Mode and Characteristics of Arrhythmia Initiation in Idiopathic Ventricular Fibrillation: A THESIS Substudy.

BACKGROUND: There is limited information on the mode of arrhythmia initiation in idiopathic ventricular fibrillation (IVF). A non-pause-dependent mechanism has been suggested to be the rule. OBJECTIVES: The aim of this study was to assess the mode and characteristics of initiation of polymorphic ventricular tachycardia (PVT) in patients with short or long-coupled PVT/IVF included in THESIS (THerapy Efficacy in Short or long-coupled idiopathic ventricular fibrillation: an International Survey), a multicenter study involving 287 IVF patients treated with drugs or radiofrequency ablation. METHODS: We reviewed the initiation of 410 episodes of ≥1 PVT triplet in 180 patients (58.3% females; age 39.6 ± 13.6 years) with IVF. The incidence of pause-dependency arrhythmia initiation (prolongation by >20 ms of the preceding cycle length) was assessed. RESULTS: Most arrhythmias (n = 295; 72%) occurred during baseline supraventricular rhythm without ambient premature ventricular complexes (PVCs), whereas 106 (25.9%) occurred during baseline rhythm including PVCs. Nine (2.2%) arrhythmias occurred during atrial/ventricular pacing and were excluded from further analysis. Mode of PVT initiation was pause-dependent in 45 (15.6%) and 64 (60.4%) of instances in the first and second settings, respectively, for a total of 109 of 401 (27.2%). More than one type of pause-dependent and/or non-pause-dependent initiation (mean: 2.6) occurred in 94.4% of patients with ≥4 events. Coupling intervals of initiating PVCs were <350 ms, 350-500 ms, and >500 ms in 76.6%, 20.72%, and 2.7% of arrhythmia initiations, respectively. CONCLUSIONS: Pause-dependent initiation occurred in more than a quarter of arrhythmic episodes in IVF patients. PVCs having long (between 350 and 500 ms) and very long (>500 ms) coupling intervals were observed at the initiation of nearly a quarter of PVT episodes.

Molecular genetic screening after non-ischaemic sudden cardiac arrest and no overt cardiomyopathy in real life: A major tool for the aetiological diagnostic work-up.

BACKGROUND: With the development of advanced sequencing techniques, genetic testing has emerged as a valuable tool for the work-up of non-ischaemic sudden cardiac arrest (SCA). AIMS: To evaluate the effectiveness of genetic testing in patients with unexplained SCA, according to clinical phenotype. METHODS: All patients who underwent molecular genetic testing for non-ischaemic SCA with no left ventricular cardiomyopathy between 2012 and 2021 in two French university hospitals were included. RESULTS: Of 66 patients (mean age 36.7±11.9years, 54.5% men), 21 (31.8%; 95% confidence interval 22.4-45.3%) carried a genetic variant: eight (12.1%) had a pathogenic or likely pathogenic (P/LP) variant and 13 (19.7%) had a variant of uncertain significance (VUS). Among 37 patients (56.1%) with no phenotypic clues, genetic testing identified a P/LP variant in five (13.5%), mainly in RYR2 (n=3) and SCN5A (n=2), and a VUS in nine (24.3%). None of the nine patients with phenotypic evidence of channelopathies had P/LP variants, but two had VUS in RYR2 and NKX2.5. Among the 20 patients with suspected arrhythmogenic cardiomyopathy, three P/LP variants (15.0%) and two VUS (10.0%) were found in DSC2, PKP2, SCN5A and DSG2, TRPM4, respectively. Genetic testing was performed sooner after cardiac arrest (P<0.001) and results were obtained more rapidly (P=0.02) after versus before 2016. CONCLUSION: This study highlights the utility of molecular genetic testing with a genetic variant of interest identified in one-third of patients with unexplained SCA. Genetic testing was beneficial even in patients without phenotypic clues, with one-fourth of patients carrying a P/LP variant that could have direct implications.

Position paper on sustainability in cardiac pacing and electrophysiology from the Working Group of Cardiac Pacing and Electrophysiology of the French Society of Cardiology.

