Role of TBX20 Truncating Variants in Dilated Cardiomyopathy and Left Ventricular Noncompaction

Cardiomyopathies; Heart ventricles; Transcription factorsMiocardiopaties; Ventricles del cor; Factors de transcripcióMiocardiopatías; Ventrículos del corazón; Factores de transcripciónBACKGROUND: Less than 40% of patients with dilated cardiomyopathy (DCM) have a pathogenic/likely pathogenic genetic variant identified. TBX20 has been linked to congenital heart defects; although an association with left ventricular noncompaction (LVNC) and DCM has been proposed, it is still considered a gene with limited evidence for these phenotypes. This study sought to investigate the association between the TBX20 truncating variant (TBX20tv) and DCM/LVNC. METHODS: TBX20 was sequenced by next-generation sequencing in 7463 unrelated probands with a diagnosis of DCM or LVNC, 22 773 probands of an internal comparison group (hypertrophic cardiomyopathy, channelopathies, or aortic diseases), and 124 098 external controls (individuals from the gnomAD database). Enrichment of TBX20tv in DCM/LVNC was calculated, cosegregation was determined in selected families, and clinical characteristics and outcomes were analyzed in carriers. RESULTS: TBX20tv was enriched in DCM/LVNC (24/7463; 0.32%) compared with internal (1/22 773; 0.004%) and external comparison groups (4/124 098; 0.003%), with odds ratios of 73.23 (95% CI, 9.90–541.45; P<0.0001) and 99.76 (95% CI, 34.60–287.62; P<0.0001), respectively. TBX20tv was cosegregated with DCM/LVNC phenotype in 21 families for a combined logarythm of the odds score of 4.53 (strong linkage). Among 57 individuals with TBX20tv (49.1% men; mean age, 35.9±20.8 years), 41 (71.9%) exhibited DCM/LVNC, of whom 14 (34.1%) had also congenital heart defects. After a median follow-up of 6.9 (95% CI, 25–75:3.6–14.5) years, 9.7% of patients with DCM/LVNC had end-stage heart failure events and 4.8% experienced malignant ventricular arrhythmias. CONCLUSIONS: TBX20tv is associated with DCM/LVNC; congenital heart defect is also present in around one-third of cases. TBX20tv-associated DCM/LVNC is characterized by a nonaggressive phenotype, with a low incidence of major cardiovascular events. TBX20 should be considered a definitive gene for DCM and LVNC and routinely included in genetic testing panels for these phenotypes.This study was funded by the Instituto de Salud Carlos III (ISCIII) through the projects PI17/01941 and PI20/01379 (cofunded by the European Regional Development Fund/European Social Fund: A Way to Make Europe/Investing in Your Future). The Centro Nacional de Investigaciones Cardiovasculares (CNIC) was supported by the ISCIII, Ministerio de Ciencia, Innovación y Universidades (MCIN), the Pro-CNIC Foundation, and the Severo Ochoa Centers of Excellence program (CEX2020-001041-S). The Hospital Universitario Puerta de Hierro, Virgen de la Arrixaca, and the Vall Hebron Hospital are members of the European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart (http://guardheart.ern-net.eu)

Network-Based Characterization of Blood Large-Scale Coherent Motion in the Healthy Human Aorta With 4D Flow MRI

