we highlight the ongoing clinical trials in pulmonary arterial hypertension targeting estrogen and dehydroepiandrosterone signaling. Hopefully, a greater understanding of the factors that promote superior RV function in females will lead to novel therapeutic approaches to combat RV dysfunction in PH and ARVC/D.

Cardiac Magnetic Resonance Imaging Macroscopic Fibro-Fatty Infiltration of the Myocardium in Pediatric Patients with Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia.

Background: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an inherited, progressive form of cardiomyopathy, which is characterized by fibrofatty replacement of the myocardium. While the gold standard for diagnosis remains pathologic evaluation of biopsy, advances in noninvasive imaging, including cardiac magnetic resonance imaging (CMRI), have led to improved clinical diagnosis.Case report: We report three additional cases of pediatric patients that have pathologically confirmed ARVC/D with CMRI images, demonstrating extensive macroscopic fatty infiltration of the right and left ventricular myocardium. The identification using CMRI allowed timely transplantation and patient survival.Conclusion: Our study is designed to highlight how fibrofatty changes are minimal using CMRI in the pediatric population and how this can be a valuable tool to provide an additional method of diagnosis.

Desmoglein-2 mutations in propeptide cleavage-site causes arrhythmogenic right ventricular cardiomyopathy/dysplasia by impairing extracellular 1-dependent desmosomal interactions upon cellular stress.

AIMS: Desmoglein-2 (DSG2) mutations, which encode a heart-specific cadherin crucial for desmosomal adhesion, are frequent in arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). DSG2 mutations have been associated with higher risk of biventricular involvement. Among DSG2 mutations, mutations of the inhibitory propeptide consensus cleavage-site (Arg-X-Arg/Lys-Arg), are particularly frequent. In the present work, we explored the functional consequences of DSG2 propeptide cleavage site mutations p.Arg49His, p.Arg46Trp, and p.Arg46Gln on localization, adhesive properties, and desmosome incorporation of DSG2. METHODS AND RESULTS: We studied the expression of mutant-DSG2 in human heart and in epithelial and cardiac cellular models expressing wild-type or mutant (p.Arg49His, p.Arg46Trp, and p.Arg46Gln) proDSG2-GFP fusion proteins. The consequences of the p.Arg46Trp mutation on DSG2 adhesiveness were studied by surface plasmon resonance. Incorporation of mutant p.Arg46Trp DSG2 into desmosomes was studied under low-calcium culture conditions and cyclic mechanical stress. We demonstrated in human heart and cellular models that all three mutations prevented N-terminal propeptide cleavage, but did not modify intercellular junction targeting. Surface plasmon resonance experiments showed a propeptide-dependent loss of interaction between the cadherin N-terminal extracellular 1 (EC1) domains. Additionally, proDSG2 mutant proteins were abnormally incorporated into desmosomes under low-calcium culture conditions or following mechanical stress. This was accompanied by an epidermal growth factor receptor-dependent internalization of proDSG2, suggesting increased turnover of unprocessed proDSG2. CONCLUSION: Our results strongly suggest weakened desmosomal adhesiveness due to abnormal incorporation of uncleaved mutant proDSG2 in cellular stress conditions. These results provide new insights into desmosomal cadherin regulation and ARVC/D pathophysiology, in particular, the potential role of mechanical stress on desmosomal dysfunction.

A case of desmoplakin mutation and delayed arrhythmogenic right ventricular cardiomyopathy/dysplasia after atrial septal defect closure.

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a slow-developing cardiomyopathy characterized by ventricular arrhythmias and fibrofatty replacement of the right ventricular (RV) myocardium. Its clinical diagnosis is challenging because of its variable clinical presentation and low genetic penetrance. We describe the case of a 67-year-old man who was diagnosed as having ARVC/D with a desmoplakin mutation that appeared after occlusion of an atrial septal defect (ASD). He underwent patch closure surgery for ASD at the age of 54 years. Four years later, he underwent catheter ablation for multifocal atrial tachycardias. Because of pre-syncope and inducible sustained monomorphic ventricular tachycardia, an implantable cardioverter defibrillator was implanted. When he was admitted for worsening heart failure at the age of 61 years, the desmoplakin mutation was detected with progressive left ventricular (LV) dysfunction. Subsequently, he was diagnosed as having ARVC/D with RV dysfunction. At cardiac autopsy, characteristics of ARVC/D, including dilatation, fibrofatty changes in the right ventricle, and diffuse fibrosis in the left ventricle were detected. Along with the effect of RV dysfunction caused by ASD, the progression of LV dysfunction after ASD closure was also possibly caused by the disease progression of ARVC/D. Physicians should carefully assess the various states of ARVC/D. .