Sustainability in healthcare, particularly within the domain of cardiac electrophysiology, assumes paramount importance for the near future. The escalating environmental constraints encountered necessitate a proactive approach. This position paper aims to raise awareness among physicians, spark critical inquiry and identify potential solutions to enhance the sustainability of our practice. Reprocessing of single-use medical devices has emerged as a potential solution to mitigate the environmental impact of electrophysiology procedures, while also offering economic advantages. However, reprocessing remains unauthorized in certain countries. In regions where it is possible, stringent regulatory standards must be adhered to, to ensure patient safety. It is essential that healthcare professionals, policymakers and manufacturers collaborate to drive innovation, explore sustainable practices and ensure that patient care remains uncompromised in the face of environmental challenges. Ambitious national/international programmes of disease prevention should be the cornerstone of the strategy. It is equally vital to implement immediate actions, as delineated in this position paper, to bring about tangible change quickly.

Pregnancy and cardiac maternal outcomes in women with inherited cardiomyopathy: interest of the CARPREG II risk score.

AIMS: Inherited cardiomyopathies are relatively rare but carry a high risk of cardiac maternal morbidity and mortality during pregnancy and postpartum. However, data for risk stratification are scarce. The new CARPREG II score improves prediction of prognosis in pregnancies associated with heart disease, though its role in inherited cardiomyopathies is unclear. We aim to describe characteristics and cardiac maternal outcomes in patients with inherited cardiomyopathy during pregnancy, and to evaluate the interest of the CARPREG II risk score in this population. METHODS AND RESULTS: In this retrospective single-centre study, 90 consecutive pregnancies in 74 patients were included (mean age 32 ± 5 years), including 28 cases of dilated cardiomyopathy (DCM), 46 of hypertrophic cardiomyopathy, 11 of arrhythmogenic right ventricular cardiomyopathy and 5 of left ventricular noncompaction, excluding peripartum cardiomyopathy. The discriminatory power of several risk scores was assessed by the area under the receiver-operating characteristic curve (AUC). Median CARPREG II score was 2 [0;3] and was higher in the DCM subgroup. A severe cardiac maternal complication was observed in 18 (20%) pregnancies, mainly driven by arrhythmia and heart failure (each event in 10 pregnancies), with 3 cardiovascular deaths. Forty-three pregnancies (48%) presented foetal/neonatal complications (18 premature delivery, 3 foetal/neonatal death). CARPREG II was significantly associated with cardiac maternal complications (P < 0.05 for all) and showed a higher AUC (0.782) than CARPREG (0.755), mWHO (0.697) and ZAHARA (0.604). CONCLUSIONS: Pregnancy in women with inherited cardiomyopathy carries a high risk of maternal cardiovascular complications. CARPREG II is the most efficient predictor of cardiovascular complications in this population.

Ventricular Tachycardia Ablation in Patients With Desmoplakin Cardiomyopathy.

BACKGROUND: Desmoplakin (DSP) pathogenic variants are rare causes of arrhythmogenic cardiomyopathy and often involve the right and left ventricles. Ventricular tachycardia (VT) ablations may be required in these patients, but procedural characteristics have not been reported. OBJECTIVES: In this study, the authors sought to report a multicenter experience of VT ablation in patients with DSP pathogenic variants. METHODS: VT ablations performed in patients with known DSP pathogenic variants were analyzed across 6 centers in 3 countries. Patient characteristics and acute and long-term procedural outcomes were reported. RESULTS: A total of 20 patients (13 men, median age 43 years [Q1-Q3: 41.5-53.0 years], left ventricular ejection fraction 43.0% [Q1-Q3: 41.5%-53.0%], 11 previous failed ablations) were referred for VT ablation procedures. All patients had symptomatic VTs, with ICD therapy in 19 patients. Epicardial procedures were performed in 16 of the 20 patients. VT target sites were located in the right ventricular (RV) endocardium (n = 11), the RV epicardium (n = 4), the left ventricular (LV) endocardium (n = 2) and the LV epicardium (n = 7). In 3 patients, the VT target sites were in close proximity to coronary arteries, limiting ablation. During follow-up, VTs recurred in 11 patients, and repeated ablations were performed in 9 patients. Allowing for multiple procedures, 19 of the 20 patients remained free of VT recurrence after a median follow-up of 18 months [Q1-Q3: 5-60 months]. CONCLUSIONS: Patients with DSP cardiomyopathy often have biventricular involvement, and ablation procedures often require ablation in both ventricles and the epicardium. Recurrences are not uncommon, and the pathologic substrate can be located in close proximity to epicardial coronary arteries, limiting the success rate of ablations.

