Proposal for a revised definition of dilated cardiomyopathy, hypokinetic non-dilated cardiomyopathy, and its implications for clinical practice: a position statement of the ESC working group on myocardial and pericardial diseases

In this paper the Working Group on Myocardial and Pericardial Disease proposes a revised definition of dilated cardiomyopathy (DCM) in an attempt to bridge the gap between our recent understanding of the disease spectrum and its clinical presentation in relatives, which is key for early diagnosis and the institution of potential preventative measures. We also provide practical hints to identify subsets of the DCM syndrome where aetiology directed management has great clinical relevance

Current use of cardiac magnetic resonance in tertiary referral centres for the diagnosis of cardiomyopathy: the ESC EORP Cardiomyopathy/Myocarditis Registry.

ims: Cardiac magnetic resonance (CMR) is recommended in the diagnosis of cardiomyopathies, but it is time-consuming, expensive, and limited in availability in some European regions. The aim of this study was to determine the use of CMR in cardiomyopathy patients enrolled into the European Society of Cardiology (ESC) cardiomyopathy registry [part of the EURObservational Research Programme (EORP)]. Methods and results: Three thousand, two hundred, and eight consecutive adult patients (34.6% female; median age: 53.0 ± 15 years) with cardiomyopathy were studied: 1260 with dilated (DCM), 1739 with hypertrophic (HCM), 66 with restrictive (RCM), and 143 with arrhythmogenic right ventricular cardiomyopathy (ARVC). CMR scans were performed at baseline in only 29.4% of patients. CMR utilization was variable according to cardiomyopathy subtypes: from 51.1% in ARVC to 36.4% in RCM, 33.8% in HCM, and 20.6% in DCM (P < 0.001). CMR use in tertiary referral centres located in different European countries varied from 1% to 63.2%. Patients undergoing CMR were younger, less symptomatic, less frequently had implantable cardioverter-defibrillator (ICD)/pacemaker implanted, had fewer cardiovascular risk factors and comorbidities (P < 0.001). In 28.6% of patients, CMR was used along with transthoracic echocardiography (TTE); 67.6% patients underwent TTE alone, and 0.9% only CMR. Conclusion: Less than one-third of patients enrolled in the registry underwent CMR and the use varied greatly between cardiomyopathy subtypes, clinical profiles of patients, and European tertiary referral centres. This gap with current guidelines needs to be considered carefully by scientific societies to promote wider availability and use of CMR in patients with cardiomyopathies

Prospective follow-up in various subtypes of cardiomyopathies: Insights from the ESC EORP Cardiomyopathy Registry

Aims: The European Society of Cardiology (ESC) European Observational Research Programme (EORP) Cardiomyopathy Registry is a prospective multinational registry of consecutive patients with cardiomyopathies. The objective of this report is to describe the short-term outcomes of adult patients (≥18 years old). Methods and results: Out of 3208 patients recruited, follow-up data at 1 year were obtained in 2713 patients (84.6%) [1420 with hypertrophic (HCM); 1105 dilated (DCM); 128 arrhythmogenic right ventricular (ARVC); and 60 restrictive (RCM) cardiomyopathies]. Improvement of symptoms (dyspnoea, chest pain, and palpitations) was globally observed over time (P < 0.05 for each). Additional invasive procedures were performed: prophylactic implantation of implantable cardioverter-defibrillator (ICD) (5.2%), pacemaker (1.2%), heart transplant (1.1%), ablation for atrial or ventricular arrhythmia (0.5% and 0.1%). Patients with atrial fibrillation increased from 28.7% to 32.2% of the cohort. Ventricular arrhythmias (VF/ventricular tachycardias) in ICD carriers (primary prevention) at 1 year were more frequent in ARVC, then in DCM, HCM, and RCM (10.3%, 8.2%, 7.5%, and 0%, respectively). Major cardiovascular events (MACE) occurred in 29.3% of RCM, 10.5% of DCM, 5.3% of HCM, and 3.9% of ARVC (P < 0.001). MACE were more frequent in index patients compared to relatives (10.8% vs. 4.4%, P < 0.001), more frequent in East Europe centres (13.1%) and least common in South Europe (5.3%) (P < 0.001). Subtype of cardiomyopathy, geographical region, and proband were predictors of MACE on multivariable analysis. Conclusions: Despite symptomatic improvement, patients with cardiomyopathies remain prone to major clinical events in the short term. Outcomes were different not only according to cardiomyopathy subtypes but also in relatives vs. index patients, and according to European regions

Current use of cardiac magnetic resonance in tertiary referral centres for the diagnosis of cardiomyopathy: the ESC EORP Cardiomyopathy/Myocarditis Registry

