Clinical course of arrhythmogenic right ventricular cardiomyopathy with end-stage heart failure and outcome after heart transplantation.

BACKGROUND: Few data exist on the characteristics and outcomes of patients with arrhythmogenic right ventricular cardiomyopathy and advanced heart failure who undergo heart transplantation. AIM: To explore the pretransplant course and outcomes of patients with arrhythmogenic right ventricular cardiomyopathy after heart transplantation. METHODS: This observational retrospective monocentric study included all consecutive patients with arrhythmogenic right ventricular cardiomyopathy who underwent heart transplantation during a 13-year period (2006-2019) at Pitié-Salpêtrière University Hospital (Paris). RESULTS: A total of 23 patients with arrhythmogenic right ventricular cardiomyopathy underwent heart transplantation between 2006 and 2019. The median time from diagnosis to heart transplantation was 9 years, and the median age at transplantation was 50 years. At diagnosis, half of the patients had left ventricular dysfunction, 59% had extensive T-wave inversion and 43% had a history of sustained ventricular tachycardia. Only five patients were involved in intensive sport activity. Indications for heart transplantation were end-stage biventricular dysfunction in 13 patients, end-stage right ventricular heart failure in seven and electrical storm in three. Only three patients had pulmonary hypertension, and half of the patients had atrial arrhythmias. The survival rate 1 year after heart transplantation was 74% (95% confidence interval 53-88%). Eight patients experienced primary graft dysfunction needing extracorporeal membrane oxygenation. CONCLUSIONS: Patients with arrhythmogenic right ventricular cardiomyopathy who eventually needed heart transplantation mostly exhibited extended disease with biventricular dysfunction at diagnosis. Intensive sport activity did not seem to be a major determinant. Advanced heart failure usually occurred late in the course of the disease. Primary graft dysfunction after heart transplantation was frequent, and should be anticipated. Additional data are needed to identify the optimal timing for heart transplantation and predictors of end-stage heart failure in patients with arrhythmogenic right ventricular cardiomyopathy.

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.

Sex differences in the origin of Purkinje ectopy-initiated idiopathic ventricular fibrillation.

BACKGROUND: Purkinje ectopics (PurkEs) are major triggers of idiopathic ventricular fibrillation (VF). Identifying clinical factors associated with specific PurkE characteristics could yield insights into the mechanisms of Purkinje-mediated arrhythmogenicity. OBJECTIVE: The purpose of this study was to examine the associations of clinical, environmental, and genetic factors with PurkE origin in patients with PurkE-initiated idiopathic VF. METHODS: Consecutive patients with PurkE-initiated idiopathic VF from 4 arrhythmia referral centers were included. We evaluated demographic characteristics, medical history, clinical circumstances associated with index VF events, and electrophysiological characteristics of PurkEs. An electrophysiology study was performed in most patients to confirm the Purkinje origin. RESULTS: Eighty-three patients were included (mean age 38 ± 14 years; 44 [53%] women), of whom 32 had a history of syncope. Forty-four patients had VF at rest. PurkEs originated from the right ventricle (RV) in 41 patients (49%), from the left ventricle (LV) in 36 (44%), and from both ventricles in 6 (7%). Seasonal and circadian distributions of VF episodes were similar according to PurkE origin. The clinical characteristics of patients with RV vs LV PurkE origins were similar, except for sex. RV PurkEs were more frequent in men than in women (76% vs 24%), whereas LV and biventricular PurkEs were more frequent in women (81% vs 19% and 83% vs 17%, respectively) (P < .0001). CONCLUSION: PurkEs triggering idiopathic VF originate dominantly from the RV in men and from the LV or both ventricles in women, adding to other sex-related arrhythmias such as Brugada syndrome or long QT syndrome. Sex-based factors influencing Purkinje arrhythmogenicity warrant investigation.

External Validation of a Risk Prediction Model for Ventricular Arrhythmias in Arrhythmogenic Right Ventricular Cardiomyopathy.