Aorta humana; Resonancia magnéticaHuman aorta; MRIAorta humana; Ressonància magnèticaObjective: The need for distilling the hemodynamic complexity of aortic flows into clinically relevant quantities resulted in a loss of the information hidden in 4D aortic fluid structures. To reduce information loss, this study proposes a network-based approach to identify and characterize in vivo the large-scale coherent motion of blood in the healthy human aorta. Methods: The quantitative paradigm of the aortic flow as a “social network” was applied on 4D flow MRI acquisitions performed on forty-one healthy volunteers. Correlations between the aortic blood flow rate waveform at the proximal ascending aorta (AAo), assumed as one of the drivers of aortic hemodynamics, and the waveforms of the axial velocity in the whole aorta were used to build “one-to-all” networks. The impact of the driving flow rate waveform and of aortic geometric attributes on the transport of large-scale coherent fluid structures was investigated. Results: The anatomical length of persistence of large-scale coherent motion was the 29.6% of the healthy thoracic aorta length (median value, IQR 23.1%–33.9%). Such length is significantly influenced by the average and peak-to-peak AAo blood flow rate values, suggesting a remarkable inertial effect of the AAo flow rate on the transport of large-scale fluid structures in the distal aorta. Aortic geometric attributes such as curvature, torsion and arch shape did not influence the anatomical length of persistence. Conclusion: The proposed in vivo approach allowed to quantitatively characterize the transport of large-scale fluid structures in the healthy aorta, strengthening the definition of coherent hemodynamic structures and identifying flow inertia rather than geometry as one of its main determinants. Significance: The findings on healthy aortas may be used as reference values to investigate the impact of aortic disease or implanted devices in disrupting/restoring the physiological spatiotemporal coherence of large-scale aortic flow.Spanish Ministry of Science, Innovation and Universities. Grant Number: IJC2018-037349-

4D Flow cardiovascular magnetic resonance consensus statement: 2023 update

4D Flow MRI; Hemodynamics; RecommendationsRessonància magnètica de flux 4D; Hemodinàmica; RecomanacionsResonancia magnética de flujo 4D; Hemodinámica; RecomendacionesHemodynamic assessment is an integral part of the diagnosis and management of cardiovascular disease. Four-dimensional cardiovascular magnetic resonance flow imaging (4D Flow CMR) allows comprehensive and accurate assessment of flow in a single acquisition. This consensus paper is an update from the 2015 ‘4D Flow CMR Consensus Statement’. We elaborate on 4D Flow CMR sequence options and imaging considerations. The document aims to assist centers starting out with 4D Flow CMR of the heart and great vessels with advice on acquisition parameters, post-processing workflows and integration into clinical practice. Furthermore, we define minimum quality assurance and validation standards for clinical centers. We also address the challenges faced in quality assurance and validation in the research setting. We also include a checklist for recommended publication standards, specifically for 4D Flow CMR. Finally, we discuss the current limitations and the future of 4D Flow CMR. This updated consensus paper will further facilitate widespread adoption of 4D Flow CMR in the clinical workflow across the globe and aid consistently high-quality publication standards.1R01HL149787-01A1 (S. Schnell, M. Markl), 1R21NS122511-01 (S. Schnell), 1R01CA233878-01 (J.Collins) J.Sotelo thanks to ANID–Millennium Science Initiative Program–ICN2021_004 and FONDECYT de iniciación en investigación #11200481. Dr. Oechtering receives funding from the German Research Foundation (OE 746/1-1)

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

Cardiomyopathy; Heart failure; Ventricular arrhythmiaMiocardiopatía; Insuficiencia cardiaca; Arritmia ventricularMiocardiopatia; Insuficiència cardíaca; Arrítmia ventricularBackground 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.The work reported in this publication was funded by: a British Heart Foundation Clinical Research Training Fellowship to D.E.C. (FS/CRTF/20/24022); a British Heart Foundation Clinical Research Training fellowship to A.P. (FS/18/82/34024); The Ministry of Health, Italy, project RC-2022-2773270 to E.B.; the National Institutes of Health (NIH) (R01HL69071, R01HL116906, R01HL147064, NIH/NCATS UL1 TR002535, and UL1 TR001082) to L.M.; and support from the Rose Foundation for K.M