The echocardiographic assessment of the right ventricle in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia compared with athletes and matched controls.

BACKGROUND: There are discrepancies in the quantitative echocardiographic criteria for the right ventricle (RV) between the revised task force criteria (TFC) for Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia (ARVC/D) and the guidelines for RV assessment endorsed by American Society of Echocardiography (ASE). Importantly, these criteria do not take into account potential adaptation of the RV to exercise. The goal of this study was to compare the revised TFC quantitative echocardiographic parameters in patients with ARVC/D, athletes and matched controls. METHODS: Echocardiographic parameters of the RV were retrospectively collected in patients who fulfilled the TFC for ARVC/D, an age- matched, sex-matched, and body surface area-matched control population, and athletes (defined as individuals who exercised for more than 7 hours per week). Patients with structural heart disease were excluded in the control and athlete groups. RESULTS: Twenty patients with ARVC/D, 11 athletes and 20 matched controls were included. There was no significant difference between ARVC/D patients and athletes with the exception of the parasternal long axis right ventricular outflow tract diameter. All parameters were significantly different between ARVC/D patients and the control group. Furthermore, when subjects were categorized into meeting 1 major revised TFC/abnormal ASE criteria or not, only ASE criteria were able to differentiate ARVC/D from control population. Both were unable to differentiate ARVC/D from athletes. CONCLUSIONS: Right ventricle quantitative echocardiographic criteria in the revised TFC are not specific for ARVC/D. Care should be taken in applying these criteria in athletes.

High risk of heart failure associated with desmoglein-2 mutations compared to plakophilin-2 mutations in arrhythmogenic right ventricular cardiomyopathy/dysplasia.

BACKGROUND: Previous studies suggested that genetic status affects the clinical course of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) patients. The aim of this study was to compare the outcome of desmoglein-2 (DSG2) mutation carriers to those who carry the plakophilin-2 (PKP2) mutation, the most common ARVC/D-associated gene. METHODS AND RESULTS: Consecutive ARVC/D patients carrying a pathogenic mutation in PKP2 or DSG2 were selected from a national ARVC/D registry. The cumulative freedom from sustained ventricular arrhythmia and cardiac transplantation/death from heart failure (HF) during follow-up was assessed, compared between PKP2 and DSG2, and predictors for ventricular arrhythmia and HF events determined. Overall, 118 patients from 78 families were included: 27 (23%) carried a DSG2 mutation and 91 (77%) a PKP2 mutation. There were no significant differences between DSG2 and PKP2 mutation carriers concerning gender, proband status, age at diagnosis, T-wave inversion, or right ventricular dysfunction at baseline. DSG2 patients displayed more frequent epsilon wave (37% vs. 17%, P = 0.048) and left ventricular dysfunction at diagnosis (54% vs. 10%, P < 0.001). During a median follow-up of 5.6 years (2.5-16), DSG2 and PKP2 mutation carriers displayed a similar risk of sustained ventricular arrhythmia (log-rank P = 0.20), but DSG2 mutation carriers were at higher risk of transplantation/HF-related death (log-rank P < 0.001). The presence of a DSG2 mutation vs. PKP2 mutation was a predictor of transplantation/HF-related death in univariate Cox analysis (P = 0.0005). CONCLUSIONS: In this multicentre cohort, DSG2 mutation carriers were found to be at high risk of end-stage HF compared to PKP2 mutation carriers, supporting careful haemodynamic monitoring of these patients. The benefit of early HF treatment needs to be assessed in DSG2 carriers.