AIMS: Cardiac magnetic resonance (CMR) is recommended in the diagnosis of cardiomyopathies, but it is time-consuming, expensive, and limited in availability in some European regions. The aim of this study was to determine the use of CMR in cardiomyopathy patients enrolled into the European Society of Cardiology (ESC) cardiomyopathy registry [part of the EURObservational Research Programme (EORP)]. METHODS AND RESULTS: Three thousand, two hundred, and eight consecutive adult patients (34.6% female; median age: 53.0 ± 15 years) with cardiomyopathy were studied: 1260 with dilated (DCM), 1739 with hypertrophic (HCM), 66 with restrictive (RCM), and 143 with arrhythmogenic right ventricular cardiomyopathy (ARVC). CMR scans were performed at baseline in only 29.4% of patients. CMR utilization was variable according to cardiomyopathy subtypes: from 51.1% in ARVC to 36.4% in RCM, 33.8% in HCM, and 20.6% in DCM (P < 0.001). CMR use in tertiary referral centres located in different European countries varied from 1% to 63.2%. Patients undergoing CMR were younger, less symptomatic, less frequently had implantable cardioverter-defibrillator (ICD)/pacemaker implanted, had fewer cardiovascular risk factors and comorbidities (P < 0.001). In 28.6% of patients, CMR was used along with transthoracic echocardiography (TTE); 67.6% patients underwent TTE alone, and 0.9% only CMR. CONCLUSION: Less than one-third of patients enrolled in the registry underwent CMR and the use varied greatly between cardiomyopathy subtypes, clinical profiles of patients, and European tertiary referral centres. This gap with current guidelines needs to be considered carefully by scientific societies to promote wider availability and use of CMR in patients with cardiomyopathies

Emery-Dreifuss muscular dystrophy Type 1 is associated with a high risk of malignant ventricular arrhythmias and end-stage heart failure

\ua9 2023 The Author(s). Published by Oxford University Press on behalf of the European Society of Cardiology.Background and Aims: Emery-Dreifuss muscular dystrophy (EDMD) is caused by variants in EMD (EDMD1) and LMNA (EDMD2). Cardiac conduction defects and atrial arrhythmia are common to both, but LMNA variants also cause end-stage heart failure (ESHF) and malignant ventricular arrhythmia (MVA). This study aimed to better characterize the cardiac complications of EMD variants. Methods: Consecutively referred EMD variant-carriers were retrospectively recruited from 12 international cardiomyopathy units. MVA and ESHF incidences in male and female variant-carriers were determined. Male EMD variant-carriers with a cardiac phenotype at baseline (EMDCARDIAC) were compared with consecutively recruited male LMNA variant-carriers with a cardiac phenotype at baseline (LMNACARDIAC). Results: Longitudinal follow-up data were available for 38 male and 21 female EMD variant-carriers [mean (SD) ages 33.4 (13.3) and 43.3 (16.8) years, respectively]. Nine (23.7%) males developed MVA and five (13.2%) developed ESHF during a median (inter-quartile range) follow-up of 65.0 (24.3-109.5) months. No female EMD variant-carrier had MVA or ESHF, but nine (42.8%) developed a cardiac phenotype at a median (inter-quartile range) age of 58.6 (53.2-60.4) years. Incidence rates for MVA were similar for EMDCARDIAC and LMNACARDIAC (4.8 and 6.6 per 100 person-years, respectively; log-rank P =. 49). Incidence rates for ESHF were 2.4 and 5.9 per 100 person-years for EMDCARDIAC and LMNACARDIAC, respectively (log-rank P =. 09). Conclusions: Male EMD variant-carriers have a risk of progressive heart failure and ventricular arrhythmias similar to that of male LMNA variant-carriers. Early implantable cardioverter defibrillator implantation and heart failure drug therapy should be considered in male EMD variant-carriers with cardiac disease

Protective and Enhancing HLA Alleles, HLA-DRB1*0901 and HLA-A*24, for Severe Forms of Dengue Virus Infection, Dengue Hemorrhagic Fever and Dengue Shock Syndrome

Dengue has become one of the most common viral diseases transmitted by infected mosquitoes (with any of the four dengue virus serotypes: DEN-1, -2, -3, or -4). It may present as asymptomatic or illness, ranging from mild to severe disease. Recently, the severe forms, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), have become the leading cause of death among children in Southern Vietnam. The pathogenesis of DHF/DSS, however, is not yet completely understood. The immune response, virus virulence, and host genetic background are considered to be risk factors contributing to disease severity. Human leucocyte antigens (HLA) expressed on the cell surface function as antigen presenting molecules and those polymorphism can change individuals' immune response. We investigated the HLA-A, -B (class I), and -DRB1 (class II) polymorphism in Vietnamese children with different severity (DHF/DSS) by a hospital-based case-control study. The study showed persons carrying HLA-A*2402/03/10 are about 2 times more likely to have severe dengue infection than others. On the other hand, HLA-DRB1*0901 persons are less likely to develop DSS with DEN-2 virus infection. These results clearly demonstrated that HLA controlled the susceptibility to severe forms of DV infection

A Systematic Analysis of the Clinical Outcome Associated with Multiple Reclassified Desmosomal Gene Variants in Arrhythmogenic Right Ventricular Cardiomyopathy Patients

The presence of multiple pathogenic variants in desmosomal genes (DSC2, DSG2, DSP, JUP, and PKP2) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) has been linked to a severe phenotype. However, the pathogenicity of variants is reclassified frequently, which may result in a changed clinical risk prediction. Here, we present the collection, reclassification, and clinical outcome correlation for the largest series of ARVC patients carrying multiple desmosomal pathogenic variants to date (n = 331). After reclassification, only 29% of patients remained carriers of two (likely) pathogenic variants. They reached the composite endpoint (ventricular arrhythmias, heart failure, and death) significantly earlier than patients with one or no remaining reclassified variant (hazard ratios of 1.9 and 1.8, respectively). Periodic reclassification of variants contributes to more accurate risk stratification and subsequent clinical management strategy. [Figure not available: see fulltext.]

