Nuestros investigadores

Juan José Gavira Gómez

Publicaciones científicas más recientes (desde 2010)

Autores: Moreno, MU; Gavira, Juan José; et al.
ISSN 0025-7125  Vol. 101  Nº 1  2017  págs. 43-52
The chronic hemodynamic load imposed by hypertension on the left ventricle leads to lesions in the myocardium that result in structural remodeling, which provides support for alterations in cardiac function, perfusion, and electrical activity that adversely influence the clinical evolution of hypertensive heart disease. Management must include detecting, reducing, and reversing left ventricular hypertrophy, as well as the detection and repair of microscopic lesions responsible for myocardial remodeling. Reducing the burden associated with hypertensive heart disease can be targeted using personalized treatment. The noninvasive, biomarker-mediated identification of subsets of patients with hypertensive heart disease is essential to provide personalized treatment.
Autores: Pose, A.; Almenar, L.; Manzano, L.; et al.
ISSN 0014-2565  Vol. 217  Nº 7  2017  págs. 398 - 404
Heart failure (HF) is currently one of the most significant healthcare problems in Spain and has a continuously increasing prevalence. Advances in our understanding of the various biological responses that promote cardiac remodelling and pulmonary venous congestion constitute the basis of current treatment. This article, prepared by members of the HF groups of the Spanish Society of Cardiology and the Spanish Society of Internal Medicine, discusses the current therapeutic strategies for patients with congestion refractory to diuretic treatment. The article includes our clinical experience with the use of tolvaptan as an additional treatment for congestion associated with hyponatraemia. To this end, we propose an algorithm for the use of tolvaptan in patients with congestive HF, natraemia < 130 mEq/l and poor response to conventional diuretic treatment. (C) 2017 Elsevier Espana, S.L.U. and Sociedad Espanola de Medicina Interna (SEMI). All rights reserved.
Autores: Collantes M; Pelacho, Beatriz; Garcia-Velloso, Maria Jose; et al.
ISSN 1479-5876  Vol. 15  Nº 1  2017  págs. 56
PET/CT imaging of 18F-FDG-labeled CSC allows quantifying biodistribution and acute retention of implanted cells in a clinically relevant pig model of chronic myocardial infarction. Similar levels of acute retention are achieved when cells are IM or IC administered. However, acute cell retention does not correlate with cell engraftment, which is improved by IM injection.
Autores: González, A; Pueyo, Jesús Ciro; et al.
ISSN 1388-9842  Vol. 19  Nº Supl. 1  2017  págs. 123
Autores: Garbayo, Elisa; Gavira, Juan José; et al.
ISSN 2045-2322  Vol. 6  2016  págs. 25932
Cardiovascular protein therapeutics such as neuregulin (NRG1) and acidic-fibroblast growth factor (FGF1) requires new formulation strategies that allow for sustained bioavailability of the drug in the infarcted myocardium. However, there is no FDA-approved injectable protein delivery platform due to translational concerns about biomaterial administration through cardiac catheters. We therefore sought to evaluate the efficacy of percutaneous intramyocardial injection of poly(lactic-co-glycolic acid) microparticles (MPs) loaded with NRG1 and FGF1 using the NOGA MYOSTAR injection catheter in a porcine model of ischemia-reperfusion. NRG1- and FGF1-loaded MPs were prepared using a multiple emulsion solvent-evaporation technique. Infarcted pigs were treated one week after ischemia-reperfusion with MPs containing NRG1, FGF1 or non-loaded MPs delivered via clinically-translatable percutaneous transendocardial-injection. Three months post-treatment, echocardiography indicated a significant improvement in systolic and diastolic cardiac function. Moreover, improvement in bipolar voltage and decrease in transmural infarct progression was demonstrated by electromechanical NOGA-mapping. Functional benefit was associated with an increase in myocardial vascularization and remodeling. These findings in a large animal model of ischemia-reperfusion demonstrate the feasibility and efficacy of using MPs as a delivery system for growth factors and provide strong evidence to move forward with clinical studies using therapeutic proteins combined with catheter-compatible biomaterials.
Autores: Calvo, N; Salterain, Nahikari; H; et al.
