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Importance: Sudden death and cardiac arrest frequently occur without explanation, even after a thorough clinical evaluation. Calcium release deficiency syndrome (CRDS), a life-threatening genetic arrhythmia syndrome, is undetectable with standard testing and leads to unexplained cardiac arrest. Objective: To explore the cardiac repolarization response on an electrocardiogram after brief tachycardia and a pause as a clinical diagnostic test for CRDS. Design, Setting, and Participants: An international, multicenter, case-control study including individual cases of CRDS, 3 patient control groups (individuals with suspected supraventricular tachycardia; survivors of unexplained cardiac arrest [UCA]; and individuals with genotype-positive catecholaminergic polymorphic ventricular tachycardia [CPVT]), and genetic mouse models (CRDS, wild type, and CPVT were used to define the cellular mechanism) conducted at 10 centers in 7 countries. Patient tracings were recorded between June 2005 and December 2023, and the analyses were performed from April 2023 to December 2023. Intervention: Brief tachycardia and a subsequent pause (either spontaneous or mediated through cardiac pacing). Main Outcomes and Measures: Change in QT interval and change in T-wave amplitude (defined as the difference between their absolute values on the postpause sinus beat and the last beat prior to tachycardia). Results: Among 10 case patients with CRDS, 45 control patients with suspected supraventricular tachycardia, 10 control patients who experienced UCA, and 3 control patients with genotype-positive CPVT, the median change in T-wave amplitude on the postpause sinus beat (after brief ventricular tachycardia at ≥150 beats/min) was higher in patients with CRDS (P < .001). The smallest change in T-wave amplitude was 0.250 mV for a CRDS case patient compared with the largest change in T-wave amplitude of 0.160 mV for a control patient, indicating 100% discrimination. Although the median change in QT interval was longer in CRDS cases (P = .002), an overlap between the cases and controls was present. The genetic mouse models recapitulated the findings observed in humans and suggested the repolarization response was secondary to a pathologically large systolic release of calcium from the sarcoplasmic reticulum. Conclusions and Relevance: There is a unique repolarization response on an electrocardiogram after provocation with brief tachycardia and a subsequent pause in CRDS cases and mouse models, which is absent from the controls. If these findings are confirmed in larger studies, this easy to perform maneuver may serve as an effective clinical diagnostic test for CRDS and become an important part of the evaluation of cardiac arrest.
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Electrocardiografía , Humanos , Ratones , Estudios de Casos y Controles , Masculino , Animales , Femenino , Adulto , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/fisiopatología , Taquicardia Ventricular/etiología , Paro Cardíaco/etiología , Paro Cardíaco/diagnóstico , Calcio/metabolismo , Calcio/sangre , Taquicardia Supraventricular/diagnóstico , Taquicardia Supraventricular/fisiopatología , Taquicardia Supraventricular/etiología , Persona de Mediana Edad , Modelos Animales de Enfermedad , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/etiología , Adolescente , Adulto Joven , Canal Liberador de Calcio Receptor de Rianodina/genéticaRESUMEN
AIM: Ventricular arrhythmias (VAs) are the most common cause of death in patients with repaired Tetralogy of Fallot (rTOF). However, risk stratifying remains challenging. We examined outcomes following programmed ventricular stimulation (PVS) with or without subsequent ablation in patients with rTOF planned for pulmonary valve replacement (PVR). METHODS: We included all consecutive patients with rTOF referred to our institution from 2010 to 2018 aged ≥18 years for PVR. Right ventricular (RV) voltage maps were acquired and PVS was performed from two different sites at baseline, and if non-inducible under isoproterenol. Catheter and/or surgical ablation was performed when patients were inducible or when slow conduction was present in anatomical isthmuses (AIs). Postablation PVS was undertaken to guide implantable cardioverter-defibrillator (ICD) implantation. RESULTS: Seventy-seven patients (36.2 ± 14.3 years old, 71% male) were included. Eighteen were inducible. In 28 patients (17 inducible, 11 non-inducible but with slow conduction) ablation was performed. Five had catheter ablation, surgical cryoablation in 9, both techniques in 14. ICDs were implanted in five patients. During a follow-up of 74 ± 40 months, no sudden cardiac death occurred. Three patients experienced sustained VAs, all were inducible during the initial EP study. Two of them had an ICD (low ejection fraction for one and important risk factor for arrhythmia for the second). No VAs were reported in the non-inducible group (p < .001). CONCLUSION: Preoperative EPS can help identifying patients with rTOF at risk for VAs, providing an opportunity for targeted ablation and may improve decision-making regarding ICD implantation.
