Browsing by MeSH term "Heart Ventricles"
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Publication BMP7-based peptide agonists of BMPR1A protect the left ventricle against pathological remodeling induced by pressure overload.(Elsevier, 2022-05) Salido-Medina, Ana B; Gil, Aritz; Expósito, Víctor; Martínez, Fernando; Redondo, Juan M; Hurlé, María A; Nistal, J Francisco; García, Raquel; Ministerio de Economía y Competitividad (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Instituto de Investigación Sanitaria Marqués de ValdecillaAortic stenosis (AS) exposes the left ventricle (LV) to pressure overload leading to detrimental LV remodeling and heart failure. In animal models of cardiac injury or hemodynamic stress, bone morphogenetic protein-7 (BMP7) protects LV against remodeling by counteracting TGF-β effects. BMP receptor 1A (BMPR1A) might mediate BMP7 antifibrotic effects. Herein we evaluated BMP7-based peptides, THR123 and THR184, agonists of BMPR1A, as cardioprotective drugs in a pressure overload model. We studied patients with AS, mice subjected to four-week transverse aortic constriction (TAC) and TAC release (de-TAC). The LV of AS patients and TAC mice featured Bmpr1a downregulation. Also, pSMAD1/5/(8)9 was reduced in TAC mice. Pre-emptive treatment of mice with THR123 and THR184, during the four-week TAC period, normalized pSMAD1/5/(8)9 levels in the LV, attenuated overexpression of remodeling-related genes (Col 1α1, β-MHC, BNP), palliated structural damage (hypertrophy and fibrosis) and alleviated LV dysfunction (systolic and diastolic). THR184 administration, starting fifteen days after TAC, halted the ongoing remodeling and partially reversed LV dysfunction. The reverse remodeling after pressure overload release was facilitated by THR184. Both peptides diminished the TGF-β1-induced hypertrophic gene program in cardiomyocytes, collagen transcriptional activation in fibroblasts, and differentiation of cardiac fibroblasts to myofibroblasts. Molecular docking suggests that both peptides bind with similar binding energies to the BMP7 binding domain at the BMPR1A. The present study results provide a preclinical proof-of-concept of potential therapeutic benefits of BMP7-based small peptides, which function as agonists of BMPR1A, against the pathological LV remodeling in the context of aortic stenosis.Publication Chronological and biological aging of the human left ventricular myocardium: Analysis of microRNAs contribution(Wiley, 2021-06-06) Ramos-Marquès, Estel; García-Mendívil, Laura; Pérez-Zabalza, María; Santander-Badules, Hazel; Srinivasan, Sabarathinam; Oliveros, Juan Carlos; Torres-Pérez, Rafael; Cebollada, Alberto; Vallejo-Gil, José María; Fresneda-Roldán, Pedro Carlos; Fañanás-Mastral, Javier; Vázquez-Sancho, Manuel; Matamala-Adell, Marta; Sorribas-Berjón, Juan Fernando; Bellido-Morales, Javier André; Mancebón-Sierra, Francisco Javier; Vaca-Núñez, Alexánder Sebastián; Ballester-Cuenca, Carlos; Jiménez-Navarro, Manuel; Villaescusa, José Manuel; Garrido-Huéscar, Elisa; Segovia-Roldán, Margarita; Oliván-Viguera, Aida; Gómez-González, Carlos; Muñiz, Gorka; Diez, Emiliano; Ordovás, Laura; Pueyo, Esther; [Ramos-Marquès,E; García-Mendívil,L; Pérez-Zabalza,M; Santander-Badules,H; Srinivasan,S; Garrido-Huéscar,E; Segovia-Roldán,M; Oliván-Viguera,A; Ordovás,L; Pueyo,E] Biomedical Signal Interpretation and Computational Simulation group (BSICoS), Aragón Institute of Engineering Research, University of Zaragoza, Zaragoza, Spain. [Ramos-Marquès,E; García-Mendívil,L; Pérez-Zabalza,M; Srinivasan,S; Garrido-Huéscar,E; Segovia-Roldán,M; Oliván-Viguera,A; Ordovás,L; Pueyo,E] BSICoS, IIS Aragón, Zaragoza, Spain. [Oliveros,JC; Torres-Pérez,R] Bioinformatics for Genomics and Proteomics, National Center of Biotechnology- Spanish National Research Council, Madrid, Spain. [Cebollada,A] Biocomputation unit, IACS, Zaragoza, Spain. [Vallejo-Gil,JM; Fresneda-Roldán,PC; Fañanás-Mastral,J; Vázquez-Sancho,M; Matamala-Adell,M; Sorribas-Berjón,JF; Bellido-Morales,JA; Mancebón-Sierra,FJ; Vaca-Núñez,AS; Ballester-Cuenca,C] Department of Cardiovascular Surgery, University Hospital Miguel Servet, Zaragoza, Spain. [Jiménez-Navarro,M] Heart Area, Hospital Clínico Universitario Virgen de la Victoria, CIBERCV, IBIMA, Universidad de Málaga, UMA, Málaga, Spain. [Villaescusa,JM] UGC Heart Area, Cardiovascular Surgery