ISSN 1099-5129  Vol. 10  2015  págs. 1533-40
The combination of CA and percutaneous LAAC in a single procedure is technically feasible in patients with symptomatic drug-refractory AF, high risk of stroke, and contraindications to OACs, although it is associated with a significant risk of major complications
Autores: Baumgartner, S.; et al.
ISSN 1547-3287  Vol. 24  Nº 4  2015  págs. 484 - 496
Stem cell-derived cardiomyocytes (CMs) are often electrophysiologically immature and heterogeneous, which represents a major barrier to their in vitro and in vivo application. Therefore, the purpose of this study was to examine whether Neuregulin-1 beta (NRG-1 beta) treatment could enhance in vitro generation of mature "working-type" CMs from induced pluripotent stem (iPS) cells and assess the regenerative effects of these CMs on cardiac tissue after acute myocardial infarction (AMI). With that purpose, adult mouse fibroblast-derived iPS from alpha-MHC-GFP mice were derived and differentiated into CMs through NRG-1 beta and/or dimethyl sulfoxide (DMSO) treatment. Cardiac specification and maturation of the iPS was analyzed by gene expression array, quantitative real-time polymerase chain reaction, immunofluorescence, electron microscopy, and patch-clamp techniques. In vivo, the iPS-derived CMs or culture medium control were injected into the peri-infarct region of hearts after coronary artery ligation, and functional and histology changes were assessed from 1 to 8 weeks post-transplantation. On differentiation, the iPS displayed early and robust in vitro cardiogenesis, expressing cardiac-specific genes and proteins. More importantly, electrophysiological studies demonstrated that a more mature ventricular-like cardiac phenotype was achieved when cells were treated with NRG-1 beta and DMSO compared with DMSO alone. Furthermore, in vivo studies demonstrated that iPS-derived CMs were able to engraft and electromechanically couple to heart tissue, ultimately preserving cardiac function and inducing adequate heart tissue remodeling. In conclusion, we have demonstrated that combined treatment with NRG-1 beta and DMSO leads to efficient differentiation of iPS into ventricular-like cardiac cells with a higher degree of maturation, which are capable of preserving cardiac function and tissue viability when transplanted into a mouse model of AMI.
Autores: L; et al.
ISSN 1941-6911  Vol. 6  2014  págs. 32 - 36
Autores: Pelacho, Beatriz; Garbayo, Elisa; et al.
ISSN 0168-3659  Vol. 173  2014  págs. 132 - 139
Acidic fibroblast growth factor (FGF1) and neuregulin-1 (NRG1) are growth factors involved in cardiac development and regeneration. Microparticles (MPs) mediate cytokine sustained release, and can be utilized to overcome issues related to the limited therapeutic protein stability during systemic administration. We sought to examine whether the administration of microparticles (MPs) containing FGF1 and NRG1 could promote cardiac regeneration in a myocardial infarction (MI) rat model. We investigated the possible underlying mechanisms contributing to the beneficial effects of this therapy, especially those linked to endogenous regeneration. FGF1- and NRG1-loaded MPs were prepared using a multiple emulsion solvent evaporation technique. Seventy-three female Sprague-Dawley rats underwent permanent left anterior descending coronary artery occlusion, and MPs were intramyocardially injected in the peri-infarcted zone four days later. Cardiac function, heart tissue remodeling, revascularization, apoptosis, cardiomyocyte proliferation, and stem cell homing were evaluated one week and three months after treatment. MPs were shown to efficiently encapsulate FGF1 and NRG1, releasing the bioactive proteins in a sustained manner. Three months after treatment, a statistically significant improvement in cardiac function was detected in rats treated with growth factor-loaded MPs (FGF1, NRG1, or FGF1/NRG1). The therapy led to inhibition of cardiac remodeling with smaller infarct size, a lower fibrosis degree and induction of tissue revascularization. Cardiomyocyte proliferation and progenitor cell recruitment were detected. Our data support the therapeutic benefit ofNRG1 and FGF1 when combined with protein delivery systems for cardiac regeneration. This approach could be scaled up for use in pre-clinical and clinical studies. (C) 2013 Elsevier B.V. All rights reserved.
Autores: Araña, M; Gavira, Juan José; Pena, E. ; et al.