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Implantación de Prótesis de Válvulas Cardíacas , Válvula Pulmonar , Taquicardia Ventricular , Tetralogía de Fallot , Humanos , Masculino , Adolescente , Adulto , Adulto Joven , Persona de Mediana Edad , Femenino , Tetralogía de Fallot/diagnóstico por imagen , Tetralogía de Fallot/cirugía , Tetralogía de Fallot/complicaciones , Válvula Pulmonar/diagnóstico por imagen , Válvula Pulmonar/cirugía , Implantación de Prótesis de Válvulas Cardíacas/efectos adversos , Resultado del Tratamiento , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/etiología , Taquicardia Ventricular/cirugíaRESUMEN
PURPOSE OF REVIEW: Imaging plays a crucial role in the therapy of ventricular tachycardia (VT). We offer an overview of the different methods and provide information on their use in a clinical setting. RECENT FINDINGS: The use of imaging in VT has progressed recently. Intracardiac echography facilitates catheter navigation and the targeting of moving intracardiac structures. Integration of pre-procedural CT or MRI allows for targeting the VT substrate, with major expected impact on VT ablation efficacy and efficiency. Advances in computational modeling may further enhance the performance of imaging, giving access to pre-operative simulation of VT. These advances in non-invasive diagnosis are increasingly being coupled with non-invasive approaches for therapy delivery. This review highlights the latest research on the use of imaging in VT procedures. Image-based strategies are progressively shifting from using images as an adjunct tool to electrophysiological techniques, to an integration of imaging as a central element of the treatment strategy.
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Ablación por Catéter , Taquicardia Ventricular , Humanos , Taquicardia Ventricular/diagnóstico por imagen , Taquicardia Ventricular/cirugía , Arritmias Cardíacas , Corazón , Frecuencia Cardíaca , Ablación por Catéter/métodos , Resultado del TratamientoRESUMEN
BACKGROUND: The pathophysiology of AKI during tumor lysis syndrome (TLS) is not well understood due to the paucity of data. We aimed to decipher crystal-dependent and crystal-independent mechanisms of TLS-induced AKI. METHODS: Crystalluria, plasma cytokine levels, and extracellular histones levels were measured in two cohorts of patients with TLS. We developed a model of TLS in syngeneic mice with acute myeloid leukemia, and analyzed ultrastructural changes in kidneys and endothelial permeability using intravital confocal microscopy. In parallel, we studied the endothelial toxicity of extracellular histones in vitro. RESULTS: The study provides the first evidence that previously described crystal-dependent mechanisms are insufficient to explain TLS-induced AKI. Extracellular histones that are released in huge amounts during TLS caused profound endothelial alterations in the mouse model. The mechanisms of histone-mediated damage implicates endothelial cell activation mediated by Toll-like receptor 4. Heparin inhibits extracellular histones and mitigates endothelial dysfunction during TLS. CONCLUSION: This study sheds new light on the pathophysiology of TLS-induced AKI and suggests that extracellular histones may constitute a novel target for therapeutic intervention in TLS when endothelial dysfunction occurs.