Department, Hospital Universitario Virgen de la Victoria de Málaga, Fundación Pública Andaluza para la Investigación de Málaga en Biomedicina y Salud (FIMABIS), CIBERCV Enfermedades Cardiovasculares, Instituto de Salud Carlos III, University of Málaga, Madrid, Spain. [Gómez-González,C; Muñiz,G] Department of Pathology, San Jorge Hospital, Huesca, Spain. [Diez,E] Institute of Experimental Medicine and Biology of Cuyo (IMBECU), CONICET, Mendoza, Argentina. [Ordovás,L] ARAID Foundation, Zaragoza, Spain. [Pueyo,E] Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Zaragoza, SpainAging is the main risk factor for cardiovascular diseases. In humans, cardiac aging remains poorly characterized. Most studies are based on chronological age (CA) and disregard biological age (BA), the actual physiological age (result of the aging rate on the organ structure and function), thus yielding potentially imperfect outcomes. Deciphering the molecular basis of ventricular aging, especially by BA, could lead to major progresses in cardiac research. We aim to describe the transcriptome dynamics of the aging left ventricle (LV) in humans according to both CA and BA and characterize the contribution of microRNAs, key transcriptional regulators. BA is measured using two CA-associated transcriptional markers: CDKN2A expression, a cell senescence marker, and apparent age (AppAge), a highly complex transcriptional index. Bioinformatics analysis of 132 LV samples shows that CDKN2A expression and AppAge represent transcriptomic changes better than CA. Both BA markers are biologically validated in relation to an aging phenotype associated with heart dysfunction, the amount of cardiac fibrosis. BA-based analyses uncover depleted cardiac-specific processes, among other relevant functions, that are undetected by CA. Twenty BA-related microRNAs are identified, and two of them highly heart-enriched that are present in plasma. We describe a microRNA-gene regulatory network related to cardiac processes that are partially validated in vitro and in LV samples from living donors. We prove the higher sensitivity of BA over CA to explain transcriptomic changes in the aging myocardium and report novel molecular insights into human LV biological aging. Our results can find application in future therapeutic and biomarker research.Publication Development of the ventricular myocardial trabeculae in Scyliorhinus canicula (Chondrichthyes): evolutionary implications.(2020-09-02) López-Unzu, Miguel A; Durán, Ana Carmen; Rodríguez, Cristina; Soto-Navarrete, María Teresa; Sans-Coma, Valentín; Fernández, BorjaThe development of the ventricular myocardial trabeculae occurs in three steps: emergence, trabeculation and remodeling. The whole process has been described in vertebrates with two different myocardial structural types, spongy (zebrafish) and compact (chicken and mouse). In this context, two alternative mechanisms of myocardial trabeculae emergence have been identified: (1) in chicken and mouse, the endocardial cells invade the two-layered myocardium; (2) in zebrafish, cardiomyocytes from the monolayered myocardium invaginate towards the endocardium. Currently, the process has not been studied in detail in vertebrates having a mixed type of ventricular myocardium, with an inner trabecular and an outer compact layer, which is presumptively the most primitive morphology in gnathostomes. We studied the formation of the mixed ventricular myocardium in the lesser spotted dogfish (Scyliorhinus canicula, Elasmobranchii), using light, scanning and transmission electron microscopy. Our results show that early formation of the mixed ventricular myocardium, specifically the emergence and the trabeculation steps, is driven by an endocardial invasion of the myocardium. The mechanism of trabeculation of the mixed ventricular myocardium in chondrichthyans is the one that best reproduces how this developmental process has been established from the beginning of the gnathostome radiation. The process has been apparently preserved throughout the entire group of sarcopterygians, including birds and mammals. In contrast, teleosts, at least those possessing a mostly spongy ventricular myocardium, seem to have introduced notable changes in their myocardial trabeculae development.Publication Effect of sildenafil on right ventricular performance in an experimental large-animal model of postcapillary pulmonary hypertension.