ISSN 0142-9612  Vol. 35  Nº 1  2014  págs. 143 - 151
Although transplantation of adipose-derived stem cells (ADSC) in chronic myocardial infarction (MI) models is associated with functional improvement, its therapeutic value is limited due to poor long-term cell engraftment and survival. Thus, the objective of this study was to examine whether transplantation of collagen patches seeded with ADSC could enhance cell engraftment and improve cardiac function in models of chronic MI. With that purpose, chronically infarcted Sprague-Dawley rats (n = 58) were divided into four groups and transplanted with media, collagen scaffold (CS), rat ADSC, or CS seeded with rat ADSC (CS-rADSC). Cell engraftment, histological changes, and cardiac function were assessed 4 months after transplantation. In addition, Gottingen minipigs (n = 18) were subjected to MI and then transplanted 2 months later with CS or CS seeded with autologous minipig ADSC (CS-pADSC). Functional and histological assessments were performed 3 months post-transplantation. Transplantation of CS-rADSC was associated with increased cell engraftment, significant improvement in cardiac function, myocardial remodeling, and revascularization. Moreover, transplantation of CS-pADSC in the pre-clinical swine model improved cardiac function and was associated with decreased fibrosis and increased vasculogenesis. In summary, transplantation of CS-ADSC resulted in enhanced cell engraftment and was associated with a significant improvement in cardiac function and myocardial remodeling. (C) 2013 Elsevier Ltd. All rights reserved.
Autores: Kaeppel, C.; et al.
ISSN 1043-0342  Vol. 24  Nº 12  2013  págs. 1007 - 1017
Acute intermittent porphyria (AIP) results from haplo-insufficient activity of porphobilinogen deaminase (PBGD) and is characterized clinically by life-threatening, acute neurovisceral attacks. To date, liver transplantation is the only curative option for AIP. The aim of the present preclinical nonhuman primate study was to determine the safety and transduction efficacy of an adeno-associated viral vector encoding PBGD (recombinant AAV serotype 5-codon-optimized human porphobilinogen deaminase, rAAV5-cohPBGD) administered intravenously as part of a safety program to start a clinical study in patients with AIP. Macaques injected with either 1 × 10(13) or 5 × 10(13) vector genomes/kg of clinical-grade rAAV5-cohPBGD were monitored by standardized clinical parameters, and vector shedding was analyzed. Liver transduction efficacy, biodistribution, vector integration, and histopathology at day 30 postvector administration were determined. There was no evidence of acute toxicity, and no adverse effects were observed. The vector achieved efficient and homogenous hepatocellular transduction, reaching transgenic PBGD expression levels equivalent to 50% of the naturally expressed PBGD mRNA. No cellular immune response was detected against the human PBGD or AAV capsid proteins. Integration site analysis in transduced liver cells revealed an almost random integration pattern supporting the good safety profile of rAAV5-cohPBGD. Together, data obtained in nonhuman primates indicate that rAAV5-cohPBGD represents a safe therapy to correct the metabolic defect present in AIP patients.
Autores: Alegre, Félix; Herrero, José Ignacio; Iñarrairaegui, Mercedes; et al.
ISSN 1784-3227  Vol. 76  Nº 2  2013  págs. 246-50
Patients with heart failure have increased liver stiffness, that appears to be related with the severity of heart failure
Autores: Araña, M; Pena, E.; Abizanda, Gloria María; et al.
