IIS Fundacion Jimenez Diaz Hospital

Madrid, Spain

IIS Fundacion Jimenez Diaz Hospital

Madrid, Spain

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Aguero J.,Mount Sinai School of Medicine | Ishikawa K.,Mount Sinai School of Medicine | Hadri L.,Mount Sinai School of Medicine | Santos-Gallego C.G.,Mount Sinai School of Medicine | And 12 more authors.
Journal of the American College of Cardiology | Year: 2016

Background Pulmonary hypertension (PH) is characterized by pulmonary arterial remodeling that results in increased pulmonary vascular resistance, right ventricular (RV) failure, and premature death. Down-regulation of sarcoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) in the pulmonary vasculature leads to perturbations in calcium ion (Ca2+) homeostasis and transition of pulmonary artery smooth muscle cells to a proliferative phenotype. Objectives We assessed the feasibility of sustained pulmonary vascular SERCA2a gene expression using aerosolized delivery of adeno-associated virus type 1 (AAV1) in a large animal model of chronic PH and evaluated the efficacy of gene transfer regarding progression of pulmonary vascular and RV remodeling. Methods A model of chronic post-capillary PH was created in Yorkshire swine by partial pulmonary vein banding. Development of chronic PH was confirmed hemodynamically, and animals were randomized to intratracheal administration of aerosolized AAV1 carrying the human SERCA2a gene (n = 10, AAV1.SERCA2a group) or saline (n = 10). Therapeutic efficacy was evaluated 2 months after gene delivery. Results Transduction efficacy after intratracheal delivery of AAV1 was confirmed by β-galactosidase detection in the distal pulmonary vasculature. Treatment with aerosolized AAV1.SERCA2a prevented disease progression as evaluated by mean pulmonary artery pressure, vascular resistance, and limited vascular remodeling quantified by histology. Therapeutic efficacy was supported further by the preservation of RV ejection fraction (p = 0.014) and improvement of the RV end-diastolic pressure-volume relationship in PH pigs treated with aerosolized AAV1.SERCA2a. Conclusions Airway-based delivery of AAV vectors to the pulmonary arteries was feasible, efficient, and safe in a clinically relevant chronic PH model. Vascular SERCA2a overexpression resulted in beneficial effects on pulmonary arterial remodeling, with attendant improvements in pulmonary hemodynamics and RV performance, and might offer therapeutic benefit by modifying fundamental pathophysiology in pulmonary vascular diseases. © 2016 American College of Cardiology Foundation.


Lopez-Melgar B.,Hospital Universitario Monteprincipe | Fernandez-Friera L.,Hospital Universitario Monteprincipe | Sanchez-Gonzalez J.,Philips | Vilchez J.P.,Hospital Universitario Clinico San Carlos | And 8 more authors.
Atherosclerosis | Year: 2016

Introduction: Direct quantification of atherosclerotic plaque volume by three-dimensional vascular ultrasound (3DVUS) is more reproducible than 2DUS-based three-dimensional (2D/3D) techniques that generate pseudo-3D volumes from summed 2D plaque areas; however, its accuracy has not been reported. We aimed to determine 3DVUS accuracy for plaque volume measurement with special emphasis on small plaques (a hallmark of early atherosclerosis). Methods: The in vitro study consisted of nine phantoms of different volumes (small and medium-large) embedded at variable distances from the surface (superficial vs. >5 cm-depth) and comparison of 3DVUS data generated using a novel volumetric-linear array method with the real phantom volumes. The in vivo study was undertaken in a rabbit model of atherosclerosis in which 3DVUS and 2D/3D volume measurements were correlated against gold-standard histological measurements. Results: In the in vitro setting, there was a strong correlation between 3DVUS measures and real phantom volume both for small (3.0-64.5 mm3 size) and medium-large (91.1-965.5 mm3 size) phantoms embedded superficially, with intraclass correlation coefficients (ICC) of 0.99 and 0.98, respectively; conversely, when phantoms were placed at >5 cm, the correlation was only moderate (ICC = 0.67). In the in vivo setting there was strong correlation between 3DVUS-measured plaque volumes and the histological gold-standard (ICC = 0.99 [4.02-92.5 mm3 size]). Conversely, the correlation between 2D/3D values and the histological gold standard (sum of plaque areas) was weaker (ICC = 0.87 [49-520 mm2 size]), with large dispersion of the differences between measurements in Bland-Altman plots (mean error, 79.2 mm2). Conclusions: 3DVUS using the volumetric-linear array method accurately measures plaque volumes, including those of small plaques. Measurements are more accurate for superficial arterial territories than for deep territories. © 2016 Elsevier Ireland Ltd.