(Elsevier, 2021-02) Santiago-Vacas, Evelyn; Garcia-Lunar, Ines; Solanes, Nuria; Dantas, Ana Paula; Ascaso, Maria; Jimenez-Trinidad, Francisco Rafael; Ramirez, Jose; Fernandez-Friera, Leticia; Galan-Arriola, Carlos; Sánchez, Javier; Sabate, Manel; Perez-Villa, Felix; Rigol, Montserrat; Pereda, Daniel; Ibáñez, Borja; Garcia-Alvarez, Ana; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Instituto de Salud Carlos III; Ministerio de Ciencia, Innovación y Universidades (España); Fundación ProCNIC; Centro de Investigación Biomédica CELLEX del IDIBAPS; Government of Catalonia (España)Right ventricle (RV) dysfunction is a main determinant of morbidity and mortality in postcapillary pulmonary hypertension (PH). However, currently there are not available therapies. Since reduced nitric oxide (NO) availability and cyclic guanylate monophosphate (cGMP) levels are central in this disease, therapies targeting the NO pathway might have a beneficial effect on RV performance. In this regard, sildenafil has shown contradictory results. Our objective was to evaluate the effect of sildenafil on RV performance in an experimental pig model of postcapillary PH induced by a fixed banding of the venous pulmonary confluent. Animals were evaluated by right heart catheterization and cardiac magnetic resonance before randomization and after 8 weeks on sildenafil (n = 8) or placebo (n = 8), and myocardial tissues were analyzed with histology and molecular biology. At the end of the study, animals receiving sildenafil showed better RV performance as compared with those on placebo (improvement in RV ejection fraction of 7.3% ± 5.8% versus -0.6% ± 5.0%, P= 0.021) associated with less apoptotic cells and gene expression related with reduced oxidative stress and increased anti-inflammatory activity in the myocardium. No differences were observed in pulmonary hemodynamics. In conclusion, in a translational large animal model of chronic postcapillary PH, sildenafil improved RV systolic function independently of afterload. Further research with pharmacological approaches able to manipulate the NO-cGMP axis are needed to confirm this potential cardioprotective effect.Publication Interaction between VA-ECMO and the right ventricle.(Elsevier, 2022) Puerto, Elena; Tavazzi, Guido; Gambaro, Alessia; Cirillo, Chiara; Pecoraro, Alessandro; Martín-Asenjo, Roberto; Delgado, Juan; Bueno, Hector; Price, Susanna; Fundación Alfonso Martín EscuderoThe response of the right ventricle (RV) to the hemodynamic effects of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is currently unpredictable. We hypothesized that the presence of uni- or bi-ventricular failure before implantation and the cannulation strategy may influence this interaction. We sought to assess the RV performance during VA-ECMO support and identify RV-related predictors of successful weaning. Changes in RV size and function during VA-ECMO support by echocardiography were retrospectively analyzed in 87 consecutive adult patients between February 2008 and June 2017. Predictors of successful weaning due to myocardial recovery were evaluated by multivariable logistic regression. RV echocardiographic parameters did not vary significantly during VA-ECMO support and neither after stratification by the type of cannulation or the presence of isolated or biventricular failure. Successful weaning was conditioned by the absence of RV dysfunction before implantation (OR, 14.7; 95% CI, 13.3-140.3; p = 0.025) or in the last day of support (OR, 9.5; 95% CI, 1.6-54; p = 0.011) and was favored by a total or partial recovery of RV function during the assistance (OR, 6.2; 95%CI, 1.7-22.4; p = 0.005). RV improvement was more often observed in patients with acute RV failure and longer support, while VA-ECMO configuration, additional mechanical support, or pharmacological therapy had no effect. Preservation or improvement of RV function during VA-ECMO is essential for successful weaning. RV echocardiographic performance does not change significantly during VA-ECMO support and is not influenced by cannulation type or the presence of uni- or bi-ventricular failure before implantation.Publication Notch and interacting signalling pathways in cardiac development, disease, and regeneration.