Pre-emptive treatment of heart failure exacerbations in patients managed with the HeartLogic™ algorithm.

AIMS: Heart failure (HF) is a chronic disease affecting 64 million people worldwide and places a severe burden on society because of its mortality, numerous re-hospitalizations and associated costs. HeartLogic™ is an algorithm programmed into implanted devices incorporating several biometric parameters which aims to predict HF episodes. It provides an index which can be monitored remotely, allowing pre-emptive treatment of congestion to prevent acute decompensation. We aim to assess the impact and security of pre-emptive HF management, guided by the HeartLogic™ index. METHODS AND RESULTS: The HeartLogic™ France Cohort Study is an investigator-initiated, prospective, multi-centre, non-randomized study. Three hundred ten patients with a history of HF (left ventricular ejection fraction ≤40%; or at least one episode of clinical HF with elevated NT-proBNP ≥450 ng/L) and implanted with a cardioverter defibrillator enabling HeartLogic™ index calculation will be included across 10 French centres. The HeartLogic™ index will be monitored remotely for 12 months and in the event of a HeartLogic™ index ≥16, the local investigator will contact the patient for assessment and adjust HF treatment as necessary. The primary endpoint is unscheduled hospitalization for HF. Secondary endpoints are all-cause mortality, cardiovascular death, HF-related death, unscheduled hospitalizations for ventricular or atrial arrhythmia and HeartLogic™ index evolution over time. Blood samples will be collected for biobanking, and quality of life will be assessed. Finally, the safety of a HeartLogic™-triggered strategy for initiating or increasing diuretic therapy will be assessed. A blind and independent committee will adjudicate the events. CONCLUSIONS: The HeartLogic™ France Cohort Study will provide robust real-world data in a cohort of HF patients managed with the HeartLogic™ algorithm allowing pre-emptive treatment of heart failure exacerbations.

NEXN Gene in Cardiomyopathies and Sudden Cardiac Deaths: Prevalence, Phenotypic Expression, and Prognosis.

BACKGROUND: Few clinical data are available on NEXN mutation carriers, and the gene's involvement in cardiomyopathies or sudden death has not been fully established. Our objectives were to assess the prevalence of putative pathogenic variants in NEXN and to describe the phenotype and prognosis of patients carrying the variants. METHODS: DNA samples from consecutive patients with cardiomyopathy or sudden cardiac death/sudden infant death syndrome/idiopathic ventricular fibrillation were sequenced with a custom panel of genes. Index cases carrying at least one putative pathogenic variant in the NEXN gene were selected. RESULTS: Of the 9516 index patients sequenced, 31 were carriers of a putative pathogenic variant in NEXN only, including 2 with double variants and 29 with a single variant. Of the 29 unrelated probands with a single variant (16 males; median age at diagnosis, 32.0 [26.0-49.0] years), 21 presented with dilated cardiomyopathy (prevalence, 0.33%), and 3 presented with hypertrophic cardiomyopathy (prevalence, 0.14%). Three patients had idiopathic ventricular fibrillation, and there were 2 cases of sudden infant death syndrome (prevalence, 0.46%). For patients with dilated cardiomyopathy, the median left ventricle ejection fraction was 37.5% (26.25-50.0) at diagnosis and improved with treatment in 13 (61.9%). Over a median follow-up period of 6.0 years, we recorded 3 severe arrhythmic events and 2 severe hemodynamic events. CONCLUSIONS: Putative pathogenic NEXN variants were mainly associated with dilated cardiomyopathy; in these individuals, the prognosis appeared to be relatively good. However, severe and early onset phenotypes were also observed-especially in patients with double NEXN variants. We also detected NEXN variants in patients with hypertrophic cardiomyopathy and sudden infant death syndrome/idiopathic ventricular fibrillation, although a causal link could not be established.

Proposed diagnostic criteria for arrhythmogenic cardiomyopathy: European Task Force consensus report.