ISSN 1742-7061  Vol. 9  Nº 4  2013  págs. 6075 - 6083
The use of scaffolds composed of natural biodegradable matrices represents an attractive strategy to circumvent the lack of cell engraftment, a major limitation of stem cell therapy in cardiovascular diseases. Bovine-derived non-porous collagen scaffolds with different degrees of cross-linking (C0, C2, C5 and C10) were produced and tested for their mechanical behavior, in vitro biocompatibility with adipose-derived stem cells (ADSCs) and tissue adhesion and inflammatory reaction. Uniaxial tensile tests revealed an anisotropic behavior of collagen scaffolds (2 x 0.5 cm) and statistically significant differences in the mechanical behavior between cross-linked and non-cross-linked scaffolds (n = 5). In vitro, ADSCs adhered homogenously and showed a similar degree of proliferation on all four types of scaffolds (cells x 10(3) cm(-2) at day 7: C0: 94.7 +/- 37.1; C2: 91.7 +/- 25.6; C5: 88.2 +/- 6.8; C10: 72.8 +/- 10.7; P = n.s.; n = 3). In order to test the in vivo biocompatibility, a chronic myocardial infarction model was performed in rats and 1.2 x 1.2 cm size collagen scaffolds implanted onto the heart I month post-infarction. Six animals per group were killed 2, 7 and 30 days after transplant. Complete and long-lasting adhesion to the heart was only observed with the non-cross-linked scaffolds with almost total degradation 1 month post-transplantation. After 7 and 30 days post-implantation, the degree of inflammation was significantly lower in the hearts treated with non-cross-linked scaffolds (day 7: C0: 10.2 +/- 2.1%; C2: 163 +/- 2.9%; C5: 15.9 +/- 4.8%; C10: 17.4 +/- 4.1%; P < 0.05 vs. C0; day 30: C0: 1.3 +/- 1.3%; C2: 9.4 +/- 3.0%; C5: 7.0 +/- 2.1%; C10: 9.8 +/- 2.5%; P < 0.01 vs. C0). In view of the results, the non-cross-linked scaffold (C0) was chosen as an ADSC-carrier sheet and tested in vivo. One week post-implantation, 25.3 +/- 7.0% of the cells transplanted were detected in those animals receiving the cell-carrier sheet whereas no cells were found in animals receiving cells alone (n = 3 animals/group). We conclude that the biocompatibility and mechanical properties of the non-cross-linked collagen scaffolds make them a useful cell carrier that greatly favors tissue cell engraftment and may be exploited for cell transplantation in models of cardiac disease. (C) 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
Autores: Salterain, Nahikari; Esteban-Fernández, Alberto; et al.
ISSN 0300-8932  Vol. 66  Nº 6  2013  págs. 503-4
nuestros resultados demuestran efectos similares en pacientes con y sin disfunción ventricular, hecho importante teniendo en cuenta que la prevalencia de hiponatremia es similar en ambos grupos. Por lo tanto, la administración de tolvaptán a pacientes no seleccionados con IC descompensada e hiponatremia refractaria sintomática aumenta significativamente las cifras de sodio y el ritmo de diuresis sin afectar significativamente a la función renal
Autores: Pascual, Juan Ignacio; et al.
ISSN 0890-5096  Vol. 27  Nº 7  2013  págs. 974.e1 - 974.e6
In the last 20 years, endovascular procedures have radically altered the treatment of diseases of the aorta. The objective of endovascular treatment of dissections is to close the entry point to redirect blood flow toward the true lumen, thereby achieving thrombosis of the false lumen. In extensive chronic dissections that have evolved with the formation of a large aneurysm, the dissection is maintained from the end of the endoprosthesis due to multiple orifices, or reentries, that communicate with the lumens. In addition, one of the primary limitations of this technique is when the visceral arteries have disease involvement. In this report we present a case where, despite having treated the entire length of the descending thoracic aorta, the dissection was maintained distally, leading to progression of the diameter of the aneurysm. After reviewing the literature, and to the best of our knowledge, we describe the first case in which renal autotransplant was performed to allow for subsequent exclusion of the aorta at the thoracoabdominal level using a fenestrated endoprosthesis for the celiac trunk and the superior mesenteric artery.
Autores: Mazo, Manuel María; Gavira, Juan José; Abizanda, Gloria María; et al.
ISSN 0963-6897  Vol. 21  Nº 12  2012  págs. 2723 - 2733
The aim of the study was to determine the long-term effect of transplantation of adipose-derived stromal cells (ADSCs) in a preclinical model of ischemia/reperfusion (I/R). I/R was induced in 28 Goettingen minipigs by 120 min of coronary artery occlusion followed by reperfusion. Nine days later, surviving animals were allocated to receive transendocardial injection of a mean of 213.6 ± 41.78 million green fluorescent protein (GFP)-expressing ADSCs (n = 7) or culture medium as control (n = 9). Heart function, cell engraftment, and histological analysis were performed 3 months after transplantation. Transplantation of ADSCs induced a statistically significant long-lasting (3 months) improvement in cardiac function and geometry in comparison with control animals. Functional improvement was associated with an increase in angiogenesis and vasculogenesis and a positive effect on heart remodeling with a decrease in fibrosis and cardiac hypertrophy in animals treated with ADSCs. Despite the lack of cell engraftment after 3 months, ADSC transplantation induced changes in the ratio between MMP/TIMP. Our results indicate that transplantation of ADSCs, despite the lack of long-term significant cell engraftment, increases vessel density and prevents adverse remodeling in a clinically relevant model of myocardial infarction, strongly suggesting a paracrine-mediated effect. ADSCs thus constitute an attractive candidate for the treatment of myocardial infarction.