SysGpr: System of Generation of Pseudo-realistic Synthetic Signals

[EN] Signals obtained from sensors are widely used in different scientific fields. However, the resources to obtain the data are not always available due to structural constraints, physical, economic, environmental, and data collection failures, etc. It is in this scenario that the generation of synthetic data is established. The generation of synthetic data has several benefits, such as, reducing waiting times compared to the long periods required by some sensors to obtain large volumes of samples. In addition, the generated data can be as robust as users need it to be. For this reason, this paper presents a pseudo-realistic synthetic signal generation system for use in the validation of methods and design of experiments. The proposed signal generation method makes use of statistical models and the gradient of the signal to generate new data. The developed system is open for the public, available as a web tool.[ES] Las señales obtenidas desde sensores son ampliamente utilizadas en diferentes campos científicos. Sin embargo, no siempre se dispone de los recursos necesarios para obtener dichos datos, debido a limitaciones estructurales, físicas, económicas, ambientales, fallos en la recolección de los datos, etc. Es en este escenario limitante, donde se erige la generación de datos sintéticos. La generación de datos sintéticos tiene la característica de reducir tiempos de espera frente a los largos periodos temporales que necesitan algunos sensores para obtener grandes volúmenes de muestras. Además, los datos generados pueden llegar a ser todo lo robustos que los usuarios necesiten. Por ello este trabajo presenta un sistema de generación de señales sintéticas con carácter pseudo-realista para su uso aplicado a la validación de métodos y diseño de experimentos. El método de la generación de señales propuesto, hace uso de modelos estadísticos y el comportamiento del gradiente de la señal para ir generando nuevos datos. El sistema desarrollado se encuentra disponible públicamente como herramienta web.Este trabajo ha sido parcialmente financiado mediante el proyecto DPI2013-47347-C2-2-R.León, F.; Rodríguez-Lozano, FJ.; Cubero-Fernández, A.; Palomares, JM.; Olivares., J. (2019). SysGpr: Sistema de generación de señales sintéticas pseudo-realistas. Revista Iberoamericana de Automática e Informática. 16(3):369-379. https://doi.org/10.4995/riai.2019.10025SWORD36937916

Fluid–structure interaction simulations outperform computational fluid dynamics in the description of thoracic aorta haemodynamics and in the differentiation of progressive dilation in Marfan syndrome patients

Abnormal fluid dynamics at the ascending aorta may be at the origin of aortic aneurysms. This study was aimed at comparing the performance of computational fluid dynamics (CFD) and fluid–structure interaction (FSI) simulations against four-dimensional (4D) flow magnetic resonance imaging (MRI) data; and to assess the capacity of advanced fluid dynamics markers to stratify aneurysm progression risk. Eight Marfan syndrome (MFS) patients, four with stable and four with dilating aneurysms of the proximal aorta, and four healthy controls were studied. FSI and CFD simulations were performed with MRI-derived geometry, inlet velocity field and Young's modulus. Flow displacement, jet angle and maximum velocity evaluated from FSI and CFD simulations were compared to 4D flow MRI data. A dimensionless parameter, the shear stress ratio (SSR), was evaluated from FSI and CFD simulations and assessed as potential correlate of aneurysm progression. FSI simulations successfully matched MRI data regarding descending to ascending aorta flow rates (R2 = 0.92) and pulse wave velocity (R2 = 0.99). Compared to CFD, FSI simulations showed significantly lower percentage errors in ascending and descending aorta in flow displacement (−46% ascending, −41% descending), jet angle (−28% ascending, −50% descending) and maximum velocity (−37% ascending, −34% descending) with respect to 4D flow MRI. FSI- but not CFD-derived SSR differentiated between stable and dilating MFS patients. Fluid dynamic simulations of the thoracic aorta require fluid–solid interaction to properly reproduce complex haemodynamics. FSI- but not CFD-derived SSR could help stratifying MFS patients.This study was funded by Ministerio de Economía y Competitividad (grant no. RTC-2016-5152-1), Fundació la Marató de TV3 (grant no. 20151330), FP7 People: Marie-Curie Actions (grant no. 267128), Instituto de Salud Carlos III (grant nos PI14/0106 and PI17/00381) and ‘la Caixa’ Foundation. M.V. was funded by CompBioMed2, grant agreement ID: 823712, funded under: H2020-EU.1.4.1.3; and SILICOFCM, grant agreement ID: 777204, funded under: H2020-EU.3.1.5.Peer ReviewedPostprint (published version

On-surface self-organization of a robust metal-organic cluster based on copper(i) with chloride and organosulphur ligands