Arrhythmogenic cardiomyopathy (ACM) is a heart muscle disease characterized by prominent "non-ischemic" myocardial scarring predisposing to ventricular electrical instability. Diagnostic criteria for the original phenotype, arrhythmogenic right ventricular cardiomyopathy (ARVC), were first proposed in 1994 and revised in 2010 by an international Task Force (TF). A 2019 International Expert report appraised these previous criteria, finding good accuracy for diagnosis of ARVC but a lack of sensitivity for identification of the expanding phenotypic disease spectrum, which includes left-sided variants, i.e., biventricular (ABVC) and arrhythmogenic left ventricular cardiomyopathy (ALVC). The ARVC phenotype together with these left-sided variants are now more appropriately named ACM. The lack of diagnostic criteria for the left ventricular (LV) phenotype has resulted in clinical under-recognition of ACM patients over the 4 decades since the disease discovery. In 2020, the "Padua criteria" were proposed for both right- and left-sided ACM phenotypes. The presently proposed criteria represent a refinement of the 2020 Padua criteria and have been developed by an expert European TF to improve the diagnosis of ACM with upgraded and internationally recognized criteria. The growing recognition of the diagnostic role of CMR has led to the incorporation of myocardial tissue characterization findings for detection of myocardial scar using the late­gadolinium enhancement (LGE) technique to more fully characterize right, biventricular and left disease variants, whether genetic or acquired (phenocopies), and to exclude other "non-scarring" myocardial disease. The "ring-like' pattern of myocardial LGE/scar is now a recognized diagnostic hallmark of ALVC. Additional diagnostic criteria regarding LV depolarization and repolarization ECG abnormalities and ventricular arrhythmias of LV origin are also provided. These proposed upgrading of diagnostic criteria represents a working framework to improve management of ACM patients.

Rationale and design of the ARAMIS trial: Anakinra versus placebo, a double blind randomized controlled trial for the treatment of acute myocarditis.

BACKGROUND: Acute myocarditis is an inflammation of the myocardium that can cause life-threatening events. However, anti-inflammatory strategies did not reduce the risk of clinical outcomes in randomized trials. Recently, experimental studies have suggested that specific blockade of the interleukin-1ß immune innate pathway could be effective in acute myocarditis. AIM: To test the hypothesis that inhibition of the interleukin-1ß immune innate pathway can reduce the risk of clinical events in acute myocarditis. METHODS: The "Anakinra versus placebo double blind Randomized controlled trial for the treatment of Acute MyocarditIS" (ARAMIS) trial (ClinicalTrials.gov identifier: NCT03018834) is a national multicentre randomized parallel-group double blind study among symptomatic patients with elevated cardiac troponin and cardiac magnetic resonance-proven acute myocarditis. Patients (n=120) are randomized within 72hours of hospital admission to receive a daily subcutaneous dose of anakinra 100mg or placebo during the hospitalization, in addition to standard of care, including an angiotensin-converting enzyme inhibitor and a beta-blocker. The primary endpoint is the number of days alive free from any myocarditis complication, including ventricular arrhythmias, heart failure, recurrent chest pain requiring medication and ventricular dysfunction (defined as left ventricular ejection fraction<50%), from randomization to 28 days after hospital discharge. At 28 days after discharge, patients with normal left ventricular ejection fraction are then randomized to angiotensin-converting enzyme inhibitor continuation or discontinuation and all patients are followed for 1 year, with regular left ventricular function evaluation. CONCLUSIONS: ARAMIS is the first trial evaluating inhibition of the interleukin-1ß immune innate pathway in the setting of acute myocarditis. Although of small size, it will be the largest randomized trial in acute myocarditis, a serious and poorly studied cardiac condition.

A worldwide survey on incidence, management, and prognosis of oesophageal fistula formation following atrial fibrillation catheter ablation: the POTTER-AF study.

AIMS: Oesophageal fistula represents a rare but dreadful complication of atrial fibrillation catheter ablation. Data on its incidence, management, and outcome are sparse. METHODS AND RESULTS: This international multicentre registry investigates the characteristics of oesophageal fistulae after treatment of atrial fibrillation by catheter ablation. A total of 553 729 catheter ablation procedures (radiofrequency: 62.9%, cryoballoon: 36.2%, other modalities: 0.9%) were performed, at 214 centres in 35 countries. In 78 centres 138 patients [0.025%, radiofrequency: 0.038%, cryoballoon: 0.0015% (P < 0.0001)] were diagnosed with an oesophageal fistula. Peri-procedural data were available for 118 patients (85.5%). Following catheter ablation, the median time to symptoms and the median time to diagnosis were 18 (7.75, 25; range: 0-60) days and 21 (15, 29.5; range: 2-63) days, respectively. The median time from symptom onset to oesophageal fistula diagnosis was 3 (1, 9; range: 0-42) days. The most common initial symptom was fever (59.3%). The diagnosis was established by chest computed tomography in 80.2% of patients. Oesophageal surgery was performed in 47.4% and direct endoscopic treatment in 19.8% and conservative treatment in 32.8% of patients. The overall mortality was 65.8%. Mortality following surgical (51.9%) or endoscopic treatment (56.5%) was significantly lower as compared to conservative management (89.5%) [odds ratio 7.463 (2.414, 23.072) P < 0.001]. CONCLUSION: Oesophageal fistula after catheter ablation of atrial fibrillation is rare and occurs mostly with the use of radiofrequency energy rather than cryoenergy. Mortality without surgical or endoscopic intervention is exceedingly high.

