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.

Relationship between Exercise Test Parameters, Device-Delivered Electric Shock and Adverse Clinical Events in Patients with an Implantable Cardioverter Defibrillator for Primary Prevention.

(1) Background: Receiving the first internal electric shock is a turning point for patients with an implantable cardioverter defibrillator (ICD) for primary prevention. However, no study has investigated whether patients who receive a first device-delivered electric shock have a poor prognosis even at the time of ICD implantation. (2) Methods: We retrospectively identified 55 patients with ischemic (n = 31) or dilated (n = 24) cardiomyopathy who underwent ICD implantation for primary prevention with exercise test at the time of implantation. We recorded baseline characteristics, exercise test parameters, and clinical events. (3) Results: After a median follow-up of 5 years, we observed an association between an appropriate device-delivered electric shock, the occurrence of death or heart transplant, and the occurrence of the composite endpoint. There was also a significant relation between a VE/VCO2 slope >35 and the occurrence of the composite endpoint. Conversely, there was no significant association between negative outcomes on the exercise test and the occurrence of a device-delivered electric shock. (4) Conclusions: The exercise test performed at the time of ICD implantation do not predict the occurrence of device-delivered electric shock. The exercise test and the first electric shock are two independent markers of poor prognosis.

Recurrences of Atrial Fibrillation Despite Durable Pulmonary Vein Isolation: The PARTY-PVI Study.

BACKGROUND: Recurrences of atrial fibrillation (AF) after pulmonary vein isolation (PVI) are mainly due to pulmonary vein reconnection. However, a growing number of patients have AF recurrences despite durable PVI. The optimal ablative strategy for these patients is unknown. We analyzed the impact of current ablation strategies in a large multicenter study. METHODS: Patients undergoing a redo ablation for AF and presenting durable PVI were included. The freedom from atrial arrhythmia after pulmonary vein-based, linear-based, electrogram-based, and trigger-based ablation strategies were compared. RESULTS: Between 2010 and 2020, 367 patients (67% men, 63±10 years, 44% paroxysmal) underwent a redo ablation for AF recurrences despite durable PVI at 39 centers. After durable PVI was confirmed, linear-based ablation was performed in 219 (60%) patients, electrogram-based ablation in 168 (45%) patients, trigger-based ablation in 101 (27%) patients, and pulmonary vein-based ablation in 56 (15%) patients. Seven patients (2%) did not undergo any additional ablation during the redo procedure. After 22±19 months of follow-up, 122 (33%) and 159 (43%) patients had a recurrence of atrial arrhythmia at 12 and 24 months, respectively. No significant difference in arrhythmia-free survival was observed between the different ablation strategies. Left atrial dilatation was the only independent factor associated with arrhythmia-free survival (HR, 1.59 [95% CI, 1.13-2.23]; P=0.006). CONCLUSIONS: In patients with recurrent AF despite durable PVI, no ablation strategy used alone or in combination during the redo procedure appears to be superior in improving arrhythmia-free survival. Left atrial size is a significant predictor of ablation outcome in this population.

Transseptal versus retrograde approach for ablation of left-sided accessory pathways: impact on radiation exposure.

Management of left-sided accessory pathways (APs) is based on catheter ablation through an antegrade or retrograde approach. Both are safe and effective but are associated with exposure to x-rays; however, recipients of ablation are generally young. We sought to evaluate the impact of the approach chosen on dose-area product (DAP). A total of 95 patients who underwent radiofrequency ablation of a left-sided AP between January 2011 and January 2020 were included. The primary endpoint was the radiation dose received by the patient. Secondary endpoints were procedural success and complication and recurrence rates. The mean age of the study population was 34.3 ± 16.6 years. The antegrade transseptal approach was used in 63.5% of cases. By multivariate analysis, the antegrade transseptal approach was associated with a 53% reduction in DAP (p< 0.001). The radiation dose received was also significantly associated with body mass index and total fluoroscopy time (p< 0.001). There was no significant difference in other secondary endpoints between approaches. The use of an antegrade transseptal approach is associated with a significant reduction in DAP compared with the retrograde approach, and procedural success and complication and recurrence rates are similar.

Low cost 3D printing of metals using filled polymer pellets.