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Lesión Renal Aguda , Síndrome de Lisis Tumoral , Lesión Renal Aguda/terapia , Animales , Endotelio , Histonas , Humanos , Riñón , Ratones , Síndrome de Lisis Tumoral/tratamiento farmacológico , Síndrome de Lisis Tumoral/etiologíaRESUMEN
AIMS: Arrhythmogenic right ventricular cardiomyopathy (ARVC) causes ventricular arrhythmias (VAs) and sudden cardiac death (SCD). In 2019, a risk prediction model that estimates the 5-year risk of incident VAs in ARVC was developed (ARVCrisk.com). This study aimed to externally validate this prediction model in a large international multicentre cohort and to compare its performance with the risk factor approach recommended for implantable cardioverter-defibrillator (ICD) use by published guidelines and expert consensus. METHODS AND RESULTS: In a retrospective cohort of 429 individuals from 29 centres in North America and Europe, 103 (24%) experienced sustained VA during a median follow-up of 5.02 (2.05-7.90) years following diagnosis of ARVC. External validation yielded good discrimination [C-index of 0.70 (95% confidence interval-CI 0.65-0.75)] and calibration slope of 1.01 (95% CI 0.99-1.03). Compared with the three published consensus-based decision algorithms for ICD use in ARVC (Heart Rhythm Society consensus on arrhythmogenic cardiomyopathy, International Task Force consensus statement on the treatment of ARVC, and American Heart Association guidelines for VA and SCD), the risk calculator performed better with a superior net clinical benefit below risk threshold of 35%. CONCLUSION: Using a large independent cohort of patients, this study shows that the ARVC risk model provides good prognostic information and outperforms other published decision algorithms for ICD use. These findings support the use of the model to facilitate shared decision making regarding ICD implantation in the primary prevention of SCD in ARVC.
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Displasia Ventricular Derecha Arritmogénica , Desfibriladores Implantables , Arritmias Cardíacas/etiología , Displasia Ventricular Derecha Arritmogénica/complicaciones , Displasia Ventricular Derecha Arritmogénica/diagnóstico , Displasia Ventricular Derecha Arritmogénica/terapia , Muerte Súbita Cardíaca/epidemiología , Muerte Súbita Cardíaca/etiología , Muerte Súbita Cardíaca/prevención & control , Desfibriladores Implantables/efectos adversos , Humanos , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Arrhythmogenic cardiomyopathy with right dominant form (ACR) is a rare heritable cardiac cardiomyopathy disorder associated with sudden cardiac death. Pathogenic variants (PVs) in desmosomal genes have been causally related to ACR in 40% of cases. Other genes encoding nondesmosomal proteins have been described in ACR, but their contribution in this pathology is still debated. A panel of 71 genes associated with inherited cardiopathies was screened in an ACR population of 172 probands and 856 individuals from the general population. PVs and uncertain significance variants (VUS) have been identified in 36% and 18.6% of patients, respectively. Among the cardiopathy-associated genes, burden tests show a significant enrichment in PV and VUS only for desmosomal genes PKP2 (plakophilin-2), DSP (desmoplakin), DSC2 (desmocollin-2), and DSG2 (desmoglein-2). Importantly, VUS may account for 15% of ACR cases and should then be considered for molecular diagnosis. Among the other genes, no evidence of enrichment was detected, suggesting an extreme caution in the interpretation of these genetic variations without associated functional or segregation data. Genotype-phenotype correlation points to (1) a more severe and earlier onset of the disease in PV and VUS carriers, underlying the importance to carry out presymptomatic diagnosis in relatives and (2) to a more prevalent left ventricular dysfunction in DSP variant carriers.