The new 5-year ventricular arrhythmia (VA) occurrence risk model is a major breakthrough for arrhythmia risk stratification in the challenging population of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). In the original study, the model resulted in a 20.6% reduction in implantable cardioverter-defibrillator (ICD) placement compared with the 2015 consensus, for the same protection level. However, only internal validation was performed, limiting generalisation. We externally validated the model in a European tertiary care cohort of 128 patients with ARVC with restrictive indications for primary prevention ICD placement. Overall, 74% were men, none had VA history, and a single patient had an ICD at baseline. Median age at diagnosis was 38 years (interquartile range [IQR] 28-50). During a median follow-up of 7.8 years (IQR 6.1-9.7), 15 patients (12%) experienced VA. The model provided good discrimination, with a C-index for 5-year VA risk prediction of 0.84 (95% confidence interval 0.74-0.93). However, the model led to an overestimation of the 5-year VA risk when applying thresholds < 50%. With a < 10% predicted risk, no patient showed VA. With a 7.5% predicted risk, the ICD:VA ratio was 6.3 vs 3.4 in the original study. The model still outperformed the 2015 International Task Force Consensus. Overall, in a relatively large European ARVC cohort with restrictive indications for ICD placement, the ARVC model for VA prediction successfully identified ARVC patients with VA during follow-up. Yet, our study underscores the need for careful threshold selection, considering the model's associated risk overestimation in low- to intermediate-risk patients.

FRAGILE: FRench Attitude reGistry in case of ICD LEad replacement.

AIMS: FRench Attitude reGistry in case of ICD LEad replacement (FRAGILE) registry was set-up to describe the attitude in different French institutions in case of implantable cardioverter-defibrillator (ICD) lead replacement, extraction, or abandonment and to compare outcomes in both groups. METHODS AND RESULTS: Prospective observational study comparing two attitudes in case of ICD lead replacement, extraction, or abandonment. Primary endpoint describes the attitude in different French centres, collect parameters that may influence the decision. Secondary endpoint compares early and mid-term (2 years) complications in both groups.Between April 2013 and April 2017, 552 patients were included in 32 centres. 434 (78.6%) were male, mean patient's age was 60.3 ± 14.4 years. In 56.9% of the cases, the decision was to explant the lead. Patients in the extraction group were younger than in the abandonment group (56.7 ± 14.5 vs. 65 ± 12.7 P < 0.0001) and less likely to have comorbidities (46.5% vs. 58.3% of the patients P = 0.022). The mean lead dwelling time was significantly longer in the abandonment group as compared with the extraction group (7.6 ± 3.9 vs. 5.2 ± 3.1 years, P < 0.0001). There was no statistical difference between both groups concerning early and 2 years complications. CONCLUSION: In this registry, the strategy in case of non-infected ICD lead replacement was mainly influenced by patient's age and comorbidities and lead dwelling time. No difference was observed in outcomes in both strategies.

Incidence, epidemiology, diagnosis and prognosis of atrio-oesophageal fistula following percutaneous catheter ablation: a French nationwide survey.

AIMS: Rate, incidence, risk factors, and optimal management of atrio-oesophageal fistula (AOF) after catheter ablation for atrial fibrillation (AF) remain obscure. METHODS AND RESULTS: All French centres performing AF ablation were identified and surveys were sent concerning the number of procedures, eventual cases of AOF, and characteristics of such cases. Eighty-two of the 103 centres (80%) performing AF ablation in France were included, with a total of 129 286 AF ablations since 2006 (93% of the whole procedures in France). Thirty-three AOF were reported (reported rate 0.026% per procedure) with a stable reported annual incidence despite the increasing number of procedures. Sensitivity of computed tomography (CT) scan for AOF was 81%. Mortality was 60%, significantly lower in case of surgical corrective therapy (31 vs. 93%, P = 0.001). CONCLUSION: The reported rate of AOF after AF ablation in this nationwide survey was 0.026%, with a stable reported annual incidence over time. A normal CT scan does not rule out the diagnosis and should be repeated in case of suspicion. Prognosis remains poor with a mortality of 60% and crucially dependant of immediate surgical correction. No clear protective strategy has been proven effective.

A novel gain-of-function mutation in SCN5A responsible for multifocal ectopic Purkinje-related premature contractions.