Nowadays, additive manufacturing of metallic materials is most often carried out using expensive and complex tools that leave the user with limited control and no possibility of modification. In order to make the printing of metal parts more accessible to small structures but also better suited for academic research, the use of a mixture of thermoplastic polymer and metal powder is a good solution as many granular feedstocks already exist for Metal Injection Molding applications. To perform the shaping process, the Fused Granular Fabrication 3D printing technology is set up by diverting the use of a feedstock in the form of pellets that are directly inserted into the print head. This solution, which is less costly, is implemented here by modifying a mid-range printer, the Tool Changer from E3D, and by making the hardware and software adaptations to mount a compact granulates extruder on it, which is also available on the market. The polymer portion present in the green part can then be removed in order to perform the heat treatments that will densify the powder by sintering and give a fully metallic dense object.

Cardiovascular outcomes after cardiac resynchronization therapy in cardiac amyloidosis.

AIMS: Cardiac resynchronization therapy (CRT) is highly effective in dilated cardiomyopathy (DCM) patients with impaired left ventricular ejection fraction (LVEF) and left bundle block branch. In cardiac amyloidosis (CA) patients, left ventricular dysfunction and conduction defects are common, but the potential of CRT to improve cardiac remodelling and survival in this particular setting remains undefined. We investigated cardiovascular outcomes in CA patients after CRT implantation in terms of CRT echocardiographic response and major cardiovascular events (MACEs). METHODS AND RESULTS: Our retrospective study included 47 CA patients implanted with CRT devices from January 2012 to February 2020, in nine French university hospitals (77 ± 6 years old, baseline LVEF 30 ± 8%) compared with propensity-matched (1:1 for age, LVEF at implantation, and CRT indication) DCM patients with a CRT device. CA patients had lower rates of CRT response (absolute delta LVEF ≥ 10%) compared with DCM patients (36% vs. 70%, P = 0.002). After multivariate Cox analysis, CA was independently associated with MACE (hospitalization for heart failure/cardiovascular death) [hazard ratio (HR) 3.73, 95% confidence interval (CI) 1.85-7.54, P < 0.001], along with the absence of CRT response (HR 3.01, 95% CI 1.56-5.79, P = 0.001). The presence of echocardiographic CRT response (absolute delta LVEF ≥ 10%) was the only predictive factor of MACE-free survival in CA patients (HR 0.36, 95% CI 0.15-0.86, P = 0.002). CONCLUSION: Compared with a matched cohort of DCM patients, CA patients had a lower rate of CRT response and consequently a worse cardiovascular prognosis after CRT implantation. However, CRT could be beneficial even in CA patients given that CRT response was associated with better cardiac outcomes in this population.

Simulation of the mobility of the pelvic system: influence of fascia between organs.

The mobility of pelvic organs is the result of an equilibrium called Pelvic Static characterizing the balance between the properties and geometries of organs, suspensions and support system. Any imbalance in this complex system can cause of pelvic static disorder. Genital prolapse is a common hypermobility pathology which is complex, multi factorial and its surgical management has high rate of complications. The use of 3 D numerical models and simulation enables the role of the various suspension structures to be objectively studied and quantified. Fascias are connective tissues located between organs. Although their role are described as important in various descriptions of pelvic statics, their influence and role has never been quantitatively objectified. This article presents a refine Finite Element (FE) model for a better understanding of biomechanical contribution of inter-organ fascia. The model is built from MRI images of a young volunteer, the mechanical properties derived from literature data to take into account the age of the patient and new experimental results have enabled an order of magnitude of the mechanical properties of the fascias to be defined. The FE results allows to quantify the biomechanical role of the fascia on pelvic mobility quantified by an analysis of dynamic MRI images and a local mapping of the gap between calculated and measured displacements. This improved numerical model integrating the fascias makes it possible to describe pelvic mobilities with a gap of 1 mm between numerical simulations and measurements, whereas without taking them into account this gap locally reaches 20 mm.

Impact of epicardial fat on the duration of radiofrequency energy delivery during catheter ablation of atrial fibrillation.

AIMS: This study aimed to determine the impact of the volume of epicardial fat on the duration of radiofrequency (RF) energy delivery during the procedure of ablation of atrial fibrillation (AF). METHODS: The volume of epicardial fat was measured from spiral computerized tomography scan. The primary endpoint was the duration of RF delivery for pulmonary vein isolation (PVI), and the overall total duration of RF application. Secondary endpoint was conversion of AF to sinus rhythm or organisation of the arrhythmia after PVI. RESULTS: From March 2015 to May 2018, 222 patients (45.5% with persistent AF) underwent a first RF catheter ablation procedure for AF. The total duration of RF delivery, and the duration of RF delivery specifically for PVI were significantly associated with higher total volume of epicardial fat (p = 0.0002; p = 0.009 respectively), periatrial (p = 0.003; p = 0.045) and periventricular epicardial fat (p = 0.001; p = 0.012). In multivariate analysis, total epicardial fat volume was not significantly associated with total RF delivery duration (p = 0.743). For patients with arrhythmia at the time of the procedure, patients who achieved conversion or organisation of their arrhythmia after PVI had similar levels of total epicardial fat to those whose arrhythmia persisted (65 ± 35.2 vs 74.5 ± 31.2 ml; p = 0.192). CONCLUSION: We observed a significant relation between total, periatrial, and periventricular epicardial fat, and the duration of RF delivery during ablation of AF. This relation was not significant by multivariate analysis meaning that epicardial fat may be a marker, but not an independent factor, of ablation complexity.

