Versican accumulation drives Nos2 induction and aortic disease in Marfan syndrome via Akt activation

Aortic aneurysm; Marfan syndrome; VersicanAneurisma aòrtic; Síndrome de Marfan; VersicanAneurisma aortico; Síndrome de Marfan; VersicanThoracic aortic aneurysm and dissection (TAAD) is a life-threatening condition associated with Marfan syndrome (MFS), a disease caused by fibrillin-1 gene mutations. While various conditions causing TAAD exhibit aortic accumulation of the proteoglycans versican (Vcan) and aggrecan (Acan), it is unclear whether these ECM proteins are involved in aortic disease. Here, we find that Vcan, but not Acan, accumulated in Fbn1C1041G/+ aortas, a mouse model of MFS. Vcan haploinsufficiency protected MFS mice against aortic dilation, and its silencing reverted aortic disease by reducing Nos2 protein expression. Our results suggest that Acan is not an essential contributor to MFS aortopathy. We further demonstrate that Vcan triggers Akt activation and that pharmacological Akt pathway inhibition rapidly regresses aortic dilation and Nos2 expression in MFS mice. Analysis of aortic tissue from MFS human patients revealed accumulation of VCAN and elevated pAKT-S473 staining. Together, these findings reveal that Vcan plays a causative role in MFS aortic disease in vivo by inducing Nos2 via Akt activation and identify Akt signaling pathway components as candidate therapeutic targets.The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation), the CBMSO is supported by Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid. CBMSO and CNIC are Severo Ochoa Centers of Excellence (grants CEX2021-001154-S and CEX2020-001041-S, respectively) funded by MICIN/AEI/10.13039/501100011033. The project leading to these results has received funding from “La Caixa” Banking Foundation under project codes HR18-00068 (to MRC and JMR); Spanish Ministerio de Ciencia e Innovación grant RTI2018-099246-B-I00 (MICIU/AEI/FEDER, UE) to JMR, and grants PID2020-115217RB-100 and PID2021-122388OB-100 to MRC and JMR, respectively, funded by MCIN/AEI/10.13039/501100011033; Instituto de Salud Carlos III (CIBER-CV CB16/11/00264 and CB16/11/00479; and grants PI17/00381 to GT-T and PI21/00084 (co-funded by Fondo Europeo de Desarrollo Regional (FEDER)) to JFN); Fundacio La Marato TV3 (20151330 to JMR); Instituto de Investigación Sanitaria Marqués de Valdecilla (IDIVAL) (INNVAL 21/24) to JFN; The Marfan Foundation USA Faculty grant 2017 MRF/1701 (to JMR); Fundación MERCK-Fundación Española de Enfermedades Raras 2022 and V-Ayudas “Muévete por los que no pueden 2021” (to JO); and Spanish Ministerio de Ciencia e Innovación contracts FPI (BES-2016-077649) to MJR-R; Sara Borrell (CD18/00028) and Juan de la Cierva (IJC2020-044581-I) to MT; Ramón y Cajal (RYC2021-033343-I) to JO; and FPU (20/04814) to IA-R

El electrocardiograma en el diagnóstico de la hipertrofia ventricular de pacientes con enfermedad renal crónica