Autores: Cerveró, Jorge; Gavira, Juan José; et al.
ISSN 0340-6245  Vol. 108  Nº 4  2012  págs. 742-749
The leading cause of cardioembolic stroke is atrial fibrillation (AF), which predisposes to atrial thrombus formation. Although rheological alterations promote a hypercoagulable environment, as yet undefined factors contribute to thrombogenesis. The role of the endocardium has barely been explored. To approach this topic, rapid atrial pacing (RAP) was applied in four pigs to mimic AF. Left and right endocardial cells were isolated separately and their gene expression pattern was compared with that of four control pigs. The AF-characteristic rhythm disorders and endothelial nitric oxide synthase down-regulation were successfully reproduced, and validated RAP to mimic AF. A change was observed in the transcriptonnic endocardial profile after RAP: the expression of 364 genes was significantly altered (p < 0.01), 29 of them having passed the B > 0 criteria. The left atrial endocardium [325 genes (7 genes, B > 0)] was largely responsible for such alterations. Blood coagulation, blood vessel morphogenesis and inflammatory response are among the most significant altered functions, and help to explain the activation of coagulation observed after RAP: D-dimer, 0.49 (1.63) vs. 0.23 (0.24) mg/l [median (interquartile range)] in controls, p=0.02. Furthermore, three genes directly related to thrombotic processes were differentially expressed after RAP: FGL2 [fold change (FC)=0.85; p=0.007], APLP2 (FC=-0.47; p=0.005) and ADAMTS-18 (FC=-0.69; p=0.004). We demonstrate for the first time that AF induces a global expression change in the left atrial endocardium associated with an activation of blood coagulation. The nature of some of the altered functions and genes provides clues to identify new therapeutic targets.
Autores: Garcia-Bolao, I; Calvo, N; Gavira, Juan José; et al.
ISSN 1405-9940  Vol. 82  Nº 3  2012  págs. 235-242
The present document reviews various aspects of the current status of cardiac resynchronization therapy: mechanisms of action, current indications and implantation technique.
Autores:  et al.
ISSN 0003-4975  Vol. 93  Nº 2  2012  págs. e23-e25
Percutaneous procedures and endovascular prostheses are becoming increasingly frequent, replacing classic interventions, and new complications are now appearing. We report the case of a liver transplant patient with a stenosis in the anastomosis of the suprahepatic veins to inferior vena cava, treated by self-expanding prosthesis, who developed an aorto-right atrial fistula and an atrial septal defect. Open heart surgery was performed to correct the defects. Transthoracic echocardiogram 1 year later revealed no evidence of residual shunt.
Autores: Mazo, Manuel María; Gavira, Juan José; et al.
ISSN 0963-6897  Vol. 21  Nº 5  2012  págs. 1023 - 1037
Fresh adipose-derived cells have been shown to be effective in the treatment of acute myocardial infarction (MI), but their role in the chronic setting is unknown. We sought to determine the long-term effect of the adipose derived-stromal vascular fraction (SVF) cell transplantation in a rat model of chronic MI. MI was induced in 82 rats by permanent coronary artery ligation and 5 weeks later rats were allocated to receive an intramyocardial injection of 10(7) GFP-expressing fresh SVF cells or culture media as control. Heart function and tissue metabolism were determined by echocardiography and F-18-FDG-microPET, respectively, and histological studies were performed for up to 3 months after transplantation. SVF induced a statistically significant long-lasting (3 months) improvement in cardiac function and tissue metabolism that was associated with increased revascularization and positive heart remodeling, with a significantly smaller infarct size, thicker infarct wall, lower scar fibrosis, and lower cardiac hypertrophy. Importantly, injected cells engrafted and were detected in the treated hearts for at least 3 months, directly contributing to the vasculature and myofibroblasts and at negligible levels to cardiomyocytes. Furthermore, SVF release of angiogenic (VEGF and HGF) and proinflammatory (MCP-1) cytokines, as well as TIMP1 and TIMP4, was demonstrated in vitro and in vivo, strongly suggesting that they have a trophic effect. These results show the potential of SVF to contribute to the regeneration of ischemic tissue and to provide a long-term functional benefit in a rat model of chronic MI, by both direct and indirect mechanisms.
