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.

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.

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.

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.

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.

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.

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.

A roadmap to improve the quality of atrial fibrillation management: proceedings from the fifth Atrial Fibrillation Network/European Heart Rhythm Association consensus conference.

At least 30 million people worldwide carry a diagnosis of atrial fibrillation (AF), and many more suffer from undiagnosed, subclinical, or 'silent' AF. Atrial fibrillation-related cardiovascular mortality and morbidity, including cardiovascular deaths, heart failure, stroke, and hospitalizations, remain unacceptably high, even when evidence-based therapies such as anticoagulation and rate control are used. Furthermore, it is still necessary to define how best to prevent AF, largely due to a lack of clinical measures that would allow identification of treatable causes of AF in any given patient. Hence, there are important unmet clinical and research needs in the evaluation and management of AF patients. The ensuing needs and opportunities for improving the quality of AF care were discussed during the fifth Atrial Fibrillation Network/European Heart Rhythm Association consensus conference in Nice, France, on 22 and 23 January 2015. Here, we report the outcome of this conference, with a focus on (i) learning from our 'neighbours' to improve AF care, (ii) patient-centred approaches to AF management, (iii) structured care of AF patients, (iv) improving the quality of AF treatment, and (v) personalization of AF management. This report ends with a list of priorities for research in AF patients.

Causes-of-death analysis of patients with cardiac resynchronization therapy: an analysis of the CeRtiTuDe cohort study.

AIMS: The choice of resynchronization therapy between with (CRT-D) and without (CRT-P) a defibrillator remains a contentious issue. Cause-of-death analysis among CRT-P, compared with CRT-D, patients could help evaluate the extent to which CRT-P patients would have additionally benefited from a defibrillator in a daily clinical practice. METHODS AND RESULTS: A total of 1705 consecutive patients implanted with a CRT (CRT-P: 535 and CRT-D: 1170) between 2008 and 2010 were enrolled in CeRtiTuDe, a multicentric prospective follow-up cohort study, with specific adjudication for causes of death at 2 years. Patients with CRT-P compared with CRT-D were older (P < 0.0001), less often male (P < 0.0001), more symptomatic (P = 0.0005), with less coronary artery disease (P = 0.003), wider QRS (P = 0.002), more atrial fibrillation (P < 0.0001), and more co-morbidities (P = 0.04). At 2-year follow-up, the annual overall mortality rate was 83.80 [95% confidence interval (CI) 73.41-94.19] per 1000 person-years. The crude mortality rate among CRT-P patients was double compared with CRT-D (relative risk 2.01, 95% CI 1.56-2.58). In a Cox proportional hazards regression analysis, CRT-P remained associated with increased mortality (hazard ratio 1.54, 95% CI 1.07-2.21, P = 0.0209), although other potential confounders may persist. By cause-of-death analysis, 95% of the excess mortality among CRT-P subjects was related to an increase in non-sudden death. CONCLUSION: When compared with CRT-D patients, excess mortality in CRT-P recipients was mainly due to non-sudden death. Our findings suggest that CRT-P patients, as currently selected in routine clinical practice, would not potentially benefit with the addition of a defibrillator.

Screening of genes encoding junctional candidates in arrhythmogenic right ventricular cardiomyopathy/dysplasia.

AIMS: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an inherited cardiomyopathy characterized by fibro-fatty replacement of the right ventricle and ventricular arrhythmias. The major disease-causing genes encode cardiac desmosomal components but are involved in only ∼50% of patients. To identify the missing genetic determinants, we used a candidate gene approach, focusing on the 3'-untranslated region (UTR) of the main ARVC/D gene PKP2 and on additional genes involved in desmosomal structure or function. METHODS AND RESULTS: We screened a population of 64 ARVC/D probands with no identified mutations in any of the five known desmosomal genes (PKP2, DSG2, DSP, DSC2, and JUP). No putative mutation was identified in the 3'-UTR of PKP2 or in PNN, CTNNA3, CAV1, or PLN coding sequences. In a single proband, we identified two rare heterozygous missense variants affecting evolutionary conserved residues: c.175G>A (p.Gly59Arg) in PERP and c.1811A>G (p.Asp604Gly) in PKP4 (minor allele frequency <0.5% in control population). CONCLUSION: Our study suggests that mutations in the candidate genes studied and regulation of PKP2 mRNA via 3'-UTR dependent mechanisms are unlikely to be major causes of ARVC/D in the studied population. Additional studies are needed to investigate the putative effects of rare PKP4 and PERP variants in this disease.

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.

Reverse electrical remodeling by cardiac resynchronization therapy: prevalence and clinical impact.