Recently, four SCN5A mutations have been associated with Multifocal Ectopic Purkinje-related Premature Contractions (MEPPC), a rare cardiac syndrome combining polymorphic ventricular arrhythmia with dilated cardiomyopathy (DCM). Here, we identified a novel heterozygous mutation in SCN5A (c.611C>A, pAla204Glu) in a young woman presenting with polymorphic premature ventricular contractions (PVCs) and DCM. After failure of antiarrhythmic drugs and an attempt of radiofrequency catheter ablation showing three exit-sites of PVCs, all with presystolic Purkinje potentials, a treatment by hydroquinidine was tried, leading to an immediate and spectacular disappearance of all PVCs and normalization of cardiac function. Electrophysiological studies showed that Nav 1.5-A204E mutant channels exhibited a significant leftward shift of 8 mV of the activation curve, leading to a larger hyperpolarized window current when compared to wild-type. Action potential modeling using Purkinje fiber and ventricular cell models predicted an arrhythmogenic effect predominant in Purkinje fibers for the A204E mutation. Comparison with other MEPPC-associated Nav 1.5 mutations revealed a common electrophysiological pattern of abnormal voltage-dependence of activation leading to a larger hyperpolarized window current as a shared biophysical mechanism of this syndrome. These features of the mutant sodium channels are likely to be responsible for the hyperexcitability of the fascicular-Purkinje system observed in patients with MEPPC.

Catheter ablation of electrical storm in patients with arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: Therapeutic strategies for electrical storm (ES) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) are not well defined. OBJECTIVE: The purpose of this study was to report the acute and long-term results of ventricular tachycardia (VT) radiofrequency catheter ablation (RFCA) as a treatment of ES in patients with ARVC. METHODS: This multicenter study retrospectively enrolled 23 consecutive patients with ARVC (mean age 43.6 ± 16.7 years; all men) who underwent 24 RFCA procedures for ES between 2003 and 2015. RESULTS: Thirteen patients (57%) had a previous VT RFCA procedure; 14 (61%) had right ventricular dysfunction and 7 (30%) left ventricular ejection fraction ≤ 50%. The clinical VT was inducible in 19 procedures (79%). Epicardial ablation was performed in 4 procedures (17%). The median number of targeted VTs was 1 (range 1-6). Complete acute success (no VT inducible) was achieved in 11 procedures (46%) and partial acute success (clinical VT nor inducible) in 11 (46%). After a median follow-up of 3.9 years (range 1 month-10 years), ES recurred in 2 patients and end-stage heart failure developed in 4 (17%), leading to 1 death and 3 heart transplantations. At 1-year follow-up, the probability of freedom from VT recurrence was 75% and did not significantly predict long-term survival. At the last evaluation, 8 patients (35%) were free of non-ß-blocker antiarrhythmic drugs as compared with 1 (4%) at baseline (P = .02). CONCLUSION: Catheter ablation was efficient to prevent ES recurrence in patients with ARVC. However, these patients were at high risk of evolution toward ARVC-related heart failure that was not associated with VT recurrence.

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.

Clinical characterization of men with long QT syndrome and torsades de pointes associated with hypogonadism: A review and pharmacovigilance study.

BACKGROUND: Long QT syndrome (LQTS) can cause the potentially fatal ventricular tachycardia torsades de pointes (TdP). QT interval corrected for heart rate (QTc) is shorter in men than in women, with testosterone contributing to shorten QTc. We recently described male hypogonadism as a reversible risk factor for acquired LQTS and TdP, but the clinical characteristics of such patients have not been characterized. AIMS: To describe the clinical characteristics of men with acquired LQTS or TdP associated with hypogonadism caused by endocrine conditions or androgen deprivation therapy (ADT), and to evaluate the relationship between testosterone concentrations and electrocardiographic changes. METHODS: We searched MEDLINE (to 04 January 2019) and the French pharmacovigilance database (to 09 August 2018) to identify male cases of acquired LQTS and TdP associated with endocrine hypogonadism or ADT; their narratives were gathered from reporting collaborators. RESULTS: We identified seven cases of TdP (one fatal) with endocrine hypogonadism, abnormally long QTc and morphologically abnormal T-wave notches. After reversion of low testosterone concentrations in the surviving patients (N=6), QTc shortened, T-wave morphology normalized and there was no TdP recurrence. Among these cases, none had mutation in the LQTS genes, three men required testosterone and three had reversible hypogonadism after resolution of a concurrent acute severe illness. We found an additional 27 reports of men with LQTS (N=6), TdP (N=9; 2/9 fatal) or sudden death (N=12; 10/12 fatal) suspected to be induced or favoured by ADT (24/27 for prostate cancer). Generally, after ADT withdrawal, QTc shortened and no TdP recurred. CONCLUSION: We propose seeking for hypogonadism caused by endocrine conditions or ADT in men presenting with TdP. Caution is warranted when ADT is used in situations at risk of TdP. Testosterone may be useful to treat or prevent TdP.