Autores: Garcia-Bolao, I; et al.
ISSN 0210-5691  Vol. 36  Nº 5  2012  págs. 377-9
Se trata por tanto de un caso particular debido a dos razones. La primera es la presentación temprana de una TA proveniente del donante que debuta con signos de IC. En el TC ortotópico con técnica bicava se conserva la aurícula derecha y se efectúa anastomosis de cada vena cava por separado. Por lo tanto, aunque esta técnica conlleva menores tasas de arritmias auriculares y menor necesidad de marcapasos6,7 que con la técnica clásica, en este caso concreto facilitó la preservación del foco responsable de la TA. En segundo lugar, el caso presenta como novedad la estrategia terapéutica escogida. Debido a la repercusión hemodinámica el arsenal terapéutico disponible para revertir las TSV presenta ciertos riesgos y las maniobras vagales no tienen utilidad en esta población particular. Por ende, la adenosina, en pacientes con taquicardias de QRS ancho, no está exenta de riesgos en caso de que se trate de una taquicardia ventricular. En este caso la simple sobreestimulación auricular con un catéter en la aurícula derecha yuguló la crisis de TA. Además el EEF proporcionó el diagnóstico certero a la par que la posibilidad de ablación del sustrato responsable
Autores: Mazo, Manuel María; Gavira, Juan José; Pelacho, Beatriz; et al.
ISSN 1937-5387  Vol. 4  Nº 2  2011  págs. 145 - 153
In recent years, stem cell treatment of myocardial infarction has elicited great enthusiasm upon scientists and physicians alike, thus making the finding of a suitable cell a compulsory subject for modern medicine. Due to its potential, accessibility and efficiency of harvesting, adipose tissue has become one of the most attractive sources of stem cells for regenerative therapies. The differentiation capacity and the paracrine activity of these cells has made them an optimal candidate for the treatment of a diverse range of diseases from immunological disorders as graft versus host disease to cardiovascular pathologies like peripheral ischemia. In this review, we will focus on the use of stem cells derived from adipose tissue for treatment of myocardial infarction, with special attention to their putative in vivo mechanisms of action.
Autores: Bastarrika, Gorka; Gavira, Juan José;
ISSN 1569-9293  Vol. 12  Nº 3  2011  págs. 490 - 491
We report a case of an unusual congenital triad consisting of absence of coronary sinus, persistent left superior vena cava and scimitar syndrome incidentally found in a CT-scan performed on a female complaining of exertional dyspnea
Autores: Pelacho, Beatriz; Mazo, Manuel María; Gavira, Juan José; et al.
ISSN 1937-5387  Vol. 4  Nº 2  2011  págs. 154 - 160
Cardiovascular diseases constitute the first cause of mortality and morbidity worldwide. Alternative treatments like transplantation of (stem) cell populations derived from several adult tissue sources, like the bone marrow, skeletal muscle, or even adipose tissue, have been already employed in diverse clinical trials. Results from these studies and previous animal studies have reached to the conclusion that stem cells induce a benefit in the treated hearts, which is exerted mainly through paracrine mechanisms and not through direct differentiation as it was initially expected. However, a strong technical limitation for the stem cell therapy, which is the low level of cell survival and engraftment, diminishes their potential. Thus, new strategies like combination of the cells with bioengineering techniques have been developed and are being subject of intense research, suggesting that new strategies may improve the efficacy of these therapies. In this review, we will discuss the different therapeutic approaches, drawbacks, and future expectations of new regenerative therapies for cardiovascular diseases.
Autores: Gavira, Juan José; et al.
ISSN 0300-8932  Vol. 64  Nº 8  2011  págs. 727-728
Autores: Gavira, Juan José; Abizanda, Gloria María; et al.