Arrhythmogenic Right Ventricular Cardiomyopathy: A Review of Living and Deceased Probands.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a potentially life-threatening genetic cardiomyopathy with a spectrum of clinical presentations including sudden cardiac death (SCD). METHODS: Clinical and genetic data of 44 probands referred to a cardiac genetics clinic (2007-2017) who met 2010 Task Force Criteria (TFC) for ARVC diagnosis were included. RESULTS: Thirty-three (33) (75%) male, 20 (45%) were referred by the Victorian Institute of Forensic Medicine. Presentation that lead to diagnosis included ARVC-related SCD (n=19), SCD due to alternate cause of death (n=1), aborted cardiac arrest (n=6), stable symptomatic ventricular tachycardia (n=14), palpitations (n=3) and presyncope (n=1). Left ventricular involvement (50%) was more common in the SCD subgroup (84% vs 21%, p<0.001). Genetic testing (n=39) revealed a pathogenic mutation in 16 (commonest: plakophillin-2 (n=9)), a variant of uncertain significance (VUS) in 15, with no abnormality in eight. In the SCD subgroup, median age at death was 44.7 years and 74% were male. Genetic testing (n=16) in this subgroup revealed a pathogenic mutation in six patients (commonest: desmoplakin (n=4)). Comparison of the two commonest mutations (PKP2 and desmoplakin [DSP]) showed DSP mutation was more frequently associated with SCD (p<0.01) and LV involvement (p<0.001). Screening of 117 relatives has lead to ARVC diagnosis in 29 patients. CONCLUSIONS: Arrhythmogenic right ventricular cardiomyopathy has a heterogeneous and often severe clinical presentation. Sudden cardiac death and aborted cardiac arrest (ACA) are common, demonstrating electrical abnormalities appear early in the ARVC phenotype. Left ventricular involvement was common and may reflect a worse prognosis. Genetic testing is essential in family screening and may be helpful in risk assessment. Desmoplakin mutation is associated with LV involvement and may be indicative of worse prognosis and increased risk of SCD. Genetic screening of proband family members in a specialised multidisciplinary clinic is essential in early diagnosis of affected family members.

Case report of familial sudden cardiac death caused by a DSG2 p.F531C mutation as genetic background when carrying with heterozygous KCNE5 p.D92E/E93X mutation.

BACKGROUND: Sudden cardiac death (SCD) induced by malignant ventricular tachycardia (MVT) among young adults with right ventricular cardiomyopathy/dysplasia (ARVC/D) is a devastating event. Parts of ARVC/D patients have a mutation in genes encoding components of cardiac desmosomes, such as desmoglein-2 (DSG2), plakophilin-2 and desmoplakin. CASE PRESENTATION: Here we report a potentially pathogenic mutation in the DSG2 gene, which was identified in a family with ARVC/D using Whole Exome Sequencing (WES) and Sanger Sequencing. In all, Patient III:1 with ARVC/D carried the compound heterozygous mutations of DSG2 p.F531C and KCNE5 p.D92E/E93X, which were both inherited from her mother (II:2), who died of SCD. Carriers of DSG2p.F531C showed various phenotypes, such as ARVC/D, SCD, MVT and dilated cardiomyopathy. For III:1, there were significant low-voltage regions in the inferior-apical, inferior-lateral wall of the right ventricular epicardium and outflow tracts of the right ventricle. Under the guidance of a three-dimensional mapping system, MVT was successfully ablated with an epicardial-endocardial approach targeting for late, double or fragmental potentials after implantable cardioverter-defibrillator (ICD) electrical storms. No VT recurrence was observed during the one year of follow-up. CONCLUSIONS: When coexisting with heterozygous KCNE5 p.D92E/E93X, heterozygous DSG2 p.F531C as a genetic background was found to predispose to ARVC/D, SCD and MVT, which were successfully ablated using an epicardial-endocardial approach.

Risk Stratification in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia Without an Implantable Cardioverter-Defibrillator.