Roolvink V.,Isala Hospital | Ibanez B.,IIS Fundacion Jimenez Diaz Hospital | Ottervanger J.P.,Isala Hospital | Pizarro G.,European University at Madrid | And 35 more authors.
Journal of the American College of Cardiology | Year: 2016

Background The impact of intravenous (IV) beta-blockers before primary percutaneous coronary intervention (PPCI) on infarct size and clinical outcomes is not well established. Objectives This study sought to conduct the first double-blind, placebo-controlled international multicenter study testing the effect of early IV beta-blockers before PPCI in a general ST-segment elevation myocardial infarction (STEMI) population. Methods STEMI patients presenting <12 h from symptom onset in Killip class I to II without atrioventricular block were randomized 1:1 to IV metoprolol (2 × 5-mg bolus) or matched placebo before PPCI. Primary endpoint was myocardial infarct size as assessed by cardiac magnetic resonance imaging (CMR) at 30 days. Secondary endpoints were enzymatic infarct size and incidence of ventricular arrhythmias. Safety endpoints included symptomatic bradycardia, symptomatic hypotension, and cardiogenic shock. Results A total of 683 patients (mean age 62 ± 12 years; 75% male) were randomized to metoprolol (n = 336) or placebo (n = 346). CMR was performed in 342 patients (54.8%). Infarct size (percent of left ventricle [LV]) by CMR did not differ between the metoprolol (15.3 ± 11.0%) and placebo groups (14.9 ± 11.5%; p = 0.616). Peak and area under the creatine kinase curve did not differ between both groups. LV ejection fraction by CMR was 51.0 ± 10.9% in the metoprolol group and 51.6 ± 10.8% in the placebo group (p = 0.68). The incidence of malignant arrhythmias was 3.6% in the metoprolol group versus 6.9% in placebo (p = 0.050). The incidence of adverse events was not different between groups. Conclusions In a nonrestricted STEMI population, early intravenous metoprolol before PPCI was not associated with a reduction in infarct size. Metoprolol reduced the incidence of malignant arrhythmias in the acute phase and was not associated with an increase in adverse events. (Early-Beta blocker Administration before reperfusion primary PCI in patients with ST-elevation Myocardial Infarction [EARLY-BAMI]; EudraCT no: 2010-023394-19) © 2016 American College of Cardiology Foundation


Barbato E.,Cardiovascular Center | Barbato E.,University of Naples Federico II | Barton P.J.,Royal Brompton Hospital | Bartunek J.,Cardiovascular Center | And 6 more authors.
Journal of Cardiovascular Translational Research | Year: 2015

The goal of this paper is to provide an updated review for scientists and clinicians on the major areas in cardiovascular medicine published in the Journal. Leading topics in regenerative and personalized medicine are presented along with a critical overview of the field. New standards in large preclinical animal models of pulmonary hypertension and left bundle branch block are highlighted. Finally, clinical care in the areas of atherosclerosis, the aortic valve, platelet biology, and myocarditis is discussed as well as autonomic modulation therapies. © 2015, Springer Science+Business Media New York.


PubMed | Hospital Universitario Monteprincipe, Philips, Hospital Universitario Clinico San Carlos, Complutense University of Madrid and 4 more.
Type: | Journal: Atherosclerosis | Year: 2016