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Displasia Ventricular Derecha Arritmogénica , Displasia Ventricular Derecha Arritmogénica/diagnóstico , Displasia Ventricular Derecha Arritmogénica/genética , Displasia Ventricular Derecha Arritmogénica/metabolismo , Desmosomas/genética , Desmosomas/metabolismo , Estudios de Asociación Genética , Heterocigoto , Humanos , Placofilinas/genética , Placofilinas/metabolismoRESUMEN
AIMS: Sports practice, especially in competition, is usually restrained in patients diagnosed with long QT syndrome (LQTS). Although data are scarce, a low incidence of cardiac arrhythmic events (CAEs) during sports practice is reported. We aim to evaluate the incidence of CAE during sports practice in LQTS patients. METHODS AND RESULTS: All consecutive patients above 18 years of age diagnosed with LQTS and prospectively followed at the referral centre for inherited arrhythmia syndrome received a survey to retrospectively assess their sports practice prior to and after the diagnosis of LQTS. Two hundred and forty-six patients were included (57% females). The median age was 43 years, and the median QTc was 457â ms (428; 482). Patients reported a total of 4092 years [1376 (34%) after diagnosis] of sports practice: 2905 (77%) [1138 (39%) after diagnosis] years of leisure practice and 1187 (23%) [238 (20%) after diagnosis] years of competitive practice. One hundred and eighty (73%) patients practiced sport prior to the diagnosis of LQTS and 170 (69%) after. Prior to the diagnosis, four (2%) patients presented a CAE during leisure sports practice and one during competition. After diagnosis, only one patient presented a CAE, appropriately treated by an implantable cardioverter defibrillator discharge, in the context of beta-blocker non-compliance. The CAE event rate was 0.0007 events/year in the 1376 years of total sports practice after the diagnosis of LQTS. CONCLUSION: After the diagnosis of LQTS, the occurrence of CAE is very low during sports practice, even in competitive practice. There was no CAE in patients properly treated with beta-blocker therapy with good compliance.
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Desfibriladores Implantables , Síndrome de QT Prolongado , Deportes , Adulto , Desfibriladores Implantables/efectos adversos , Electrocardiografía , Femenino , Humanos , Síndrome de QT Prolongado/diagnóstico , Síndrome de QT Prolongado/epidemiología , Síndrome de QT Prolongado/terapia , Masculino , Estudios RetrospectivosRESUMEN
Histones are widely recognized as pro-inflammatory mediators upon their release from the nucleus into the extracellular space. However, their impact on endothelial cell immunogenicity is unknown. Endothelial cells, Human Microvascular Endothelial cells 1 (HMEC1), have been exposed to recombinant histones in order to study their effect on the endothelial phenotype. We then studied the differentiation of CD4+-T lymphocytes subpopulations after three days of interaction with endothelial cells in vitro and observed that histone-treated endothelial cells differentiate a suppressive FoxP3+ T regulator subpopulation that expressed Human Leucocyte Antigen DR (HLA-DR) and Cytotoxic T-Lymphocyte-Associated protein 4 (CTLA4). Toll-Like Receptor 4 (TLR4) inhibition significantly decreased the expansion of these Treg cells. Moreover, blockade of Interleukin (IL)-6 and Intercellular Adhesion Molecule (ICAM)-1 in cocultures significantly decreased the expansion of Tregs, suggesting an IL-6 and ICAM-1 dependent pathway. Thus, beyond their inflammatory effects, extracellular histones may induce an increase of immunosuppressive Treg population via their action on endothelial cells. Further studies are needed to evaluate the impact on immunosuppression of an increase of peripheral suppressive Treg via endothelial cell activation by histones in vivo.