Androgenic Effects on Ventricular Repolarization: A Translational Study From the International Pharmacovigilance Database to iPSC-Cardiomyocytes.

BACKGROUND: Male hypogonadism, arising from a range of etiologies including androgen-deprivation therapies (ADTs), has been reported as a risk factor for acquired long-QT syndrome (aLQTS) and torsades de pointes (TdP). A full description of the clinical features of aLQTS associated with ADT and of underlying mechanisms is lacking. METHODS: We searched the international pharmacovigilance database VigiBase for men (n=6 560 565 individual case safety reports) presenting with aLQTS, TdP, or sudden death associated with ADT. In cardiomyocytes derived from induced pluripotent stem cells from men, we studied electrophysiological effects of ADT and dihydrotestosterone. RESULTS: Among subjects receiving ADT in VigiBase, we identified 184 cases of aLQTS (n=168) and/or TdP (n=68; 11% fatal), and 99 with sudden death. Of the 10 ADT drugs examined, 7 had a disproportional association (reporting odds ratio=1.4-4.7; P<0.05) with aLQTS, TdP, or sudden death. The minimum and median times to sudden death were 0.25 and 92 days, respectively. The androgen receptor antagonist enzalutamide was associated with more deaths (5430/31 896 [17%]; P<0.0001) than other ADT used for prostate cancer (4208/52 089 [8.1%]). In induced pluripotent stem cells, acute and chronic enzalutamide (25 µM) significantly prolonged action potential durations (action potential duration at 90% when paced at 0.5 Hz; 429.7±27.1 (control) versus 982.4±33.2 (acute, P<0.001) and 1062.3±28.9 ms (chronic; P<0.001), and generated afterdepolarizations and/or triggered activity in drug-treated cells (11/20 acutely and 8/15 chronically). Enzalutamide acutely and chronically inhibited delayed rectifier potassium current, and chronically enhanced late sodium current. Dihydrotestosterone (30 nM) reversed enzalutamide electrophysiological effects on induced pluripotent stem cells. CONCLUSIONS: QT prolongation and TdP are a risk in men receiving enzalutamide and other ADTs. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03193138.

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.

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.

Characteristics and clinical assessment of unexplained sudden cardiac arrest in the real-world setting: focus on idiopathic ventricular fibrillation.

Aims: Recent studies have shown that in more than half of apparently unexplained sudden cardiac arrests (SCA), a specific aetiology can be unmasked by a careful evaluation. The characteristics and the extent to which such cases undergo a systematic thorough investigation in real-life practice are unknown. Methods and results: Data were analysed from an ongoing study, collecting all cases of out-of-hospital cardiac arrest in Paris area. Investigations performed during the index hospitalization or planned after discharge were gathered to evaluate the completeness of assessment of unexplained SCA. Between 2011 and 2016, among the 18 622 out-of-hospital cardiac arrests, 717 survivors (at hospital discharge) fulfilled the definition of cardiac SCA. Of those, 88 (12.3%) remained unexplained after electrocardiogram, echocardiography, and coronary angiography. Cardiac magnetic resonance imaging yielded the diagnosis in 25 (3.5%) cases, other investigations accounted for 14 (2.4%) additional diagnoses, and 49 (6.8%) patients were labelled as idiopathic ventricular fibrillation (IVF) (48.7 ± 15 years, 69.4% male). Among those labelled IVF, only 8 (16.3%) cases benefited from a complete workup (including pharmacological testing). Younger patients [odds ratio (OR) 6.00, 95% confidence interval (CI) 1.80-22.26] and those admitted to university centres (OR 3.60, 95% CI 1.12-12.45) were more thoroughly investigated. Genetic testing and family screening were initiated in only 9 (18.4%) and 12 (24.5%) cases, respectively. Conclusion: Our findings suggest that complete investigations are carried out in a very low proportion of unexplained SCA. Standardized, systematic approaches need to be implemented to ensure that opportunities for specific therapies and preventive strategies (including relatives) are not missed.