(Springer, 2018-10) MacGrogan, Donal; Munch, Juliane; de la Pompa, Jose Luis; Ministerio de Ciencia, Innovación y Universidades (España); Fundación BBVA; Fundación La Marató TV3; Fundación ProCNIC; Centro de Investigación Biomedica en Red - CIBERCardiogenesis is a complex developmental process involving multiple overlapping stages of cell fate specification, proliferation, differentiation, and morphogenesis. Precise spatiotemporal coordination between the different cardiogenic processes is ensured by intercellular signalling crosstalk and tissue-tissue interactions. Notch is an intercellular signalling pathway crucial for cell fate decisions during multicellular organismal development and is aptly positioned to coordinate the complex signalling crosstalk required for progressive cell lineage restriction during cardiogenesis. In this Review, we describe the role of Notch signalling and the crosstalk with other signalling pathways during the differentiation and patterning of the different cardiac tissues and in cardiac valve and ventricular chamber development. We examine how perturbation of Notch signalling activity is linked to congenital heart diseases affecting the neonate and adult, and discuss studies that shed light on the role of Notch signalling in heart regeneration and repair after injury.Publication Nrg1 Regulates Cardiomyocyte Migration and Cell Cycle in Ventricular Development.(Lippincott Williams & Wilkins (LWW), 2023-11-10) Grego-Bessa, Joaquim; Gomez-Apinaniz, Paula; Prados, Belen; Gómez, Manuel José; MacGrogan, Donal; de la Pompa, Jose Luis; Ministerio de Ciencia e Innovación (España); Fundación BBVA; Fundación La Marató TV3; Sociedad Española de Cardiología; Comunidad de Madrid (España); Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España)BACKGROUND Cardiac ventricles provide the contractile force of the beating heart throughout life. How the primitive endocardium-layered myocardial projections called trabeculae form and mature into the adult ventricles is of great interest for biology and regenerative medicine. Trabeculation is dependent on the signaling protein Nrg1 (neuregulin-1). However, the mechanism of action of Nrg1 and its role in ventricular wall maturation are poorly understood. METHODS We investigated the functions and downstream mechanisms of Nrg1 signaling during ventricular chamber development using confocal imaging, transcriptomics, and biochemical approaches in mice with cardiac-specific inactivation or overexpression of Nrg1. RESULTS Analysis of cardiac-specific Nrg1 mutant mice showed that the transcriptional program underlying cardiomyocyte-oriented cell division and trabeculae formation depends on endocardial Nrg1 to myocardial ErbB2 (erb-b2 receptor tyrosine kinase 2) signaling and phospho-Erk (phosphorylated extracellular signal-regulated kinase; pErk) activation. Early endothelial loss of Nrg1 and reduced pErk activation diminished cardiomyocyte Pard3 and Crumbs2 (Crumbs Cell Polarity Complex Component 2) protein and altered cytoskeletal gene expression and organization. These alterations are associated with abnormal gene expression related to mitotic spindle organization and a shift in cardiomyocyte division orientation. Nrg1 is crucial for trabecular growth and ventricular wall thickening by regulating an epithelial-to-mesenchymal transition-like process in cardiomyocytes involving migration, adhesion, cytoskeletal actin turnover, and timely progression through the cell cycle G2/M phase. Ectopic cardiac Nrg1 overexpression and high pErk signaling caused S-phase arrest, sustained high epithelial-to-mesenchymal transition-like gene expression, and prolonged trabeculation, blocking compact myocardium maturation. Myocardial trabecular patterning alterations resulting from above- or below-normal Nrg1-dependent pErk activation were concomitant with sarcomere actin cytoskeleton disorganization. The Nrg1 loss- and gain-of-function transcriptomes were enriched for Yap1 (yes-associated protein-1) gene signatures, identifying Yap1 as a potential downstream effector. Furthermore, biochemical and imaging data reveal that Nrg1 influences pErk activation and Yap1 nuclear-cytoplasmic distribution during trabeculation. CONCLUSIONS These data establish the Nrg1-ErbB2/ErbB4-Erk axis as a crucial regulator of cardiomyocyte cell cycle progression and migration during ventricular development.Publication Origin of congenital coronary arterio-ventricular fistulae from anomalous epicardial and myocardial development.