OBJECTIVES: The purpose of this study was to identify clinical factors associated with arrhythmic events and sudden cardiac death (SCD), and to evaluate the prognostic value of electrophysiological study (EPS) in arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) patients without implantable cardioverter-defibrillators (ICDs). BACKGROUND: ARVC/D is an inherited cardiomyopathy characterized by a risk of SCD. Few studies have evaluated predictive factors of ventricular arrhythmias (VAs) in patients without ICDs. METHODS: Between 2000 and 2010, all consecutive patients with ARVC/D without ICDs and with EPS at diagnosis were enrolled. Patients that received an ICD during follow-up were censored at the date of implantation, and in that case, only VAs that occurred before ICD implantation were analyzed. Risk factors for any VA event were determined by Cox regression. Patients that only experienced SCD or aborted cardiac arrest (ACA) were reported. RESULTS: A total of 137 consecutive patients (78% male) diagnosed with ARVC/D without ICD were enrolled. 31% had sustained ventricular tachycardia at diagnosis. After mean follow-up of 42 ± 31 months, 19 patients experienced an episode of sustained VA and 5 patients experienced a SCD/ACA. No event occurred in asymptomatic patients. Left ventricular ejection fraction ≤50% (p = 0.024), positive EPS (p = 0.017), and physical activity >6 h/week (p = 0.025) were independently associated with occurrence of VAs. SCD/ACA exclusively occurred in male probands with definite diagnosis and syncope. CONCLUSIONS: In this cohort of ARVC/D patients without ICD, left ventricular ejection fraction ≤50%, positive EPS, and physical activity >6 h/week were independent predictors of VAs, whereas asymptomatic patients at diagnosis were at low risk. EPS predicted all VAs but had limited value to predict SCD/ACA.

Association of regional epicardial right ventricular electrogram voltage amplitude and late gadolinium enhancement distribution on cardiac magnetic resonance in patients with arrhythmogenic right ventricular cardiomyopathy: Implications for ventricular tachycardia ablation.

BACKGROUND: Criteria for identification of anatomic ventricular tachycardia substrates in arrhythmogenic right ventricular cardiomyopathy (ARVC) on late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) are unclear. OBJECTIVE: The purpose of this study was to define (1) the association of regional right ventricular (RV) epicardial voltage amplitude with the distribution of LGE; and (2) appropriate image signal intensity (SI) thresholds for ventricular tachycardia substrate identification in ARVC. METHODS: Preprocedural LGE-CMR and epicardial electrogram mapping were performed in 10 ARVC patients. The locations of epicardial electrogram map points, obtained during sinus rhythm with intrinsic conduction or RV pacing, were retrospectively registered to the corresponding LGE image regions. Standardized SI z-scores (standard deviation distance from the mean) were calculated for each 10-mm region surrounding map points. RESULTS: In patient-clustered, generalized estimating equations models that included 3205 epicardial electroanatomic points and corresponding SI measures, bipolar (-1.43 mV/z-score; P <.001) and unipolar voltage amplitude (-1.22 mV/z-score; P <.001) were associated with regional SI z-scores. In contrast to the QRS-late potential (LP) interval (P = .362), the LP activation index, defined as electrogram duration divided by QRS-LP, was associated with regional SI z-scores (P <.001). SI z-score thresholds >0.05 (95% confidence interval -0.05 to 0.15) and <-0.16 (95% confidence interval -0.26 to 0.06) corresponded to bipolar voltage measures <0.5 and >1.0 mV, respectively. CONCLUSION: Increased RV gadolinium uptake is associated with lower epicardial bipolar and unipolar electrogram voltage amplitude. Standardized LGE-CMR SI z-scores may augment preprocedural planning for identification of low-voltage zones and abnormal myocardium in ARVC.

Implantable Cardioverter-Defibrillator Therapy in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy: Predictors of Appropriate Therapy, Outcomes, and Complications.