An Induced Mutation in Tomato eIF4E Leads to Immunity to Two Potyviruses

BACKGROUND: The characterization of natural recessive resistance genes and Arabidopsis virus-resistant mutants have implicated translation initiation factors of the eIF4E and eIF4G families as susceptibility factors required for virus infection and resistance function. METHODOLOGY/PRINCIPAL FINDINGS: To investigate further the role of translation initiation factors in virus resistance we set up a TILLING platform in tomato, cloned genes encoding for translation initiation factors eIF4E and eIF4G and screened for induced mutations that lead to virus resistance. A splicing mutant of the eukaryotic translation initiation factor, S.l_eIF4E1 G1485A, was identified and characterized with respect to cap binding activity and resistance spectrum. Molecular analysis of the transcript of the mutant form showed that both the second and the third exons were miss-spliced, leading to a truncated mRNA. The resulting truncated eIF4E1 protein is also impaired in cap-binding activity. The mutant line had no growth defect, likely because of functional redundancy with others eIF4E isoforms. When infected with different potyviruses, the mutant line was immune to two strains of Potato virus Y and Pepper mottle virus and susceptible to Tobacco each virus. CONCLUSIONS/SIGNIFICANCE: Mutation analysis of translation initiation factors shows that translation initiation factors of the eIF4E family are determinants of plant susceptibility to RNA viruses and viruses have adopted strategies to use different isoforms. This work also demonstrates the effectiveness of TILLING as a reverse genetics tool to improve crop species. We have also developed a complete tool that can be used for both forward and reverse genetics in tomato, for both basic science and crop improvement. By opening it to the community, we hope to fulfill the expectations of both crop breeders and scientists who are using tomato as their model of study

Less invasive methods of advanced hemodynamic monitoring: principles, devices, and their role in the perioperative hemodynamic optimization.

The monitoring of the cardiac output (CO) and other hemodynamic parameters, traditionally performed with the thermodilution method via a pulmonary artery catheter (PAC), is now increasingly done with the aid of less invasive and much easier to use devices. When used within the context of a hemodynamic optimization protocol, they can positively influence the outcome in both surgical and non-surgical patient populations. While these monitoring tools have simplified the hemodynamic calculations, they are subject to limitations and can lead to erroneous results if not used properly. In this article we will review the commercially available minimally invasive CO monitoring devices, explore their technical characteristics and describe the limitations that should be taken into consideration when clinical decisions are made

Melanoma Spheroids Grown Under Neural Crest Cell Conditions Are Highly Plastic Migratory/Invasive Tumor Cells Endowed with Immunomodulator Function

International audienceBACKGROUND: The aggressiveness of melanoma tumors is likely to rely on their well-recognized heterogeneity and plasticity. Melanoma comprises multi-subpopulations of cancer cells some of which may possess stem cell-like properties. Although useful, the sphere-formation assay to identify stem cell-like or tumor initiating cell subpopulations in melanoma has been challenged, and it is unclear if this model can predict a functional phenotype associated with aggressive tumor cells. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed the molecular and functional phenotypes of melanoma spheroids formed in neural crest cell medium. Whether from metastatic or advanced primary tumors, spheroid cells expressed melanoma-associated markers. They displayed higher capacity to differentiate along mesenchymal lineages and enhanced expression of SOX2, NANOG, KLF4, and/or OCT4 transcription factors, but not enhanced self-renewal or tumorigenicity when compared to their adherent counterparts. Gene expression profiling attributed a neural crest cell signature to these spheroids and indicated that a migratory/invasive and immune-function modulating program could be associated with these cells. In vitro assays confirmed that spheroids display enhanced migratory/invasive capacities. In immune activation assays, spheroid cells elicited a poorer allogenic response from immune cells and inhibited mitogen-dependent T cells activation and proliferation more efficiently than their adherent counterparts. Our findings reveal a novel immune-modulator function of melanoma spheroids and suggest specific roles for spheroids in invasion and in evasion of antitumor immunity. CONCLUSION/SIGNIFICANCE: The association of a more plastic, invasive and evasive, thus a more aggressive tumor phenotype with melanoma spheroids reveals a previously unrecognized aspect of tumor cells expanded as spheroid cultures. While of limited efficiency for melanoma initiating cell identification, our melanoma spheroid model predicted aggressive phenotype and suggested that aggressiveness and heterogeneity of melanoma tumors can be supported by subpopulations other than cancer stem cells. Therefore, it could be constructive to investigate melanoma aggressiveness, relevant to patients and clinical transferability