BACKGROUND: Cardiac resynchronization therapy (CRT) improves left ventricular ejection fraction (LVEF) in patients with congestive heart failure, LV systolic dysfunction, and a wide QRS complex. Previous reports suggest that CRT may also induce electrical remodeling but the impact on clinical outcome remains unknown. OBJECTIVE: We sought to determine (1) if chronic CRT induces a relevant shortening of the intrinsic QRS (iQRS), (2) whether changes in the native conduction system correlate with clinical or echocardiographic response to CRT, and (3) to identify predictors of iQRS width shortening. METHODS: We prospectively included 85 consecutive patients with left bundle-branch block who received a CRT device in 3 French centers. NYHA class, iQRS duration, LVEF, and left ventricular volumes were assessed before and 1 year after CRT implantation. Clinical and echocardiographic CRT responders were defined respectively as NYHA class improvement >1 class without heart failure hospitalization and an increase of LVEF by ≥10% and/or a decrease in LVESV by ≥15%. Electrocardiographic responders were defined as a decrease in iQRS duration by ≥20 ms. RESULTS: Baseline and 1-year follow-up mean iQRS durations were, respectively, 168.0 ± 19.7 ms and 149.6 ± 31.6 ms (P < 0.0001). Electrocardiographic response, observed in 43/85 patients (51%), was associated with a greater rate of clinical (P = 0.035) and echocardiographic (P = 0.023) response. Younger age, male gender, and longer baseline QRS width were independent predictors of electrocardiographic response. CONCLUSION: CRT decreases iQRS duration. A reduction of at least 20 ms in iQRS duration is associated with better clinical and echocardiographic response.

Correlations between long-term results after cryoablation for atrioventricular nodal reentry tachycardia and a residual jump associated or not with a single echo.

AIMS: While in radiofrequency ablation for atrioventricular nodal reentry tachycardia (AVNRT) a residual jump and a single echo do not seem to substantially modify long-term results, in cryoablation procedures their effects are still under evaluation. The purpose of this study was to evaluate if a residual jump associated or not with an isolated echo is correlated with outcome. INCLUSION CRITERIA: acute successful slow pathway cryoablation for slow-fast AVNRT. EXCLUSION CRITERIA: use of a 4 mm tip cryocatheter, no baseline elicitable jump or inducible AVNRT, and unwanted persistent first degree atrioventricular (AV) block at the end of the procedure. Cryoablation (-80°C × 4 min) was applied after successful cryomapping. Atrioventricular nodal reentry tachycardia inducibility was checked 30 min later on and off isoproterenol. Acute success was defined as AVNRT non-inducibility. Among 332 patients (pts) who had undergone cryoablation from May 2002 to March 2010 in our institutions, 245 of them fulfilled the entry criteria (173 women, mean age 41 ± 16 years, ineffective drugs 1.3 ± 1.1). A 7-Fr 6-mm tip cryocatheter (CryoCath®) was used in all cases. Baseline AV nodal effective refractory period (ERP) was 271 ± 55 ms, post-procedural ERP 331 ± 60 ms (P< 0.001), and the mean of the difference between baseline and post-procedural ERP 63 ± 38 ms. A/V ratio at successful site was 1 ± 0.4. Forty-four pts (18%) had a residual jump at the end of the procedure, and 14 of them had an associated single echo. Global cryoapplication time was 993 ± 797 s. During a follow-up of 40 ± 10 months, 43 pts (17.5%) had recurrences. At 12 months follow-up, actuarial rate of recurrence-free pts was 85% in the group without residual jump (201 pts), 63.3% with residual jump and no echo (30 pts), and 60.6% with residual jump associated with a single echo (P< 0.003 among groups). Univariate predictors of recurrences were persistence of a residual jump (P< 0.001) and total cryoapplication time (P< 0.02). In a multivariate model, only residual jump was independently correlated with recurrences (P< 0.01). CONCLUSIONS: In patients undergoing AVNRT cryoablation, slow-pathway suppression is correlated with a better outcome. A single echo is associated with a recurrence risk similar to residual jump without echo. It may be suggested that pursuing a procedural endpoint up to slow pathway complete suppression may improve long-term success.

Adverse effects of long-term right ventricular apical pacing and identification of patients at risk of atrial fibrillation and heart failure.

In patients needing a pacemaker (PM) for bradycardia indications, the amount of right ventricular (RV) apical pacing has been correlated with atrial fibrillation (AFib) and heart failure (HF) in both DDD and VVI mode. RV pacing was linked with left ventricular (LV) dyssynchrony in almost 50% of patients with PM implantation and atrioventricular (AV) node ablation for AFib. In patients with normal systolic function needing a PM, apical RV pacing resulted in LV ejection fraction (LVEF) reduction. These negative effects were prevented by cardiac resynchronization therapy (CRT). Algorithms favoring physiological AV conduction are possible useful tools able to maintain both atrial and ventricular support and limit RV pacing. However, when chronic RV pacing cannot be avoided, it appears necessary to reconsider the cut-off value of basic LVEF for CRT. In HF patients, RV pacing can induce greater LV dyssynchrony, enhanced by underlying conduction diseases. In this context, a more deleterious effect of RV pacing in implantable cardioverter-defibrillator (ICD) patients with low LVEF can be expected. In some major ICD trials, DDD mode was correlated with increased mortality/HF. This negative impact was attributed to unnecessary RV pacing >40-50%, virtually absent in VVI-40 mode. However, some data suggest that avoiding RV pacing may also not be the best option for patients requiring an ICD. In patients with impaired LV function, AV synchrony should therefore be ensured. The best pacing mode in ICD patients with HF should be defined on an individual basis.