Direct quantification of atherosclerotic plaque volume by three-dimensional vascular ultrasound (3DVUS) is more reproducible than 2DUS-based three-dimensional (2D/3D) techniques that generate pseudo-3D volumes from summed 2D plaque areas; however, its accuracy has not been reported. We aimed to determine 3DVUS accuracy for plaque volume measurement with special emphasis on small plaques (a hallmark of early atherosclerosis).The invitro study consisted of nine phantoms of different volumes (small and medium-large) embedded at variable distances from the surface (superficial vs. >5cm-depth) and comparison of 3DVUS data generated using a novel volumetric-linear array method with the real phantom volumes. The invivo study was undertaken in a rabbit model of atherosclerosis in which 3DVUS and 2D/3D volume measurements were correlated against gold-standard histological measurements.In the invitro setting, there was a strong correlation between 3DVUS measures and real phantom volume both for small (3.0-64.5mm(3) size) and medium-large (91.1-965.5mm(3) size) phantoms embedded superficially, with intraclass correlation coefficients (ICC) of 0.99 and 0.98, respectively; conversely, when phantoms were placed at >5cm, the correlation was only moderate (ICC=0.67). In the invivo setting there was strong correlation between 3DVUS-measured plaque volumes and the histological gold-standard (ICC=0.99 [4.02-92.5mm(3) size]). Conversely, the correlation between 2D/3D values and the histological gold standard (sum of plaque areas) was weaker (ICC=0.87 [49-520mm(2) size]), with large dispersion of the differences between measurements in Bland-Altman plots (mean error, 79.2mm(2)).3DVUS using the volumetric-linear array method accurately measures plaque volumes, including those of small plaques. Measurements are more accurate for superficial arterial territories than for deep territories.


PubMed | Mount Sinai School of Medicine, IIS Fundacion Jimenez Diaz Hospital, Harvard University and Biovest Consulting LLC
Type: Journal Article | Journal: Journal of the American College of Cardiology | Year: 2016

Pulmonary hypertension (PH) is characterized by pulmonary arterial remodeling that results in increased pulmonary vascular resistance, right ventricular (RV) failure, and premature death. Down-regulation of sarcoplasmic reticulum Ca(2+)-ATPase 2a (SERCA2a) in the pulmonary vasculature leads to perturbations in calcium ion (Ca(2+)) homeostasis and transition of pulmonary artery smooth muscle cells to a proliferative phenotype.We assessed the feasibility of sustained pulmonary vascular SERCA2a gene expression using aerosolized delivery of adeno-associated virus type 1 (AAV1) in a large animal model of chronic PH and evaluated the efficacy of gene transfer regarding progression of pulmonary vascular and RV remodeling.A model of chronic post-capillary PH was created in Yorkshire swine by partial pulmonary vein banding. Development of chronic PH was confirmed hemodynamically, and animals were randomized to intratracheal administration of aerosolized AAV1 carrying the human SERCA2a gene (n= 10, AAV1.SERCA2a group) or saline (n= 10). Therapeutic efficacy was evaluated 2 months after gene delivery.Transduction efficacy after intratracheal delivery of AAV1 was confirmed by -galactosidase detection in the distal pulmonary vasculature. Treatment with aerosolized AAV1.SERCA2a prevented disease progression as evaluated by mean pulmonary artery pressure, vascular resistance, and limited vascular remodeling quantified by histology. Therapeutic efficacy was supported further by the preservation of RV ejection fraction (p= 0.014) and improvement of the RV end-diastolic pressure-volume relationship in PH pigs treated with aerosolized AAV1.SERCA2a.Airway-based delivery of AAV vectors to the pulmonary arteries was feasible, efficient, and safe in aclinically relevant chronic PH model. Vascular SERCA2a overexpression resulted in beneficial effects on pulmonary arterial remodeling, with attendant improvements in pulmonary hemodynamics and RV performance, and might offertherapeutic benefit by modifying fundamental pathophysiology in pulmonary vascular diseases.


Perez-Jorge C.,IIS Fundacion Jimenez Diaz Hospital | Conde A.,CSIC - National Center for Metallurgical Research | Arenas M.A.,CSIC - National Center for Metallurgical Research | Perez-Tanoira R.,IIS Fundacion Jimenez Diaz Hospital | And 4 more authors.
Journal of Biomedical Materials Research - Part A | Year: 2012