BACKGROUND: Left ventricular hypertrophy (LVH) is an independent predictor of cardiovascular risk, and its characterization and prevalence in chronic renal disease (CRD) should be further studied. OBJECTIVE: To establish the diagnosis of LVH in patients with stage-5 CRD using six different electrocardiographic criteria, and to correlate them with left ventricular mass index (LVMI) as obtained by echocardiography. METHODS: Cross-sectional study including 100 patients (58 men and 42 women, mean age 46.2 ± 14.0 years) with CRD of all causes undergoing hemodialysis (HD) for at least six months. Electrocardiography (ECG) and echocardiography were performed in all patients, always up to one hour after the end of the HD sessions. RESULTS: LVH was detected in 83 patients (83%), of whom 56 (67.4%) had the concentric pattern and 27 (32.6%) the eccentric pattern of LVH. Diagnostic sensitivity, specificity and accuracy of all the electrocardiographic methods studied were higher than 50%. Using Pearson's linear correlation for LVMI, only the Sokolow-Lyon voltage criterion did not show a > 0.50 coefficient. Calculation of the likelihood ratio, in turn, showed that ECG has a discriminatory power for the diagnosis of LVH in the population studied, with emphasis on the Cornell-product and Romhilt-Estes criteria. No correlation was observed between LVMI and QTc and QTc dispersion. CONCLUSION: ECG is a useful, efficient, and highly reproducible method for the diagnosis of LVH in HD patients. In this population, the Cornell-product proved to be the most reliable criterion for the detection of LVH.FUNDAMENTO: La hipertrofia ventricular izquierda (HVI) es un factor predictor independiente de riesgo cardiovascular y su caracterización y prevalencia en la enfermedad renal crónica (ERC) carecen de mejor estudio. OBJETIVO: Establecer el diagnóstico de HVI en pacientes con ERC en estadio 5 por seis diferentes criterios electrocardiográficos, correlacionándolos al índice de masa del ventrículo izquierdo (IMVI) que se obtuvo mediante el ecocardiograma. MÉTODOS: Estudio transversal que incluyó a 100 pacientes (58 varones y 42 mujeres, edad de 46,2 ± 14,0 años) con ERC de todas las etiologías, desde hace al menos 6 meses en hemodiálisis (HD). Se obtuvieron electrocardiograma (ECG) y ecocardiograma de los pacientes, siempre hasta una hora tras el término de las sesiones de HD. RESULTADOS: La HVI se detectó en 83 pacientes (83%), de los que 56 (67,4%) presentaban el estándar concéntrico y 27 (32,6%) el estándar excéntrico de HVI. Todos los métodos electrocardiográficos estudiados tuvieron sensibilidad, especificidad y exactitud diagnósticas superiores al 50%. Mediante la correlación lineal de Pearson con el IMVI, solamente el criterio de Sokolow-Lyon voltaje no presentó coeficiente > 0,50. Sin embargo, el cálculo de la razón de verosimilitud evidenció que el ECG tiene poder discriminatorio para diagnóstico de HVI en la población estudiada, con énfasis para los criterios de Producto de Cornell y Romhilt-Estes. No hubo correlación entre IMVI con el QTc y su dispersión. CONCLUSIÓN: El ECG es un método útil, eficaz y de alta reproductibilidad en el diagnóstico de HVI de los pacientes en HD. En esa población, el criterio de Producto de Cornell fue más fiable para la detección de HVI.FUNDAMENTO: A hipertrofia ventricular esquerda (HVE) é um fator preditor independente de risco cardiovascular e sua caracterização e prevalência na doença renal crônica (DRC) carecem de melhor estudo. OBJETIVO: Estabelecer o diagnóstico de HVE em pacientes com DRC em estágio 5 por seis diferentes critérios eletrocardiográficos, correlacionando-os com o índice de massa do ventrículo esquerdo (IMVE) obtido pelo ecocardiograma. MÉTODOS: Estudo transversal que incluiu 100 pacientes (58 homens e 42 mulheres, idade de 46,2 ± 14,0 anos) com DRC de todas as etiologias, há pelo menos seis meses em hemodiálise (HD). Foram obtidos eletrocardiograma (ECG) e ecocardiograma dos pacientes, sempre até uma hora após o término das sessões de HD. RESULTADOS: A HVE foi detectada em 83 pacientes (83%), dos quais 56 (67,4%) apresentavam o padrão concêntrico e 27 (32,6%) o padrão excêntrico de HVE. Todos os métodos eletrocardiográficos estudados tiveram sensibilidade, especificidade e acurácia diagnósticas acima de 50%. Pela correlação linear de Pearson com o IMVE, apenas o critério de Sokolow-Lyon voltagem não apresentou coeficiente > 0,50. Já o cálculo da razão de verossimilhança mostrou que o ECG possui poder discriminatório para diagnóstico de HVE na população estudada, com ênfase para os critérios de Cornell produto e Romhilt-Estes. Não houve correlação entre IMVE com o QTc e sua dispersão. CONCLUSÃO: O ECG é um método útil, eficaz e de alta reprodutibilidade no diagnóstico de HVE dos pacientes em HD. Nessa população, o critério de Cornell produto mostrou-se o mais fidedigno para a detecção de HVE.Universidade Estadual de Ciências da Saúde de AlagoasUniversidade Federal de São Paulo (UNIFESP) Escola Paulista de MedicinaUNIFESP, EPMSciEL

Left ventricular mass and cardiothoracic index in patients with chronic renal disease on hemodialysis