BACKGROUND: Arrhythmogenic right ventricular dysplasia/cardiomyopathy is characterized by ventricular arrhythmias and sudden cardiac death. Once the diagnosis is established, risk stratification to determine whether implantable cardioverter-defibrillator (ICD) placement is warranted is critical. METHODS AND RESULTS: The cohort included 312 patients (163 men, age at presentation 33.6±13.9 years) with definite arrhythmogenic right ventricular dysplasia/cardiomyopathy who received an ICD. Over 8.8±7.33 years, 186 participants (60%) had appropriate ICD therapy and 58 (19%) had an intervention for ventricular fibrillation/flutter. Ventricular tachycardia at presentation (hazard ratio [HR]: 1.86; 95% confidence interval [CI], 1.38-2.49; P<0.001), inducibility on electrophysiology study (HR: 3.14; 95% CI, 1.95-5.05; P<0.001), male sex (HR: 1.62; 95% CI, 1.20-2.19; P=0.001), inverted T waves in ≥3 precordial leads (HR: 1.66; 95% CI, 1.09-2.52; P=0.018), and premature ventricular contraction count ≥1000/24 hours (HR: 2.30; 95% CI, 1.32-4.00; P=0.003) were predictors of any appropriate ICD therapy. Inducibility at electrophysiology study (HR: 2.28; 95% CI, 1.10-4.70; P=0.025) remained as the only predictor after multivariable analysis. The predictors for ventricular fibrillation/flutter were premature ventricular contraction ≥1000/24 hours (HR: 4.39; 95% CI, 1.32-14.61; P=0.016), syncope (HR: 1.85; 95% CI, 1.10-3.11; P=0.021), aged ≤30 years at presentation (HR: 1.76; 95% CI, 1.04-3.00; P<0.036), and male sex (HR: 1.73; 95% CI, 1.01-2.97; P=0.046). Younger age at presentation (HR: 3.14; 95% CI, 1.32-7.48; P=0.010) and high premature ventricular contraction burden (HR: 4.43; 95% CI, 1.35-14.57; P<0.014) remained as independent predictors of ventricular fibrillation/flutter. Complications occurred in 66 participants (21%), and 64 (21%) had inappropriate ICD interventions. Overall mortality was low at 2%, and 4% underwent heart transplantation. CONCLUSION: These findings represent an important step in identifying predictors of ICD therapy for potentially fatal ventricular fibrillation/flutter and should be considered when developing a risk stratification model for arrhythmogenic right ventricular dysplasia/cardiomyopathy.

Catheter Ablation of Ventricular Tachycardia/Fibrillation in a Patient with Right Ventricular Amyloidosis with Initial Manifestations Mimicking Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy.

Differentiating arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) from other cardiomyopathies is clinically important but challenging. Although the modified Task Force Criteria can facilitate diagnosis of ARVD/C according to clinical manifestations, histopathological examination plays a pivotal role in excluding other diseases that can mimic ARVD/C. Here, we report a patient with amyloidosis that initially presented similarly to ARVD/C. The diagnosis was confirmed by endomyocardial biopsy, and catheter ablation eliminated the ventricular tachyarrhythmias through an epicardial approach.

Remodelling of myocardial intercalated disc protein connexin 43 causes increased susceptibility to malignant arrhythmias in ARVC/D patients.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a primary cardiomyopathy characterised by fibrofatty replacement and ventricular arrhythmias. The occurrence of malignant arrhythmias may be associated with fatty infiltration and intercalated disk remodelling, but the specific pathological remodelling pattern is not yet clear. METHODS: Twelve explanted hearts from patients diagnosed with ARVC/D according to the 2010 Task Force Criteria and pathology examination were divided into two groups with (SVT, n=6) or without (non-SVT, n=6) recurrent sustained ventricular tachycardia (SVT) before heart transplantation. Six ARVC autopsy hearts and six normal donor hearts were also collected. We evaluated the fibrofatty infiltration by Masson staining and the expression of intercalated disc proteins through immunohistochemistry staining combined with western blot using the ventricular tissue of ARVC as well as normal hearts. RESULTS: There was significant fatty replacement in the right ventricles of both the SVT and the non-SVT groups compared to normal hearts, but no significant differences were found in fibre, fatty and residual myocardium components between these two groups. Immunohistochemistry and western blot further showed disturbed distribution and significantly reduced expression of Connexin 43 (Cx43) in the SVT group (SVT vs. Normal P=0.010, SVT vs. non-SVT P=0.012). No significantly diminished expression was found in the non-SVT group. The cardiac histology of ARVC/D patients with sudden death verified by forensic pathology confirmed a similar phenomenon. CONCLUSION: Our pathology study on explanted and autopsied hearts indicates that the expression of Cx43 was significantly reduced and disturbed in distribution in ARVC/D myocardium with sustained ventricular tachycardia, but not in patients without malignant ventricular arrhythmias. This implies a correlation between Cx43 remodelling and malignant arrhythmias in ARVC/D patients.