The aim of this study was to evaluate Staphylococcus sp. adhesion to modified surfaces of titanium alloy (Ti-6Al-4V). Specimens of Ti-6Al-4V alloy 6-4 ELI-grade 23 that meets the requirements of ASTM F136 2002A (AMS 2631B class A1) were anodized in a mixture of sulfuric/hydrofluoric acid at 20 V for 5 and 60 min to form nanoporous (NP) and nanotubular (NT) oxide layers with pore diameter of 20 and 100 nm, respectively. The amount of fluorine incorporated in the oxide films from the electrolyte was 6 and 4 wt %, respectively. Bacterial adherence was studied using laboratory strains and six clinical strains each of Staphylococcus aureus and Staphylococcus epidermidis. Lower adherence of laboratory strains was demonstrated on fluoride nanostructured surfaces in comparison with the fluoride-free surfaces. Significant differences between clinical strains and laboratory strains were also found (p < 0.0001, Kruskal-Wallis test) when NP and NT specimens were compared with chemically polished (CP) surfaces. The results of the tests using multiple clinical strains confirmed a decrease in bacterial adherence on F-containing titanium oxide surfaces, suggesting a potential applicability of this surface, with a confirmed added value of decreasing clinical staphylococci adherence, for medical prosthetic devices. © 2012 Wiley Periodicals, Inc.


Arenas M.A.,CSIC - National Center for Metallurgical Research | Perez-Jorge C.,IIS Fundacion Jimenez Diaz Hospital | Conde A.,CSIC - National Center for Metallurgical Research | Matykina E.,CSIC - National Center for Metallurgical Research | And 5 more authors.
Colloids and Surfaces B: Biointerfaces | Year: 2013

Ti-6Al-4V joint replacement implants foster uncemented fixation in orthopaedic surgery. However, bacterial colonization competes with host cells and ultimately may produce implant-related difficult-to-treat infections, justifying the efforts to obtain infection-resistant materials. In a previous work, the authors demonstrated the antibacterial properties of anodic fluoride-TiO2 nanostructured layers on Ti-6Al-4V alloy. In this work, the anodizing bath has been modified in order to grow fluoride-TiO2 barrier layers (FBL). A bacterial adherence protocol, run with reference and six different clinical strains of Staphylococcus aureus and Staphylococcus epidermidis, showed a statistically significant decrease in the percentage of covered surface (p<0.0001, Kruskal-Wallis test) for FBL specimens when compared with non fluoride-containing specimens, i.e. chemically polished Ti-6Al-4V and F-free TiO2 barrier layers. The results obtained on the F-barrier layers allowed discrimination between the effects of the presence of fluoride in the layer and the layer nanostructure on bacterial adhesion. © 2013 Elsevier B.V.


Peremarch C.P.-J.,IIS Fundacion Jimenez Diaz Hospital | Tanoira R.P.,IIS Fundacion Jimenez Diaz Hospital | Arenas M.A.,CSIC - National Center for Metallurgical Research | Matykina E.,CSIC - National Center for Metallurgical Research | And 4 more authors.
Journal of Physics: Conference Series | Year: 2010

The aim of this study was to evaluate Staphylococcus sp adhesion to modified surfaces of anodized titanium alloy (Ti-6Al-4V). Surface modification involved generation of fluoride-containing titanium oxide nanotube films. Specimens of Ti-6Al-4V alloy 6-4 ELI-grade 23- meets the requirements of ASTM F136 2002A (AMS 2631B class A1) were anodized in a mixture of sulphuric/hydrofluoric acid at 20 V for 5 and 60 min to form a 100 nm-thick porous film of 20 nm pore diameter and 230 nm-thick nanotube films of 100 nm in diameter. The amount of fluorine in the oxide films was of 6% and of 4%, respectively. Collection strains and six clinical strains each of Staphylococcus aureus and Staphylococcus epidermidis were studied. The adherence study was performed using a previously published protocol by Kinnari et al. The experiments were performed in triplicates. As a result, lower adherence was detected for collection strains in modified materials than in unmodified controls. Differences between clinical strains were detected for both species (p<0.0001, Kruskal-Wallis test), although global data showed similar results to that of collection strains (p<0.0001, Kruskal-Wallis test). Adherence of bacteria to modified surfaces was decreased for both species. The results also reflect a difference in the adherence between S. aureus and S. epidermidis to the modified material. As a conclusion, not only we were able to confirm the decrease of adherence in the modified surface, but also the need to test multiple clinical strains to obtain more realistic microbiological results due to intraspecies differences. © 2010 IOP Publishing Ltd.

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