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Histonas , Linfocitos T Reguladores , Diferenciación Celular , Técnicas de Cocultivo , Células Endoteliales/metabolismo , Factores de Transcripción Forkhead/metabolismo , Histonas/metabolismo , Activación de LinfocitosRESUMEN
BACKGROUND: Differentiating between atypical atrioventricular nodal reentrant tachycardia (AVNRT) and orthodromic reciprocating tachycardia utilizing a septal accessory pathway is a complex challenge. OBJECTIVE: The purpose of this study was to describe the "local VA index," a straightforward method based on signals from the coronary sinus catheter, to distinguish between these arrhythmias during tachycardia and entrainment. The ventriculoatrial (VA) interval on the coronary sinus catheter is measured during tachycardia and entrainment, at the site of earliest atrial activity. The difference between these 2 situations defines the "local VA index." We also propose a mechanism to clarify the limitations of historical pacing maneuvers, such as postpacing interval minus tachycardia cycle length (PPI-TCL) and stimulus-atrial interval minus ventriculoatrial interval (SA-VA), by examining nodal decrement and intraventricular conduction delay. METHODS: In a retrospective study of 75 patients referred for supraventricular tachycardia evaluation, 37 were diagnosed with atrioventricular reentrant tachycardia (AVRT) with orthodromic reciprocating tachycardia, and 38 with AVNRT (27 typical, 11 atypical). RESULTS: In comparison to AVRT patients, AVNRT patients exhibited longer PPI-TCL (176 ± 47 ms vs 113 ± 42 ms; P <.01) and SA-VA (138 ± 47 ms vs 64 ± 28 ms; P <.01). The AVRT group had mean local VA index of -1 ± 13 ms, whereas the AVNRT group had a significantly longer index of 91 ± 46 ms (P <.01). An optimal threshold for differentiation was a local VA index of 40 ms. Importantly, there was no significant correlation between pacing cycle length and nodal decrement as well as intraventricular delay related to pathway location. This interindividual variability might explain misleading interpretations of PPI-TCL and SA-VA. CONCLUSION: This novel approach is advantageous because of its simplicity and effectiveness, requiring only 2 diagnostic catheters. A local VA interval difference <40 ms provides a clear distinction for AVRT.
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Taquicardia por Reentrada en el Nodo Atrioventricular , Taquicardia Supraventricular , Humanos , Diagnóstico Diferencial , Femenino , Masculino , Estudios Retrospectivos , Taquicardia por Reentrada en el Nodo Atrioventricular/diagnóstico , Taquicardia por Reentrada en el Nodo Atrioventricular/fisiopatología , Persona de Mediana Edad , Taquicardia Supraventricular/diagnóstico , Taquicardia Supraventricular/fisiopatología , Electrocardiografía/métodos , Adulto , Sistema de Conducción Cardíaco/fisiopatología , Técnicas Electrofisiológicas Cardíacas/métodos , Taquicardia Reciprocante/diagnóstico , Taquicardia Reciprocante/fisiopatologíaRESUMEN
BACKGROUND: Omnipolar technology (OT) was recently proposed to generate electroanatomic voltage maps with orientation-independent electrograms. We describe the first cohort of patients undergoing ventricular tachycardia (VT) ablation guided by OT. OBJECTIVE: The purpose of this study was to compare omnipolar and bipolar high-density maps with regard to voltage amplitude, late potential (LP) annotation, and isochronal late activation mapping distribution. METHODS: A total of 24 patients (16 [66%] ischemic cardiomyopathy and 12 [50%] redo cases) underwent VT ablation under OT guidance. Twenty-seven sinus rhythm substrate maps and 10 VT activation maps were analyzed. Omnipolar and bipolar (HD Wave Solution algorithm, Abbott, Abbott Park, IL) voltages were compared. Areas of LPs were correlated with the VT isthmus areas, and late electrogram misannotation was evaluated. Deceleration zones based on isochronal late activation maps were analyzed by 2 blinded operators and compared to the VT isthmuses. RESULTS: OT maps had higher point density (13.8 points/cm2 vs 8.0 points/cm2). Omnipolar points had 7.1% higher voltages than bipolar points within areas of dense scar and border zone. The number of misannotated points was significantly lower for OT maps (6.8% vs 21.9%; P = .01), showing comparable sensitivity (53% vs 59%) but higher specificity (79% vs 63%). The sensitivity and specificity of detection of the VT isthmus in the deceleration zones were, respectively, 75% and 65% for OT and 35% and 55% for bipolar mapping. At 8.4 months, 71% freedom from VT recurrence was achieved. CONCLUSION: OT is a valuable tool for guiding VT ablation, providing more accurate identification of LPs and isochronal crowding due to slightly higher voltages.