Impact of peri-procedural management of direct oral anticoagulants on pocket haematoma after cardiac electronic device implantation: the StimAOD multicentre prospective study.

AIMS: The study aims to investigate the impact of direct oral anticoagulant (DOAC) management on the incidence of pocket haematoma in patients undergoing pacemaker or implantable cardioverter-defibrillator implantation. METHODS AND RESULTS: All consecutive patients receiving DOAC and undergoing cardiac electronic device implantation were included in a large multicentre prospective observational study (NCT03879473). The primary endpoint was clinically relevant haematoma within 30 days after implantation. Overall, 789 patients were enrolled [median age 80 (IQR 72-85) years old, 36.4% women, median CHA2DS2-VASc score 4 (IQR 0-8)], of which 632 (80.1%) received a pacemaker implantation. Antiplatelet therapy was combined with DOAC in 146 patients (18.5%). Direct oral anticoagulants (DOACs) were interrupted 52 (IQR 37-62) h before the procedure and resumed 31 (IQR 21-47) h later. Ninety-six percent of the patients had at least 12 h DOAC interruption before the procedure, and 78% had at least 12 h DOAC interruption after the procedure. Overall, anticoagulation was interrupted for 72 (IQR 48-96) h. Pre- or post-procedural heparin bridging was used in 8.2% and 3.9%, respectively. Timing of DOAC interruption of resumption was not associated with clinically relevant haematoma. Clinically relevant haematoma occurred in 26 patients (3.3%), and thromboembolic events occurred in 5 patients (0.6%). CONCLUSION: In this large real-life registry where most patients had DOAC interruption, clinically relevant haematoma was rare. Despite DOAC interruption and high CHA2DS2-VASc score, thromboembolic events occurred seldomly, highlighting that bleeding exceeds thromboembolic risk in this peri-procedural period. Future research is needed to identify risk factors for clinically relevant haematoma and meaningfully guide clinicians in optimizing DOAC management.

Feasibility of a New Regional Myocardial Strain Parameter for the Detection of Wall Motion Abnormalities in Arrhythmogenic Right Ventricular Cardiomyopathy.

Purpose: To evaluate a cardiac MRI feature tracking (FT)-derived parameter that combines right ventricular (RV) longitudinal and radial motions in detecting arrhythmogenic right ventricular cardiomyopathy (ARVC). Materials and Methods: Patients with ARVC (n = 47; median age, 46 [IQR, 30-52] years; 31 men) were compared with controls (n = 39; median age, 46 [IQR, 33-53] years; 23 men) and separated into two groups based on fulfillment of major structural 2020 International criteria. Cine data from 1.5-T cardiac MRI examinations were analyzed using FT, resulting in conventional strain parameters and a novel composite index named the longitudinal-to-radial strain loop (LRSL). Receiver operating characteristic (ROC) analysis was used to assess diagnostic performance of RV parameters. Results: Volumetric parameters differed significantly between patients in the major structural criteria group and controls but not between patients in the no major structural criteria group and controls. Patients in the major structural criteria group had significantly lower magnitudes of all FT parameters than controls, including RV basal longitudinal strain, radial motion fraction, circumferential strain, and LRSL (-15.6% ± 6.4 vs -26.7% ± 13.9; -9.6% ± 4.89 vs -13.8% ± 4.7; -6.9% ± 4.6 vs -10.1% ± 3.8; and 217.0 ± 128.9 versus 618.6 ± 356.3, respectively). Only LRSL differed between patients in the no major structural criteria group and controls (359.5 ± 195.8 vs 618.6 ± 356.3; P < .0001). Parameters with the highest area under the ROC curve values for discriminating patients in the no major structural criteria group from controls were LRSL, RV ejection fraction, and RV basal longitudinal strain (0.75, 0.70, and 0.61, respectively). Conclusion: A new parameter combining RV longitudinal and radial motions showed good diagnostic performance in ARVC, even in patients without major structural abnormalities.Keywords: Arrhythmogenic Right Ventricular Dysplasia, Strain, Wall Motion Abnormalities, Right Ventricle, MRI, Inherited Cardiomyopathy Supplemental material is available for this article. © RSNA, 2023.

