Focus on malignant ventricular premature contractions.

Premature ventricular contractions (PVCs) are common. Although often benign, they can also be associated with increased morbidity and mortality. The aim of this review was to assess the risk evaluation of PVCs in patients with or without structural heart disease and discuss the management of this arrhythmia. Reports published in English were searched in PubMed with the following search terms: premature ventricular contraction, ectopic ventricular beat, ventricular extrasystole, antiarrhythmic drugs, ablation, ventricular arrhythmia, ventricular tachycardia, ventricular fibrillation and torsade de pointe. This analysis suggests that all patients with frequent PVCs should be assessed for PVC burden, symptom status and the presence of structural heart disease. PVCs in patients with structurally normal hearts was once considered a benign phenomenon. Uncommonly, PVCs may provoke life-threatening arrhythmias. Ventricular fibrillation is the initial mode of malignant rapid ventricular arrhythmias (MRVAs). Patients with malignant PVC and PVC burden >10% are at increased risk of MRVA in case of myocardial infarction and heart failure. MRVA is the primary cause of sudden cardiac death in patients with and without structural heart disease. Therapeutic options include medical therapy and catheter ablation, the latter more effective and potentially curable, particularly in patients with left ventricular dysfunction. The timely recognition and effective treatment of malignant PVCs in symptomatic patients with underling cardiomyopathy are mandatory to initiate early therapies before the occurrence of adverse clinical outcomes and to improve the long-term prognosis.

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 (25µM) significantly prolonged action potential durations (action potential duration at 90% when paced at 0.5Hz; 429.7±27.1 (control) versus 982.4±33.2 (acute, P<0.001) and 1062.3±28.9ms (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 (30nM) reversed enzalutamide electrophysiological effects on induced pluripotent stem cells. CONCLUSION: 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.

Joint Position Paper of the Working Group of Pacing and Electrophysiology of the French Society of Cardiology (SFC) and the Société française d'imagerie cardiaque et vasculaire diagnostique et interventionnelle (SFICV) on magnetic resonance imaging in patients with cardiac electronic implantable devices.

Magnetic resonance imaging (MRI) has become the reference imaging for the management of a large number of diseases. The number of MR examinations increases every year, simultaneously with the number of patients receiving a cardiac electronic implantable device (CEID). A CEID was considered an absolute contraindication for MRI for years. The progressive replacement of conventional pacemakers and defibrillators by MR-conditional CEIDs and recent data on the safety of MRI in patients with "MR-nonconditional" CEIDs have progressively increased the demand for MRI in patients with a CEID. However, some risks are associated with MRI in CEID carriers, even with "MR-conditional" devices because these devices are not "MR-safe". A specific programing of the device in "MR-mode" and monitoring patients during MRI remain mandatory for all patients with a CEID. A standardized patient workflow based on an institutional protocol should be established in each institution performing such examinations. This joint position paper of the Working Group of Pacing and Electrophysiology of the French Society of Cardiology and the Société française d'imagerie cardiaque et vasculaire diagnostique et interventionnelle (SFICV) describes the effect and risks associated with MRI in CEID carriers. We propose recommendations for patient workflow and monitoring and CEID programming in MR-conditional, "MR-conditional nonguaranteed" and MR-nonconditional devices.

Pregnancy and newborn outcomes in arrhythmogenic right ventricular cardiomyopathy/dysplasia.

INTRODUCTION: The prognosis of pregnancy in patients with Arrhythmogenic Right Ventricular Cardiomyopathy/dysplasia (ARVC/D) is poorly documented. The aim of this study is to assess the cardiac risks during pregnancy and the impact of ARVC/D on fetuses/neonates/children. METHODS: We included all ARVC/D women with a history of pregnancy from the ARVC/D Pitié-Salpêtrière registry. Cardiac and obstetrical events having occurred during pregnancy/delivery/post-partum periods and neonatal data/follow-up were collected. RESULTS: Sixty pregnancies in twenty-three patients were identified between 1968 and 2016. Only two major non-fatal cardiac events (one sustained non-documented tachycardia and one ventricular tachycardia) were recorded during pregnancy in two different mothers (3% of pregnancies, 9% of mothers). None occurred during delivery or in the postpartum period. No mother developed heart failure. Beta-blocker therapy during pregnancy (n=15) was associated with lower birthweight (2730 vs 3400g, p=0.004). Only two preterm deliveries occurred, unrelated to cardiac condition. Caesarean section was performed in 13% of cases. Premature sudden-death occurred in 10% (n=5) of children before 25years-old including two in the first year of life. CONCLUSION: ARVC/D is associated with a low rate of major cardiac events during pregnancy and vaginal delivery appears safe. The risk of sustained ventricular arrhythmia seems poorly predictable and supports the continuation of beta-blockers during pregnancy. Major cardiac events were frequent in childhood, justifying close cardiac monitoring.