High Risk of Sustained Ventricular Arrhythmia Recurrence After Acute Myocarditis.

Acute myocarditis is associated with cardiac arrhythmia in 25% of cases; a third of these arrhythmias are ventricular tachycardia (VT) or ventricular fibrillation (VF). The implantation of a cardiac defibrillator (ICD) following sustained ventricular arrhythmia remains controversial in these patients. We sought to assess the risk of major arrhythmic ventricular events (MAEs) over time in patients implanted with an ICD following sustained VT/VF in the acute phase of myocarditis compared to those implanted for VT/VF occurring on myocarditis sequelae. Our retrospective observational study included patients implanted with an ICD following VT/VF during acute myocarditis or VT/VF on myocarditis sequelae, from 2007 to 2017, in 15 French university hospitals. Over a median follow-up period of 3 years, MAE occurred in 11 (39%) patients of the acute myocarditis group and 24 (60%) patients of the myocarditis sequelae group. Kaplan-Meier MAE rate estimates at one and three years of follow-up were 19% and 45% in the acute group, and 43% and 64% in the sequelae group. Patients who experienced sustained ventricular arrhythmias during acute myocarditis had a very high risk of VT/VF recurrence during follow-up. These results show that the risk of MAE recurrence remains high after resolution of the acute episode.

Impact of Obesity on Overall Radiation Exposure for Patients Who Underwent Radiofrequency Ablation of Atrial Fibrillation.

Patients who underwent radiofrequency ablation of atrial fibrillation are exposed to X-rays not only during the procedure but also during the preprocedural computed tomography. No study has investigated the cumulative effective dose received by patients who underwent atrial fibrillation ablation and identified factors influencing this dose. We aimed to evaluate the overall exposure to ionizing radiation in patients who underwent radiofrequency ablation of atrial fibrillation. The secondary objective was to estimate the impact of obesity on this exposure. All patients who underwent a first attempt of radiofrequency ablation of atrial fibrillation in our center over a 21 months period were included. Dosimetric indicators from preprocedural computed tomography and the ablation procedure were collected and converted into an effective dose. A total of 144 radiofrequency ablation of atrial fibrillation were included. The mean cumulative effective dose was 11.4 mSv, and 82% of the dose was from the computed tomography. Obese patients received a dose that was 75% higher than normal-weight patients, and this increase remained significant by multivariate analysis. In conclusion, overall exposure to ionizing radiation for patients who underwent radiofrequency ablation of atrial fibrillation seems acceptable, and the majority of the overall effective dose comes from the computed tomography. Obese patients are exposed to a 75% higher dose than normal-weight patients.

Physicians' exposure to radiation during electrophysiology procedures.

PURPOSE: Cardiologists are among the health professionals that are most exposed to ionizing radiation, but there is no study comparing the level of exposure of physicians during different electrophysiology procedures. We aimed to measure and compare cardiologists' exposure to radiation during different electrophysiology procedures. METHODS: The study population comprised all electrophysiology procedures performed over a 6-month period in a large referral centre. The endpoint was operator radiation exposure, assessed using a personal electronic dosimeter located on the operator's left arm. RESULTS: In total, 150 electrophysiology procedures were analyzed. Compared with electrophysiology studies (reference category), physician radiation exposure was 3-fold greater during ablation of atrial fibrillation, 9-fold greater during ablation of atrioventricular nodal reentrant tachycardia (AVNRT)/atrioventricular reentrant tachycardia (AVNT), and 10-fold greater during ablation of atrial flutter (p < 0.001). Physician exposure was mainly related to X-ray time (R2 = 0.28). CONCLUSIONS: Our study showed significant differences in cardiologists' exposure to ionizing radiation depending on the type of electrophysiology procedure. Atrial flutter and AVNRT/AVNT ablations are the procedures in which operators are most exposed to ionizing radiation.

Impact of cardiac resynchronisation therapy on cardiologists' exposure to radiation during implantation of pacemakers and implantable cardioverter-defibrillators.