Abatacept/Ruxolitinib and Screening for Concomitant Respiratory Muscle Failure to Mitigate Fatality of Immune-Checkpoint Inhibitor Myocarditis.

Immune-checkpoint-inhibitor (ICI)-associated myotoxicity involves the heart (myocarditis) and skeletal muscles (myositis), which frequently occur concurrently and are highly fatal. We report the results of a strategy that included identification of individuals with severe ICI myocarditis by also screening for and managing concomitant respiratory muscle involvement with mechanical ventilation, as well as treatment with the CTLA4 fusion protein abatacept and the JAK inhibitor ruxolitinib. Forty cases with definite ICI myocarditis were included with pathologic confirmation of concomitant myositis in the majority of patients. In the first 10 patients, using recommended guidelines, myotoxicity-related fatality occurred in 60%, consistent with historical controls. In the subsequent 30 cases, we instituted systematic screening for respiratory muscle involvement coupled with active ventilation and treatment using ruxolitinib and abatacept. The abatacept dose was adjusted using CD86 receptor occupancy on circulating monocytes. The myotoxicity-related fatality rate was 3.4% (1/30) in these 30 patients versus 60% in the first quartile (P < 0.0001). These clinical results are hypothesis-generating and need further evaluation. SIGNIFICANCE: Early management of respiratory muscle failure using mechanical ventilation and high-dose abatacept with CD86 receptor occupancy monitoring combined with ruxolitinib may be promising to mitigate high fatality rates in severe ICI myocarditis. See related commentary by Dougan, p. 1040. This article is highlighted in the In This Issue feature, p. 1027.

Idiopathic ventricular fibrillation associated with long-coupled Purkinje ectopy.

INTRODUCTION: Idiopathic ventricular fibrillation (IVF) is mainly associated with and triggered by short-coupled (R-on-T) ventricular ectopics. However, little is known about the risk of VF associated with long-coupled premature ventricular complexes (LCPVCs). OBJECTIVE: To examine the prevalence and characteristics of IVF patients presenting with LCPVCs. METHODS: Consecutive patients with IVF and PVCs from five arrhythmia referral centers were reviewed. We included patients presenting LCPVCs, defined as PVCs falling after the end of the T wave, with a normal QTc interval. We evaluated demographics, medical history, and clinical circumstances associated with PVCs and VF episodes. The origin of PVCs was determined by invasive mapping. RESULTS: Seventy-nine patients with IVF were reviewed. Among them, 12 (15.2%) met the inclusion criteria (8 women, age 36 ± 14 years). Eleven patients had documented LCPVCs initiating repetitive PVCs or sustained VF, whereas 1 had only documented isolated PVCs. In 10 of 12 patients, PVCs were recorded showing both long and short coupling intervals of 418 ± 46 and 304 ± 33 ms, respectively. Mapping showed that PVCs originated from the left Purkinje in 10 patients, from the right Purkinje in 1 patient, and both in 1 patient. Compared to other patients from the initial cohort, IVF with LCPVCs was associated with a left-sided origin of PVCs (92% in long-coupled IVF vs. 46% of left Purkinje PVCs in short-coupled IVF, p = .004). CONCLUSION: Long-coupled fascicular PVCs, traditionally recognized as benign, can be associated with IVF in a subset of patients. They can induce IVF by themselves or in association with short-coupled PVCs.

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.

Electrocardiographic findings in patients with arrhythmogenic cardiomyopathy and right bundle branch block ventricular tachycardia.