Introduction:Left ventricular hypertrophy (LVH) is an independent predictor of cardiovascular risk in patients with chronic renal disease (CRD) on hemodialysis (HD). Objective:To show the usefulness of chest radiography in the diagnosis of LVH in CRD patients on HD. Methods:Cross-sectional study including 100 patients (58 men and 42 women), mean age 46.2 ± 14.0 years, with CRD of all causes, for at least six months on HD. Were obtained echocardiogram and chest x-rays of patients, always up to one hour after the end of HD sessions. Results:LVH was detected in 83 patients (83%), of whom 56 (67.4%) had the concentric pattern and 27 (32.6%) with eccentric pattern of LVH. Cardiomegaly - defined by cardiothoracic index (CTI) > 0.5 - was present in 61 patients (61%). The following were the sensitivity, specificity and accuracy, respectively, for the variable ICT: 66.2%, 70.5% and 68.0%. The Pearson correlation between ICT and index of left ventricular mass (LVMI) was 0.552 (p 0,5 - esteve presente em 61 pacientes (61%). Foram os seguintes os valores de sensibilidade, especificidade e acurácia, respectivamente, para a variável ICT: 66,2%, 70,5% e 68,0%. A correlação de Pearson entre ICT e índice de massa do ventrículo esquerdo (IMVE) foi de 0,552 (p < 0,05) e razão de verossimilhança positivo de 2,2. Conclusão:A radiografia de tórax é um exame seguro e útil como ferramenta diagnóstica de HVE em pacientes com DRC em HD.Universidade Federal de São Paulo (UNIFESP)Universidade Estadual de Ciências da Saúde de AlagoasUniversidade de São PauloUniversidade Federal de AlagoasUniversidade Federal de SergipeUNIFESPSciEL

Insights of Active Extension Within a Collisional Orogen From GNSS (Central Betic Cordillera, S Spain)

The coexistence of shortening and extensional tectonic regimes is a common feature in orogenic belts. The westernmost end of the Western Mediterranean is an area undergoing shortening related to the 5 mm/yr NNW‒SSE convergence of the Nubia and Eurasia Plates. In this region, the Central Betic Cordillera shows a regional ENE‒WSW extension. Here, we present GNSS-derived geodetic data along a 170 km-long transect orthogonal to the main active normal faults of the Central Betic Cordillera. Our data indicate that the total extension rate along the Central Betic Cordillera is 2.0 ± 0.3 mm/yr. Extension is accommodated in the eastern (0.8 ± 0.3 mm/yr in the Guadix-Baza Basin) and western (1.3 ± 0.3 mm/yr in the Granada Basin) parts of the Central Betic Cordillera, while no extension is recorded in the central part of the study area. Moreover, our data permit us to quantify, for the first time, short-term fault slip rates of the Granada Fault System, which is one of the main seismogenic sources of the Iberian Peninsula. We deduce a fault slip rate of ∼1.3 ± 0.3 mm/yr for the whole Granada Basin, with 0.9 ± 0.3 mm/yr being accommodated in the Granada Fault System and 0.4 ± 0.3 mm/yr being accommodated in the southwestern sector of the Granada Basin, where no active faults have been previously described at the surface. The heterogeneous extension in the Central Betic Cordillera could be accommodated by shallow high-angle normal faults that merge with a detachment at depth. Part of the active extension could be derived from gravitational instability because of underlying over-thickened crust.This research was funded by the Generalitat Valenciana (Valencian Regional Government, Research project AICO/2021/196), Spanish Ministry of Science, Innovation and University (Research Projects RTI2018-100737-B-I00 and PID2021-127967NB-I00), the University of Alicante (Research Project VIGROB053), the University of Jaén (POAIUJA 2021–2022, CEACTEMA and Programa Operativo FEDER Andalucía, 2014–2020—call made by UJA, 2018, Ref. 1263446), P18-RT-3275 (Junta de Andalucía/FEDER), and the Junta de Andalucía regional government (RNM282 and RNM 148 research groups). The Institut Cartogràfic Valencià, Agencia Valenciana de Seguridad y Respuesta a las Emergencias (Generalitat Valenciana), Consorcio Provincial para el Servicio de Prevención y Extinción de Incendios y Salvamento de Alicante, Excelentísimas Diputaciones Provinciales de Alicante y Castellón, and the Ayuntamiento de Almoradí also provided partial funding

Technical recommendations for clinical translation of renal MRI: a consensus project of the Cooperation in Science and Technology Action PARENCHIMA.