Cardiologists are among the health professionals that are most exposed to ionizing radiation, but there is no recent study quantifying overexposure of physicians during cardiac resynchronisation therapy (CRT) procedures compared to 'classical' implantation of pacemakers (PMs) or implantable cardioverter-defibrillators (ICDs). We aimed to measure and compare operator exposure to radiation during implantation of PM and ICD with or without CRT. The study population comprised all PMs and ICDs implanted in a large referral centre over a six months period. The endpoint was operator radiation exposure, assessed using a personal electronic dosimeter located on operator's chest. In total, 169 PM/ICD implantations were analysed, 19 of which included CRT. Compared with 'classical' implantation, cardiologist radiation exposure was 9-fold greater during CRT procedures (p < 0.001). Physician exposure was related to dose-area product (R2 = 0.21 during 'classical' implantations and R2 = 0.57 during CRT procedures). Our study shows that cardiologists' exposure to radiation during CRT implantation was 9-fold greater than during procedures without CRT.

Enterovirus but not Parvovirus B19 is associated with idiopathic dilated cardiomyopathy and endomyocardial CD3, CD68, or HLA-DR expression.

We assessed Enterovirus (EV) &Parvovirus B19 (PVB19) genomes and CD3, CD68&HLA-DR detection in dilated cardiomyopathies (DCM). EV&PVB19 genomes and CD3, CD68&HLA-DR were detected by PCR and immunohistochemistry assays in 115 endomyocardial biopsies obtained in 13 idiopathic DCM (iDCM) and 10 explained DCM (eDCM) patients. Results were compared with those of 47 atrial surgical samples (47 surgery controls) and 22 autoptic cardiac samples (11 healthy heart controls) (2008-2014, Reims, France). EV was detected in 23.1% of iDCM patients but not in eDCM and controls (P = 0.003) (viral load 803 copies/µg). PVB19 was detected in 76.9%, 80.0%, 63.6% and 78.2% of iDCM, eDCM, healthy heart and surgery controls (P = 0.99) with a mean viral load of 413, 346, 1,428, and 71 copies/µg. CD3, CD68 or HLA-DR were detected in 100 and 50% of EV and PVB19 "mono-infected" iDCM patients. EV was exclusively detected in iDCM cases in association with CD3, CD68, or HLA-DR indicating that EV could be an etiological cause in a subset of iDCM cases. By contrast the equal frequent detection of PVB19 in iDCM cases and controls without association with CD3, CD68, or HLA-DR suggested that PVB19 could be a bystander in many DCM cases. J. Med. Virol. 89:55-63, 2017. © 2016 Wiley Periodicals, Inc.

Echocardiography to predict adverse cardiac and vascular events in patients with severe chronic kidney disease (stage 4): a prospective study.

BACKGROUND: Cardiovascular disease is the primary cause of mortality and morbidity among patients with chronic kidney disease. AIMS: To investigate whether echocardiography can predict the occurrence of major cardiovascular events in patients with severe chronic kidney disease. PATIENTS: Patients with stable stage 4 chronic kidney disease (estimated glomerular filtration rate 15-29 mL/min/1.73 m(2)) and followed in the nephrology department were included. Clinical, biological, electrocardiographic and echocardiographic data were recorded. Endpoint was defined as fatal or non-fatal cardiovascular event (acute coronary syndrome, acute heart failure, stroke, sustained ventricular arrhythmias, arterial thrombotic events and death). RESULTS: We included 71 patients (46 men); mean age 72±14 years. Mean glomerular filtration rate was 21.9±4.8 mL/min/1.73 m(2). Over a mean follow-up of 258±30 days, 18 (25%) patients reached endpoint (death in 7/18). Male sex, blood urea, atrial fibrillation, Sokolow index, left atrial size, pulmonary arterial pressure, indexed left ventricular mass and protodiastolic peak velocity of transmitral Doppler flow were significantly higher whereas left ventricular ejection fraction was significantly lower in these patients. By multivariable analysis, blood urea and left ventricular ejection fraction remained predictive of major cardiovascular event with odds ratios of 1.10 (95% confidence interval 1.02-1.18) and 0.93 (95% confidence interval 0.89-0.97), respectively. The negative predictive value was 95% when left ventricular ejection fraction was>50% with blood urea<15 mmol/L. CONCLUSION: Patients with stage 4 chronic kidney disease are at high risk of major cardiovascular events and death. Echocardiographic evaluation is effective in identifying patients at highest risk of adverse cardiac events.