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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.
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Fibrilación Atrial , Ablación por Catéter , Venas Pulmonares , Masculino , Humanos , Femenino , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/cirugía , Venas Pulmonares/cirugía , Ablación por Catéter/efectos adversos , Ablación por Catéter/métodos , Atrios Cardíacos , Reoperación/métodos , Recurrencia , Resultado del TratamientoRESUMEN
AIMS: Heart transplantation (HT) can be proposed as a therapeutic strategy for patients with severe refractory electrical storm (ES). Data in the literature are scarce and based on case reports. We aimed at determining the characteristics and survival of patients transplanted for refractory ES. METHODS AND RESULTS: Patients registered on HT waiting list during the following days after ES and eventually transplanted, from 2010 to 2021, were retrospectively included in 11 French centres. The primary endpoint was in-hospital mortality. Forty-five patients were included [82% men; 55.0 (47.8-59.3) years old; 42.2% and 26.7% non-ischaemic dilated or ischaemic cardiomyopathies, respectively]. Among them, 42 (93.3%) received amiodarone, 29 received (64.4%) beta blockers, 19 (42.2%) required deep sedation, 22 had (48.9%) mechanical circulatory support, and 9 (20.0%) had radiofrequency catheter ablation. Twenty-two patients (62%) were in cardiogenic shock. Inscription on wait list and transplantation occurred 3.0 (1.0-5.0) days and 9.0 (4.0-14.0) days after ES onset, respectively. After transplantation, 20 patients (44.4%) needed immediate haemodynamic support by extracorporeal membrane oxygenation (ECMO). In-hospital mortality rate was 28.9%. Predictors of in-hospital mortality were serum creatinine/urea levels, need for immediate post-operative ECMO support, post-operative complications, and surgical re-interventions. One-year survival was 68.9%. CONCLUSION: Electrical storm is a rare indication of HT but may be lifesaving in those patients presenting intractable arrhythmias despite usual care. Most patients can be safely discharged from hospital, although post-operative mortality remains substantial in this context of emergency transplantation. Larger studies are warranted to precisely determine those patients at higher risk of in-hospital mortality.
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Oxigenación por Membrana Extracorpórea , Trasplante de Corazón , Masculino , Humanos , Persona de Mediana Edad , Femenino , Estudios Retrospectivos , Arritmias Cardíacas/etiología , Choque Cardiogénico/etiología , Oxigenación por Membrana Extracorpórea/métodosRESUMEN
The role of the vascular microenvironment is increasingly studied in acute myeloid leukaemia (AML). Complex interactions between endothelial cells (ECs) and pre-leukaemic cells may contribute to the clonal evolution of pre-leukaemic stem cells in the bone marrow niche and to the proliferation, survival and chemoresistance of leukaemic cells. Through the expression of different adhesion molecules, ECs play a key role in the development of specific acute complications of AML, including leukostasis, acute respiratory failure, acute kidney injury or neurological complications. Moreover, in newly diagnosed patients, leukaemic cells promote endothelial activation and subsequent disseminated intravascular coagulation. Mechanisms of this bi-directional dialogue between leukaemic cells and ECs will reveal possible therapeutic targets to be explored to improve the survival of AML patients.
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Células Endoteliales , Leucemia Mieloide Aguda , Médula Ósea/metabolismo , Células de la Médula Ósea/metabolismo , Evolución Clonal , Células Endoteliales/metabolismo , Humanos , Leucemia Mieloide Aguda/metabolismo , Microambiente Tumoral/fisiologíaRESUMEN
Catecholamine-induced QT prolongation (CIQTP) is an inherited cardiac disease characterized by a normal baseline ECG and a risk of sudden cardiac death by ventricular arrhythmia due to a QT prolongation that only appears during catecholergic stimulation, especially mental stress. Induced pluripotent stem cells (hiPSCs) were generated from peripheral blood mononuclear cells collected from two CIQTP-affected patients from two different families. These two hiPSC lines are a valuable model to study biological alterations due to CIQTP.