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.

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.

Predictors for short-term progressive heart failure death in New York Heart Association II patients implanted with a cardioverter defibrillator--the EVADEF study.

BACKGROUND: Sudden cardiac death (SCD) is the predominant cause of mortality in patients with mild heart failure (HF). This 2-year follow-up, multicenter, cohort study aimed to assess the extent to which implantable cardioverter defibrillators (ICDs), by reducing SCD, lead to predominant progressive HF death in mildly symptomatic HF patients at baseline in daily medical practice. METHODS: Between June 2001 and June 2003, 1,030 New York Heart Association II patients received an ICD in 22 French centers. Sudden cardiac death and progressive HF mortality rates were assessed using competing risk methodology, and predictors for progressive HF at baseline were tested in a multivariate regression model. RESULTS: During a mean follow-up of 22 +/- 6 months, 114 deaths occurred: 12 (10.5%) due to SCD and 52 (45.6%) due to progressive HF (24-month cause-specific mortality rates of 1.2% [95% CI 0.6-1.9] and 5.4% [95% CI 4.0-6.8], respectively). Diuretics use (hazard ratio [HR] 2.8, 95% CI 1.5-5.5, P = .002), history of atrial fibrillation (HR 2.09, 95% CI 1.2-3.65, P = .01), and low ejection fraction (HR 2.7, 95% CI 1.4-4.8, P = .0008) were independent predictors for progressive HF death, whereas beta-blocker therapy was a protector (HR 0.6, 95% CI 0.3-0.9, P = .04). Half of the patients (48%) who died from progressive HF within 2 years of ICD implant initially presented with enlarged QRS (> or =120 milliseconds). CONCLUSIONS: Because of ICD efficiency, progressive HF is the main cause of death within 2 years of implant, although these patients are only mildly symptomatic at implantation. In addition to optimal pharmacologic therapy, these results raise the question of systematically implanting ICDs with cardiac resynchronization therapy in patients with electrical asynchronism at baseline.

Percutaneous epicardial radiofrequency ablation of ventricular arrhythmias after failure of endocardial approach: a 9-year experience.

INTRODUCTION: Management of recurrent ventricular tachycardia (VT) remains difficult. Neither medical treatments nor conventional endocardial radiofrequency (RF) ablation are efficient to prevent some recurrences. In these cases, a percutaneous pericardial approach may be required. METHODS: Among all the patients referred to our center between 1998 and 2007 for a VT ablation, 276 endocardial and 35 epicardial procedures were performed, the latter in case of failure of the conventional approach. We report in this study the efficacy and the safety of these 35 interventions analyzed retrospectively. RESULTS: Thirty-five epicardial procedures were attempted in 32 patients. An electric storm was present in 5 of 32 (16%) patients, with other individuals presenting with a recurrent VT despite drug therapy and a previous endocardial ablation. Pericardial space was reached in 28 of 32 patients by a xyphoidian puncture. An immediate success of RF on clinical VT was obtained in 22 of 29 (76%) cases. During a mean follow-up of 384 +/- 405 days, only 9 patients (26%) experienced a recurrence of a sustained VT. One patient died from tamponade during the procedure despite surgical drainage. Other complications had no significant consequences. CONCLUSION: Percutaneous epicardial puncture is feasible and relatively safe in patients with recurrent VT in whom conventional endocardial RF ablation failed. Epicardial RF ablation offers a high success rate in these challenging patients with only few severe complications.

A case for ambidextrous doctors.

We report the case of a 30-year-old man with situs inversus totalis, recurrent orthodromic reciprocal tachycardia, and the Wolff-Parkinson-White syndrome. He underwent, in our department, radiofrequency ablation of an accessory pathway (AP) located in the lateral mitral atrioventricular ring. Ablation of the AP was carried out successfully through a patent foramen ovale under fluoroscopic guidance, in a right anterior oblique projection with a 30° tilt and in anteroposterior views. We also used a mirror reversal of electrocardiogram (ECG) leads to better judge the site of the AP by using existing ECG algorithms. Complete situs inversus is a rare disorder, which has no consequence for the patient in the absence of cardiac or extracardiac involvement. Ablation of APs in situs inversus has been previously reported in only three cases of complete situs inversus and one case of situs ambiguous. In patients with mirror-image dextrocardia, APs seem more often located on the 'left' free wall (mitral annulus), as in the normal population. Radiofrequency ablation is feasible and safe after mirror reversion of the ECG electrodes and fluoroscopy.