Catheter ablation of organized atrial arrhythmias in orthotopic heart transplantation.

BACKGROUND: Organized atrial arrhythmias (OAAs) are common after orthotopic heart transplantation (OHT). Some controversies remain about their clinical presentation, relationship with atrial anastomosis and electrophysiologic features. The objectives of this retrospective study were to determine the mechanisms of OAAs after OHT and describe the outcomes of radiofrequency catheter ablation (RFCA). METHODS: Thirty consecutive transplanted patients (mean age 48 ± 17 years, 86.6% male) underwent 3-dimensional electroanatomic mapping and RFCA of their OAA from 2004 to 2012 at our center. RESULTS: Twenty-two patients had biatrial anastomosis and 8 had bicaval anastomosis. Macro-reentry was the arrhythmia mechanism for 96% of patients. The electrophysiologic diagnoses were: cavotricuspid isthmus (CTI)-dependent atrial flutter (AFL) in 93% of patients (n = 28); perimitral AFL in 3% (n = 1); and focal atrial tachycardia (FAT) in 3% (n = 1). In 5 patients with biatrial anastomosis, a right FAT was inducible. Primary RFCA success was obtained in 93% of patients. Mean follow-up time was 39 ± 26.8 months. Electrical repermeation between recipient and donor atria, present in 20% of patients (n = 6), did not account for any of the OAAs observed. Survival without OAA relapse at 12, 24 and 60 months was 93%, 89% and 79%, respectively. CONCLUSIONS: CTI-dependent AFL accounted for most instances of OAA after OHT, regardless of anastomosis type. Time from transplantation to OAA was shorter with bicaval than with biatrial anastomosis. RFCA was safe and provided good long-term results.

Contribution of exome sequencing for genetic diagnostic in arrhythmogenic right ventricular cardiomyopathy/dysplasia.

BACKGROUND: Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia (ARVC/D) is an inherited cardiomyopathy mainly caused by heterozygous desmosomal gene mutations, the major gene being PKP2. The genetic cause remains unknown in ~50% of probands with routine desmosomal gene screening. The aim of this study was to assess the diagnostic accuracy of whole exome sequencing (WES) in ARVC/D with negative genetic testing. METHODS: WES was performed in 22 patients, all without a mutation identified in desmosomal genes. Putative pathogenic variants were screened in 96 candidate genes associated with other cardiomyopathies/channelopathies. The sequencing coverage depth of PKP2, DSP, DSG2, DSC2, JUP and TMEM43 exons was compared to the mean coverage distribution to detect large insertions/deletions. All suspected deletions were verified by real-time qPCR, Multiplex-Ligation-dependent-Probe-Amplification (MLPA) and cGH-Array. MLPA was performed in 50 additional gene-negative probands. RESULTS: Coverage-depth analysis from the 22 WES data identified two large heterozygous PKP2 deletions: one from exon 1 to 14 and one restricted to exon 4, confirmed by qPCR and MLPA. MLPA identified 2 additional PKP2 deletions (exon 1-7 and exon 1-14) in 50 additional probands confirming a significant frequency of large PKP2 deletions (5.7%) in gene-negative ARVC/D. Putative pathogenic heterozygous variants in EYA4, RBM20, PSEN1, and COX15 were identified in 4 unrelated probands. CONCLUSION: A rather high frequency (5.7%) of large PKP2 deletions, undetectable by Sanger sequencing, was detected as the cause of ARVC/D. Coverage-depth analysis through next-generation sequencing appears accurate to detect large deletions at the same time than conventional putative mutations in desmosomal and cardiomyopathy-associated genes.