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Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel NaV1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on NaV1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings.
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Síndrome de Brugada , Alelos , Síndrome de Brugada/complicaciones , Síndrome de Brugada/genética , Síndrome de Brugada/metabolismo , Susceptibilidad a Enfermedades/complicaciones , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Proteínas Asociadas a Microtúbulos/genética , Mutación , Canal de Sodio Activado por Voltaje NAV1.5/genética , Canal de Sodio Activado por Voltaje NAV1.5/metabolismo , Adulto JovenRESUMEN
BACKGROUND: Beta-blocker therapy is the cornerstone of treatment for patients with long QT syndrome (LQTS). Few details on the dose to be used are available. As the response is variable between patients, we systematically evaluated the effect of treatment by performing an exercise test. OBJECTIVE: The purpose of this study was to explore dose response to nadolol on exercise test in LQTS patients in order to propose a more personalized therapeutic approach. METHODS: LQTS patients followed at the Reference Centre for Hereditary Arrhythmic Diseases of Nantes with at least 1 exercise test under nadolol were included retrospectively between 1993 and 2017. All patients underwent gradual cycle exercise tests. Doses adjusted to weight and response to treatment were recorded and evaluated by the percentage of age-predicted maximum heart rate reached on exercise test. RESULTS: Ninety-five patients were included in the study, and 337 stress tests under nadolol were analyzed. No correlation existed between dose and percentage of age-predicted maximum heart rate on exercise tests. Twenty-one patients were overresponders, mostly LQTS1, and 20 were underresponders, mainly LQTS2 (P = .0229). Forty-two patients had at least 3 stress tests under nadolol. We found a negative correlation between dose change and percentage of age-predicted maximum heart rate change (P <.0001). We then proposed a table to adapt dose according to exercise test response. CONCLUSION: Our study demonstrated a major variability of dose response to nadolol in patients with LQTS, thus underlining the need for a tailored dosage for each patient. Intraindividual analysis showed a relatively constant dose-response relationship, allowing guided dose adaptation after the first exercise test.
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Adaptación Fisiológica/fisiología , Electrocardiografía/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Síndrome de QT Prolongado/tratamiento farmacológico , Nadolol/administración & dosificación , Adolescente , Adulto , Antiarrítmicos/administración & dosificación , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Prueba de Esfuerzo , Femenino , Estudios de Seguimiento , Humanos , Lactante , Inyecciones Intravenosas , Síndrome de QT Prolongado/fisiopatología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Adulto JovenRESUMEN
OBJECTIVES: Sepsis is defined as the host's inflammatory response to a life-threatening infection. The endothelium is implicated in immunoregulation during sepsis. Macrolides have been proposed to display immunomodulatory properties. The goal of this study was to analyze whether macrolides can exert immunomodulation of endothelial cells (ECs) in an experimental model of sepsis. METHODS: Human ECs were stimulated by proinflammatory cytokines and lipopolysaccharide before exposure to macrolides. ECs phenotypes were analyzed by flow cytometry. Cocultures of ECs and peripheral blood mononuclear cells (PBMCs) were performed to study the ECs ability to alter T-cell viability and differentiation in the presence of macrolides. Soluble factor production was assessed. RESULTS: ECs act as non-professional antigen presenting cells and expressed human leukocyte antigen (HLA) antigens, the adhesion molecules CD54, CD106, and the coinhibitory molecule CD274 after septic stimulation. Incubation with macrolides induced a significant decrease of HLA class I and HLA class II HLA-DR on septic-stimulated ECs, but did not alter either CD54, CD106, nor CD274 expression. Interleukin-6 (IL-6) and IL-8 production by stimulated ECs were unaltered by incubation with macrolides, whereas Clarithromycin exposure significantly decreased IL-6 gene expression. In cocultures of septic ECs with PBMCs, neither the proportion of CD4 + , CD8 + T nor their viability was altered by macrolides. T-helper lymphocyte subsets Th1, Th17, and Treg polarization by stimulated ECs were unaltered by macrolides. CONCLUSION: This study reports phenotypic and gene expression changes in septic-stimulated ECs exposed to macrolides, without resulting in altered immunogenicity of ECs in co-cultures with PBMCs. In vivo studies may help to further understand the impact of macrolide therapy on ECs immune homeostasis during sepsis.