PURPOSE: The potential of renal MRI biomarkers has been increasingly recognised, but clinical translation requires more standardisation. The PARENCHIMA consensus project aims to develop and apply a process for generating technical recommendations on renal MRI. METHODS: A task force was formed in July 2018 focused on five methods. A draft process for attaining consensus was distributed publicly for consultation and finalised at an open meeting (Prague, October 2018). Four expert panels completed surveys between October 2018 and March 2019, discussed results and refined the surveys at a face-to-face meeting (Aarhus, March 2019) and completed a second round (May 2019). RESULTS: A seven-stage process was defined: (1) formation of expert panels; (2) definition of the context of use; (3) literature review; (4) collection and comparison of MRI protocols; (5) consensus generation by an approximate Delphi method; (6) reporting of results in vendor-neutral and vendor-specific terms; (7) ongoing review and updating. Application of the process resulted in 166 consensus statements. CONCLUSION: The process generated meaningful technical recommendations across very different MRI methods, while allowing for improvement and refinement as open issues are resolved. The results are likely to be widely supported by the renal MRI community and thereby promote more harmonisation

Analysis of baseline parameters in the HALT polycystic kidney disease trials

HALT PKD consists of two ongoing randomized trials with the largest cohort of systematically studied patients with autosomal dominant polycystic kidney disease to date. Study A will compare combined treatment with an angiotensin-converting inhibitor and receptor blocker to inhibitor alone and standard compared with low blood pressure targets in 558 early-stage disease patients with an eGFR over 60ml/min per 1.73m2. Study B will compare inhibitor-blocker treatment to the inhibitor alone in 486 late-stage patients with eGFR 25–60ml/min per 1.73m2. We used correlation and multiple regression cross-sectional analyses to determine associations of baseline parameters with total kidney, liver, or liver cyst volumes measured by MRI in Study A and eGFR in both studies. Lower eGFR and higher natural log-transformed urine albumin excretion were independently associated with a larger natural log–transformed total kidney volume adjusted for height (ln(HtTKV)). Higher body surface area was independently associated with a higher ln(HtTKV) and lower eGFR. Men had larger height-adjusted total kidney volume and smaller liver cyst volumes than women. A weak correlation was found between the ln(HtTKV) and natural log–transformed total liver volume adjusted for height or natural log liver cyst volume in women only. Women had higher urine aldosterone excretion and lower plasma potassium. Thus, our analysis (1) confirms a strong association between renal volume and functional parameters, (2) shows that gender and other factors differentially affect the development of polycystic disease in the kidney and liver, and (3) suggests an association between anthropomorphic measures reflecting prenatal and/or postnatal growth and disease severity

Consensus-based technical recommendations for clinical translation of renal ASL MRI

Objectives: To develop technical recommendations for the acquisition, processing and analysis of renal ASL data in the human kidney at 1.5T and 3T field strengths that can promote standardization of renal perfusion measurements and facilitate the comparability of results across scanners and in multi-center clinical studies.Methods: An international panel of 23 renal ASL experts followed a modified Delphi process, including on-line surveys and two in-person meetings, to formulate a series of consensus statements regarding patient preparation, hardware, acquisition protocol, analysis steps and data reporting.Results: Fifty-nine statements achieved consensus, while agreement could not be reached on two statements related to patient preparation. As a default protocol, the panel recommends pseudo-continuous (PCASL) or flow-sensitive alternating inversion recovery (FAIR) labeling with a single-slice spin-echo EPI readout with background suppression, and a simple but robust quantification model.Discussion: This approach is considered robust and reproducible and can provide renal perfusion images of adequate quality and SNR for most applications. If extended kidney coverage is desirable, a 2D multislice readout is recommended. These recommendations are based on current available evidence and expert opinion. Nonetheless they are expected to be updated as more data becomes available, since the renal ASL literature is rapidly expanding

Technical recommendations for clinical translation of renal MRI: a consensus project of the Cooperation in Science and Technology Action PARENCHIMA

Purpose The potential of renal MRI biomarkers has been increasingly recognised, but clinical translation requires more standardisation. The PARENCHIMA consensus project aims to develop and apply a process for generating technical recommendations on renal MRI. Methods A task force was formed in July 2018 focused on fve methods. A draft process for attaining consensus was distributed publicly for consultation and fnalised at an open meeting (Prague, October 2018). Four expert panels completed surveys between October 2018 and March 2019, discussed results and refned the surveys at a face-to-face meeting (Aarhus, March 2019) and completed a second round (May 2019). Results A seven-stage process was defned: (1) formation of expert panels; (2) defnition of the context of use; (3) literature review; (4) collection and comparison of MRI protocols; (5) consensus generation by an approximate Delphi method; (6) reporting of results in vendor-neutral and vendor-specifc terms; (7) ongoing review and updating. Application of the process resulted in 166 consensus statements. Conclusion The process generated meaningful technical recommendations across very diferent MRI methods, while allowing for improvement and refnement as open issues are resolved. The results are likely to be widely supported by the renal MRI community and thereby promote more harmonisation