(Springer, 2023-01) Palmquist-Gomes, P; Ruiz-Villalba, A; Guadix, J A; Romero, J P; Bessiéres, B; MacGrogan, D; Conejo, L; Ortiz, A; Picazo, B; Houyel, L; Gómez-Cabrero, D; Meilhac, S M; de la Pompa, J L; Pérez-Pomares, J MCoronary Artery Fistulae (CAFs) are cardiac congenital anomalies consisting of an abnormal communication of a coronary artery with either a cardiac chamber or another cardiac vessel. In humans, these congenital anomalies can lead to complications such as myocardial hypertrophy, endocarditis, heart dilatation, and failure. Unfortunately, despite their clinical relevance, the aetiology of CAFs remains unknown. In this work, we have used two different species (mouse and avian embryos) to experimentally model CAFs morphogenesis. Both conditional Itga4 (alpha 4 integrin) epicardial deletion in mice and cryocauterisation of chick embryonic hearts disrupted epicardial development and ventricular wall growth, two essential events in coronary embryogenesis. Our results suggest that myocardial discontinuities in the embryonic ventricular wall promote the early contact of the endocardium with epicardial-derived coronary progenitors at the cardiac surface, leading to ventricular endocardial extrusion, precocious differentiation of coronary smooth muscle cells, and the formation of pouch-like aberrant coronary-like structures in direct connection with the ventricular lumen. The structure of these CAF-like anomalies was compared with histopathological data from a human CAF. Our results provide relevant information for the early diagnosis of these congenital anomalies and the molecular mechanisms that regulate their embryogenesis.Publication Ventricular anatomical complexity and sex differences impact predictions from electrophysiological computational models.(Public Library of Science (PLOS), 2023) Gonzalez-Martin, Pablo; Sacco, Federica; Butakoff, Constantine; Doste, Ruben; Bederian, Carlos; Gutierrez Espinosa de Los Monteros, Lilian K; Houzeaux, Guillaume; Iaizzo, Paul A; Iles, Tinen L; Vazquez, Mariano; Aguado-Sierra, Jazmin; Unión Europea. Comisión Europea. H2020; Ministerio de Ciencia e Innovación (España)The aim of this work was to analyze the influence of sex hormones and anatomical details (trabeculations and false tendons) on the electrophysiology of healthy human hearts. Additionally, sex- and anatomy-dependent effects of ventricular tachycardia (VT) inducibility are presented. To this end, four anatomically normal, human, biventricular geometries (two male, two female), with identifiable trabeculations, were obtained from high-resolution, ex-vivo MRI and represented by detailed and smoothed geometrical models (with and without the trabeculations). Additionally one model was augmented by a scar. The electrophysiology finite element model (FEM) simulations were carried out, using O'Hara-Rudy human myocyte model with sex phenotypes of Yang and Clancy. A systematic comparison between detailed vs smooth anatomies, male vs female normal hearts was carried out. The heart with a myocardial infarction was subjected to a programmed stimulus protocol to identify the effects of sex and anatomical detail on ventricular tachycardia inducibility. All female hearts presented QT-interval prolongation however the prolongation interval in comparison to the male phenotypes was anatomy-dependent and was not correlated to the size of the heart. Detailed geometries showed QRS fractionation and increased T-wave magnitude in comparison to the corresponding smoothed geometries. A variety of sustained VTs were obtained in the detailed and smoothed male geometries at different pacing locations, which provide evidence of the geometry-dependent differences regarding the prediction of the locations of reentry channels. In the female phenotype, sustained VTs were induced in both detailed and smooth geometries with RV apex pacing, however no consistent reentry channels were identified. Anatomical and physiological cardiac features play an important role defining risk in cardiac disease. These are often excluded from cardiac electrophysiology simulations. The assumption that the cardiac endocardium is smooth may produce inaccurate predictions towards the location of reentry channels in in-silico tachycardia inducibility studies.