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Antígenos HLA-DR , Macrólidos , Células Endoteliales , Humanos , Inmunomodulación , Leucocitos Mononucleares , Macrólidos/farmacologíaRESUMEN
BACKGROUND: In this study we aimed to assess long-term outcomes in subcutaneous implantable cardioverter-defibrillator (S-ICD) recipients with structural heart disease by focussing especially on shock incidence, predictors, and associated prognoses. METHODS: In this multicenter registryâbased study, we retrospectively included all patients who underwent S-ICD implantation at 3 tertiary centers. The prognostic impact of S-ICD shock was assessed with a composite outcome that included all-cause death and hospitalisation for heart failure. RESULTS: A total of 351 patients with underlying cardiomyopathy were included in the investigation. Using multivariable Fine and Gray regression models, secondary prevention, left ventricular ejection fraction (LVEF), conditional shock threshold, and QRS duration appeared to be independent predictors of appropriate S-ICD shock occurrence. In the multivariate Cox regression model adjusted for age, baseline LVEF, underlying cardiomyopathy subtype, New York Heart Association class, and appropriate shocks were significantly associated with increased composite prognostic outcome risk (hazard ratio [HR], 2.61; 95% confidence interval [CI], 1.21-5.65; P = 0.014), whereas inappropriate shocks were not (HR, 1.35; 95% CI, 0.75-4.48; P = 0.18). The analysis of each component of the composite prognostic outcome highlighted that the occurrence of appropriate shocks was associated with an increased risk of hospitalisation for heart failure (HR, 3.10; 95% CI, 1.26-7.58; P = 0.013) and a trend for mortality (HR, 2.19; 95% CI, 0.78-6.16; P = 0.14). CONCLUSIONS: Appropriate S-ICD shocks were associated with a 3-fold increase in acute heart failure admission, whereas inappropriate shocks were not. Conditional shock threshold programming is an independent predictor of S-ICD shock, and its prognostic impact should be investigated further in patients with structural heart disease.
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Cardiomiopatías , Muerte Súbita Cardíaca/prevención & control , Desfibriladores Implantables , Cardioversión Eléctrica , Insuficiencia Cardíaca , Adulto , Cardiomiopatías/clasificación , Cardiomiopatías/fisiopatología , Cardiomiopatías/terapia , Muerte Súbita Cardíaca/etiología , Desfibriladores Implantables/efectos adversos , Desfibriladores Implantables/normas , Desfibriladores Implantables/estadística & datos numéricos , Cardioversión Eléctrica/instrumentación , Cardioversión Eléctrica/métodos , Cardioversión Eléctrica/mortalidad , Cardioversión Eléctrica/estadística & datos numéricos , Femenino , Francia/epidemiología , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/terapia , Hospitalización/estadística & datos numéricos , Humanos , Masculino , Pronóstico , Sistema de Registros/estadística & datos numéricos , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Insuficiencia del TratamientoRESUMEN
The vascular endothelium provides a direct interface between circulating blood cells and parenchymal cells. Thus, it has a key role in vasomotor tone regulation, primary hemostasis, vascular barrier, and immunity. In the case of systemic inflammation, endothelial cell (EC) activation initiates a powerful innate immune response to eliminate the pathogen. In some specific conditions, ECs may also contribute to the activation of adaptive immunity and the recruitment of antigen-specific lymphocytes. However, the loss of EC functions or an exaggerated activation of ECs during sepsis can lead to multiorgan failure.