Respective role of surface electrocardiogram and His bundle recordings to assess the risk of atrioventricular block after transcatheter aortic valve replacement.

BACKGROUND: Atrioventricular block (AVB) is common after transcatheter aortic valve replacement (TAVR) and permanent pacemaker (PPM) implantation is needed in up to 30% of patients. Main predictors of long term AVB are electrocardiographic. The purpose of this study is to assess the prognostic value of serial HV intervals measured before and after TAVR to shorten the timing of PPM implantation. METHODS: His bundle recordings were performed before (HV1), immediately after TAVR (HV2) and at day 2 for Edwards Sapien (ES) and 5 for Medtronic CoreValve (CV) (HV3). PPM indications were high degree AVB before day 5 or prolonged HV interval ≥80ms at the last recording. High degree AVB after discharge was evaluated from the pacemaker memories and ECG at 1 and 6months. RESULTS: Data were obtained in 84 patients (33% CV and 67% ES). HV values were not associated with early or late AVB. PPM were implanted in 27 patients (34%) for documented AVB (n=17, 24%), prolonged HV interval (n=9) or sick sinus syndrome (n=1). Persistent complete AVB during the procedure and postoperative high degree AVB were the only perioperative factors associated with further long term occurrence of high degree AVB (p=0.001 and p<0.001). On multivariate analysis, only postoperative high degree AVB was significant (p=0.001). CONCLUSION: Pre- and post-operative HV measurements were not correlated with late AVB after TAVR. Perioperative persistent complete AVB and postoperative high degree AVB are the only factors to predict late AVB and should be considered for the decision of PPM implantation.

[Valvular replacement with the Bicarbon mechanical valve. Results after 7 years in 104 patients]. / Remplacement valvulaire par la valve mécanique Bicarbon. Résultats à 7 ans chez 104 patients.

OBJECTIVE: Study of the medium term results of aortic and mitral valve replacement with the Bicarbon' prosthesis. METHOD: From 1990 to 1996, 109 valves were implanted (70 in aortic position, 31 in mitral position and 4 double replacements). The average age was 61 years and 75% were male. According to the NYHA, 59% of patients were stage III or IV. The average pre-operative ejection fraction was 59.6%. There was re-intervention in 21.1% of patients and 35.3% had an associated procedure during the intervention. RESULTS: The average follow up was 5.4 +/- 1.98 years in 98 patients (that is 522 patient years). One patient died post-operatively and 19 died later. The overall survival at 7 years was 69.4 +/- 6.3%. Complications, expressed in patient years, were 1.15% for thrombo-embolic complications, 2.1% for haemorrhagic complications. 0.38% for endocarditis, 1.72% for non-infectious peri-prosthetic leaks, and 0.76% for re-interventions. At 7 years, the absence of thrombo-embolic, haemorrhagic, endocarditis, and re-intervention complications was 91.8 +/- 4.2%, 85.3 +/- 4.8%, 95.8 +/- 3.2%, 93.8 +/- 3.5% respectively. According to the NYHA, 95% of patients were in stage 1 or II (p < 0.001). CONCLUSION: Valvular replacement in the aortic or mitral position with the Bicarbon' valve is satisfactory as much in terms of survival as of clinical complications.

Plakophilin 2A is the dominant isoform in human heart tissue: consequences for the genetic screening of arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease in which mutations affecting Plakophilin-2 (PKP2) are the most frequently detected. However, pathogenicity of variants is not always fully determined. PKP2 encodes two isoforms, the longest (PKP2b) includes the alternatively spliced exon 6, which is routinely screened for molecular diagnosis, despite the absence of data on cardiac expression of PKP2 isoforms. OBJECTIVE: To examine the pathogenicity of PKP2 exon 6 mutations by focusing on a missense variant located in this exon. METHODS AND RESULTS: The PKP2 heterozygous p.Arg490Trp variant was identified in two unrelated ARVC probands (absent from 470 controls). In silico analysis suggested that PKP2 exon 6 is an Alu-derived sequence with very low expression level. PKP2a mRNA, which does not include the sequence encoded by exon 6, was the dominant isoform transcribed; at western blot analysis PKP2A was the only clearly detectable isoform in all human heart samples analysed (from six different controls and the proband). Moreover, in the proband's sample, p.Arg490Trp was not associated with aberrant exon 6 splicing or mutant mRNA downregulation. Finally, a heterozygous missense variant (p.Glu2343Lys) in Desmoplakin was identified in this proband and is likely to be the disease-causing mutation. CONCLUSION: PKP2A was shown to be the major isoform expressed in human heart tissue and PKP2B protein was undetectable. The results strongly suggest that p.Arg490Trp and other variants located in PKP2 exon 6 may not be disease causing. Variant splicing also has important consequences for the interpretation of mutation analysis and genetic counselling in ARVC and other hereditary cardiac diseases.