Risk factors for infection of implantable cardiac devices: data from a registry of 2496 patients.

AIMS: The increased use of implantable cardiac devices has been accompanied by an increase in infection. However, risk factors for infection of implanted devices are poorly documented. We aimed to identify risk factors in patients with long-term follow-up after implantation of cardiac devices. METHODS AND RESULTS: Patients with first implantation of a cardiac device in our centre between October 1996 and July 2007 were entered in a registry. Each confirmed infection of the implanted device was matched to two controls for age, sex, and implantation year. We recorded cardiovascular risk factors (hypertension, diabetes), previous history of heart disease, renal failure, antiplatelet or anticoagulant therapy, as well as pre- and post-procedural characteristics (antibiotic prophylaxis, hyperthermia, number of leads, associated interventions, and early complications). During the study period, 2496 patients underwent implantation of a cardiac device; 35 infections were diagnosed (1.2%). Among these, 75% occurred during the first year after implantation. Early non-infectious complication requiring surgical intervention was observed only in patients with infection (9 of 35, P < 0.001). Factors independently associated with infection were diabetes [odds ratio (OR) 3.5, 95% confidence interval (CI) [1.03, 12.97]], underlying heart disease (OR 3.12, 95% CI [1.13; 8.69]), and use of >1 lead (OR 4.07, 95% CI [1.23, 13.47]). These latter two risk factors were also independently associated with occurrence of infection within 1 year of implantation. CONCLUSION: Our data show that the presence of diabetes and underlying heart disease are independent risk factors for infection after cardiac device implantation. As regards procedural characteristics, the use of several leads and early re-intervention are associated with a higher infection rate.

Quantitative genomic and antigenomic enterovirus RNA detection in explanted heart tissue samples from patients with end-stage idiopathic dilated cardiomyopathy.

Standardized one-step real-time RT-PCR assay detected enterovirus RNA in cardiac biopsy samples from 4 of 20 patients suffering from idiopathic dilated cardiomyopathy (IDCM). The median viral load was 287 copies per microgram of total extracted nucleic acids, with positive- to negative-strand RNA ratios ranging from 2 to 20. These results demonstrate enterovirus persistence in the heart of IDCM patients, characterized by low viral loads and low positive- to negative-RNA ratios.

A fatal case of Human Herpesvirus 6 chronic myocarditis in an immunocompetent adult.

BACKGROUND: Human Herpesvirus 6 (HHV-6) is an important cause of fulminant or acute viral myocarditis in immunocompromised or immunocompetent patients. However the physiopathological mechanisms of HHV-6 related acute myocarditis and the involvement of subsequent HHV-6 reactivation phases in the development of chronic cardiomyopathies remain to be assessed. OBJECTIVES: To describe a case of fatal HHV-6 chronic myocarditis in an immunocompetent adult. STUDY DESIGN: Case report and detailed histological and viral diagnoses by combination of histology/immunohistochemistry and polymerase chain reaction techniques on cardiac tissues. RESULTS: Histopathological analysis of ventricular tissues showed large interstitial and scarring fibrotic areas with a moderate mononuclear cell infiltrate compatible with histological aspect of chronic myocarditis. Detection of both HHV-6 by real-time PCR and viral glycoproteins in mononuclear and endothelial cells by immunohistochemistry evidenced an ongoing cardiac HHV-6 replication with viral late protein synthesis activity. CONCLUSIONS: This case report indicates that HHV-6 can establish a chronic active myocarditis leading to heart failure in immunocompetent subjects.

[Edema and protein-losing enteropathy complicating chronic constrictive pericarditis associated with an ascending aortic aneurysm]. / Oedèmes et entéropathie exsudative compliquant une péricardite chronique constrictive associée à un anévrisme de l'aorte ascendante.

INTRODUCTION: Chronic constrictive pericarditis is suspected on clinical and echocardiographic grounds. Its treatment is surgical. CASE: We report here the case of a 45-year-old man, admitted for edema characteristic of lymphatic obstruction. Examination revealed ascending aorta ectasia, associated with chronic constrictive pericarditis. Measurement of alpha-1 antitrypsin clearance confirmed protein-losing enteropathy. Total recovery followed pericardectomy and aneurysm resection. DISCUSSION: The clinical edema in this case was due to several phenomena: protein-losing enteropathy from a functional lymphatic overload, induced by chronic constrictive pericarditis and by compression of the right atrium and vena cava by an aortic aneurysm. The hypoalbuminemia induced by protein loss may also magnify edema. An association between chronic constrictive pericarditis and ascending aortic aneurysm is uncommon. No cause for this association was found.