AIMS: Little is known about patients with right bundle branch block (RBBB)-ventricular tachycardia (VT) and arrhythmogenic cardiomyopathy (ACM). Our aims were: (i) to describe electrocardiogram (ECG) characteristics of sinus rhythm (SR) and VT; (ii) to correlate SR with RBBB-VT ECGs; and (iii) to compare VT ECGs with electro-anatomic mapping (EAM) data. METHODS AND RESULTS: From the European Survey on ACM, 70 patients with spontaneous RBBB-VT were included. Putative left ventricular (LV) sites of origin (SOOs) were estimated with a VT-axis-derived methodology and confirmed by EAM data when available. Overall, 49 (70%) patients met definite Task Force Criteria. Low QRS voltage predominated in lateral leads (n = 37, 55%), but QRS fragmentation was more frequent in inferior leads (n = 15, 23%). T-wave inversion (TWI) was equally frequent in inferior (n = 28, 42%) and lateral (n = 27, 40%) leads. TWI in inferior leads was associated with reduced LV ejection fraction (LVEF; 46 ± 10 vs. 53 ± 8, P = 0.02). Regarding SOOs, the inferior wall harboured 31 (46%) SOOs, followed by the lateral wall (n = 17, 25%), the anterior wall (n = 15, 22%), and the septum (n = 4, 6%). EAM data were available for 16 patients and showed good concordance with the putative SOOs. In all patients with superior-axis RBBB-VT who underwent endo-epicardial VT activation mapping, VT originated from the LV. CONCLUSIONS: In patients with ACM and RBBB-VT, RBBB-VTs originated mainly from the inferior and lateral LV walls. SR depolarization and repolarization abnormalities were frequent and associated with underlying variants.

Correlations Between Endocardial Voltage Mapping, Diagnosis, and Genetics in Patients With Arrhythmogenic Right Ventricular Cardiomyopathy.

The relations between endocardial voltage mapping and the genetic background of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) have not been investigated so far. A total of 97 patients with proved or suspected ARVC who underwent 3-dimensional endocardial mapping and genetic testing have been retrospectively included. Presence, localization, and size of scar areas were correlated to ARVC diagnosis and the presence of a pathogenic variant. A total of 78 patients (80%) presented with some bipolar or unipolar scar on endocardial voltage mapping, whereas 43 carried pathogenic variants (44%). Significant associations were observed between presence of endocardial scars on voltage mapping and previous or inducible ventricular tachycardia, right ventricular function and dimensions, or electrocardiogram features of ARVC. A total of 60 of the 78 patients (77%) with an endocardial scar fulfilled the criteria for a definitive arrhythmogenic right ventricular dysplasia diagnosis versus 8 of 19 patients (42%) without scar (p = 0.003). Patients with a definitive diagnosis of ARVC had more scars from any location and the scars were larger in patients with ARVC. In the 68 patients with a definitive diagnosis of ARVC, the presence of any endocardial scar was similar whether an ARVC-causal mutation was present or not. Only scar extent was significantly greater in patients with pathogenic variants. There was no difference in the presence and characteristics of scars in PKP2 mutated versus other mutated patients. The 3-dimensional endocardial mapping could have an important role for refining ARVC diagnosis and may be able to detect minor forms with otherwise insufficient criteria for diagnosis. The trend for larger scar extent were observed in mutated patients, without any difference according to the mutated genes.

Abnormal Cellular Phenotypes Induced by Three TMPO/LAP2 Variants Identified in Men with Cardiomyopathies.

A single missense variant of the TMPO/LAP2α gene, encoding LAP2 proteins, has been associated with cardiomyopathy in two brothers. To further evaluate its role in cardiac muscle, we included TMPO in our cardiomyopathy diagnostic gene panel. A screening of ~5000 patients revealed three novel rare TMPO heterozygous variants in six males diagnosed with hypertrophic or dilated cardiomypathy. We identified in different cellular models that (1) the frameshift variant LAP2α p.(Gly395Glufs*11) induced haploinsufficiency, impeding cell proliferation and/or producing a truncated protein mislocalized in the cytoplasm; (2) the C-ter missense variant LAP2α p.(Ala240Thr) led to a reduced proximity events between LAP2α and the nucleosome binding protein HMGN5; and (3) the LEM-domain missense variant p.(Leu124Phe) decreased both associations of LAP2α/ß with the chromatin-associated protein BAF and inhibition of the E2F1 transcription factor activity which is known to be dependent on Rb, partner of LAP2α. Additionally, the LAP2α expression was lower in the left ventricles of male mice compared to females. In conclusion, our study reveals distinct altered properties of LAP2 induced by these TMPO/LAP2 variants, leading to altered cell proliferation, chromatin structure or gene expression-regulation pathways, and suggests a potential sex-dependent role of LAP2 in myocardial function and disease.