Direct sublimation of a Cu4Cl4 metal-organic cluster on Cu(110) under ultra-high vacuum allows the formation of ultra-large well-organized metal-organic supramolecular wires. Our results show that the large monomers assemble with each other by π-π interactions connecting dipyrimidine units and are stabilized by the surfaceWe thank Spanish MINECO (Grants: MAT2013-46753-C2-1-P, MAT2013-47878-C2-1-R and MAT2011-26534) for financial support. JIM acknowledges a CSIC-JaeDoc fellowship, cofunded by ES

Intraventricular Conundrum in a SARS-CoV-2-Positive Patient With Elevated Biomarkers of Myocardial Injury

We present a case of acute myocarditis with left ventricular dysfunction and intracavitary thrombosis in a 55-year-old man with severe acute respiratory syndrome coronavirus 2 infection (coronavirus disease 2019) who was admitted with bilateral atypical pneumonia. The patient was treated with anticoagulation and optimal heart failure therapy and had an improvement of left ventricular function and thrombus resolution. (Level of Difficulty: Intermediate.

Competitive Asymmetries in the Use of Supplementary Food by the Endangered Iberian Lynx (Lynx pardinus)

Background: As a conservation tool, supplementary feeding programs may be directed to specific individuals or sectors of the target population whose productivity or survival is thought to be limited by food scarcity. However, the use of supplemental food by different sex and age classes has received little attention. We studied individual variation in the access of the endangered Iberian lynx (Lynx pardinus) to supplementary food. Methodology/Principal Findings: From 5349 pictures taken with automatic cameras placed in 25 feeding stations, we identified 28 individuals whose sex and age were known. All individuals known to live in areas subjected to supplementation regularly visited feeding stations. Food consumption was not proportional to expected variations in energy demand within sex and age classes. Food consumption by males was higher than by females, and increased with age, in agreement with a despotic distribution. Food consumption also increased with lynx body mass, and this pattern held for individuals sharing the same breeding territories. The access of inferior competitors increased with the number of feeding stations available within lynx territories. Conclusions/Significance: All lynx exposed to food supplementation made a regular use of extra food but individuals predicted to be competitively dominant visited stations more frequently than subordinates of the same breeding territory. Our results suggest that insufficient provision of supplementary food could restrict the access of juveniles, or even adult females, to feeding stations. Limited consumption by these target individuals may compromise the efficiency of the supplementary feeding programme at the population level, in endangered species that, as the Iberian lynx, exhibit marked sexual dimorphism in body size.Peer reviewe

High sensitivity and negative predictive value of the DETECT algorithm for an early diagnosis of pulmonary arterial hypertension in systemic sclerosis : application in a single center

Pulmonary arterial hypertension (PAH) is one of the most relevant causes of death in systemic sclerosis. The aims of this study were to analyse the recently published DETECT algorithm comparing it with European Society of Cardiology/European Respiratory Society (ESC/ERS) 2009 guidelines: as screening of PAH; (2) identifying median pulmonary arterial pressure (mPAP) ≥21 mmHg; and (3) determining any group of pulmonary hypertension (PH). Eighty-three patients fulfilling LeRoy's systemic sclerosis diagnostic criteria with at least right heart catheterization were studied retrospectively. Clinical data, serological biomarkers, echocardiographic and hemodynamic features were collected. SPSS 20.0 was used for statistical analysis. According to right heart catheterization findings, 35 patients with PAH and 28 with no PH met the standards for DETECT algorithm analysis: 27.0% of patients presented with functional class III/IV. Applying DETECT, the sensitivity was 100%, specificity 42.9%, the positive predictive value 68.6% and the negative predictive value 100%, whereas employing the ESC/ERS guidelines these were 91.4%, 85.7%, 88.9% and 89.3%, respectively. There were no missed diagnoses of PAH using DETECT compared with three patients missed (8.5%) using ESC/ERS guidelines. The DETECT algorithm also showed greater sensitivity and negative predictive value to identify patients with mPAP ≥21 mmHg or with any type of PH. The DETECT algorithm is confirmed as an excellent screening method due to its high sensitivity and negative predictive value, minimizing missed diagnosis of PAH. DETECT would be accurate either for early diagnosis of borderline mPAP or any group of PH