ISSN 0195-668X  Vol. 31  Nº 8  2010  págs. 1013 - 1021
Aims Although transplantation of skeletal myoblast (SkM) in models of chronic myocardial infarction (MI) induces an improvement in cardiac function, the limited engraftment remains a major limitation. We analyse in a pre-clinical model whether the sequential transplantation of autologous SkM by percutaneous delivery was associated with increased cell engraftment and functional benefit. Methods and results Chronically infarcted Goettingen minipigs (n = 20) were divided in four groups that received either media control or one, two, or three doses of SkM (mean of 329.6 x 10(6) cells per dose) at intervals of 6 weeks and were followed for a total of 7 months. At the time of sacrifice, cardiac function was significantly better in animals treated with SkM in comparison with the control group. A significantly greater increase in the Delta LVEF was detected in animals that received three doses vs. a single dose of SkM. A correlation between the total number of transplanted cells and the improvement in LVEF and Delta LVEF was found (P < 0.05). Skeletal myoblast transplant was associated with an increase in tissue vasculogenesis and decreased fibrosis (collagen vascular fraction) and these effects were greater in animals receiving three doses of cells. Conclusion Repeated injection of SkM in a model of chronic MI is feasible and safe and induces a significant improvement in cardiac function.
Autores: Pelacho, Beatriz; Garbayo, Elisa; et al.
ISSN 0168-3659  Vol. 147  Nº 1  2010  págs. 30 - 37
The use of pro-angiogenic growth factors in ischemia models has been associated with limited success in the clinical setting, in part owing to the short lived effect of the injected cytokine. The use of a microparticle system could allow localized and sustained cytokine release and consequently a prolonged biological effect with induction of tissue revascularization. To assess the potential of VEGF(165) administered as continuous release in ischemic disease, we compared the effect of delivery of poly(lactic-co-glycolic acid) (PLGA) microparticles (MP) loaded with VEGF(165) with free-VEGF or control empty microparticles in a rat model of ischemia-reperfusion. VEGF165 loaded microparticles could be detected in the myocardium of the infarcted animals for more than a month after transplant and provided sustained delivery of active protein in vitro and in vivo. One month after treatment, an increase in angiogenesis (small caliber caveolin-1 positive vessels) and arteriogenesis (alpha-SMA-positive vessels) was observed in animals treated with VEGF microparticles (p < 0.05), but not in the empty microparticles or free-VEGF groups. Correlating with this data, a positive remodeling of the heart was also detected in the VEGF-microparticle group with a significantly greater LV wall thickness (p < 0.01). In conclusion, PICA microparticle is a feasible and promising cytokine delivery system for treatment of myocardial ischemia. This strategy could be scaled up and explored in pre-clinical and clinical studies. (C) 2010 Elsevier B.V. All rights reserved.
Autores: Mazo, Manuel María; Gavira, Juan José; Abizanda, Gloria María; et al.
ISSN 0963-6897  Vol. 19  Nº 3  2010  págs. 313 - 328
The aim of this study is to assess the long-term effect of mesenchymal stem cells (MSC) transplantation in a rat model of chronic myocardial infarction (MI) in comparison with the effect of bone marrow mononuclear cells (BM-MNC) transplant. Five weeks after induction of MI, rats were allocated to receive intramyocardial injection of 10(6) GFP-expressing cells (BM-MNC or MSC) or medium as control. Heart function (echocardiography and (18)F-FDG-microPET) and histological studies were performed 3 months after transplantation and cell fate was analyzed along the experiment (1 and 2 weeks and 1 and 3 months). The main findings of this study were that both BM-derived populations, BM-MNC and MSC, induced a long-lasting (3 months) improvement in LVEF (BM-MNC: 26.61 +/- 2.01% to 46.61 +/- 3.7%, p <0.05; MSC: 27.5 +/- 1.28% to 38.8 +/- 3.2%, p < 0.05) but remarkably, only MSC improved tissue metabolism quantified by (18)F-FDG uptake (71.15 +/- 1.27 to 76.31 +/- 1.11, p<0.01), which was thereby associated with a smaller infarct size and scar collagen content and also with a higher revascularization degree. Altogether, results show that MSC provides a long-term superior benefit than whole BM-MNC transplantation in a rat model of chronic MI.
Autores: Ravassa, S; Garcia-Bolao, I; et al.
ISSN 0008-6363  Vol. 88  Nº 2  2010  págs. 304 - 313
Autores: Pelacho, Beatriz; Mazo, Manuel María; et al.
Libro:  Regenerative medicine and cell therapy
Vol. 316  2013  págs. 65 - 112