The use of allogeneic adipose-derived mesenchymal stromal cells (alloADSCs) represents an attractive approach for treating myocardial infarction (MI). Furthermore, adding a natural support improves alloADSCs engraftment and survival in heart tissues, leading to a greater therapeutic effect. We aimed to examine the safety and immunological reaction induced by epicardial implantation of a clinical-grade collagen scaffold (CS) seeded with alloADSCs for its future application in humans. Thus, cellularized scaffolds were myocardially or subcutaneously implanted in immunosuppressed rodent models. The toxicological parameters were not significantly altered, and tumor formation was not found over the short or long term. Furthermore, biodistribution analyses in the infarcted immunocompetent rats displayed cell engraftment in the myocardium but no migration to other organs. The immunogenicity of alloADSC-CS was also evaluated in a preclinical porcine model of chronic MI; no significant humoral or cellular alloreactive responses were found. Moreover, CS cellularized with human ADSCs cocultured with human allogeneic immune cells produced no alloreactive response. Interestingly, alloADSC-CS significantly inhibited lymphocyte responses, confirming its immunomodulatory action. Thus, alloADSC-CS is likely safe and does not elicit any alloreactive immunological response in the host. Moreover, it exerts an immunomodulatory action, which supports its translation to a clinical setting.

El tratamiento percutáneo de la estenosis aórtica severa es una opción terapéutica para paciente inoperables y para aquellos de moderado o elevado riesgo quirúrgico. Presentamos el caso de un paciente joven inicialmente considerado inoperable, sometido a una implantación transcatéter de válvula aórtica, que comenzó a mostrar signos de degeneración tras seis años, que evolucionaron hasta requerir tratamiento quirúrgico a los ocho años del implante. Durante este tiempo, su estado de salud mejoró, por lo que fue presentado en sesión médico quirúrgica para la resección de la válvula previamente implantada y sustitución por otra bioprótesis. El procedimiento transcurrió sin complicaciones. No obstante, la resección de estas válvulas no es un procedimiento exento de riesgo, por las densas adherencias del marco a la raíz aórtica. Por este motivo, la expansión de esta tecnología a pacientes jóvenes y de bajo riesgo, no estaría justificada.

In hypertensive patients with heart failure (HF) a serum biomarker combination of high carboxy-terminal propeptide of procollagen type-I (PICP) and low carboxy-terminal telopeptide of collagen type-I to matrix metalloproteinase-1 (CITP:MMP-1) ratio identifies a histomolecular phenotype of malignant myocardial fibrosis (mMF) associated with severe diastolic dysfunction (DD) and poor outcomes. As chronic kidney disease (CKD) facilitates MF and DD, we investigated the influence of CKD on the mMF biomarker combination in HF patients with preserved ejection fraction (HFpEF). Hypertensives (n = 365), 232 non-HF and 133 HFpEF, were studied, and 35% non-HF and 46% HFpEF patients had CKD (estimated glomerular filtration rate < 60 mL/min/1.73 m2 or urine albumin-to-creatinine ratio ¿ 30 mg/g). Specific immunoassays were performed to determine biomarkers. Medians were used to establish the high PICP and low CITP:MMP-1 combination. A comparison with non-HF showed that the biomarker combination presence was increased in HFpEF patients, being associated with CKD in all patients. CKD influenced the association of the biomarker combination and HFpEF (p for interaction ¿ 0.019). The E:e' ratio was associated with the biomarker combination in CKD patients. Among CKD patients with HFpEF, those with the biomarker combination exhibited higher (p = 0.016) E:e' ratio than those without the pattern. These findings suggest that CKD facilitates the development of biomarker-assessed mMF and DD in hypertensive HFpEF patients.

Introduction and objectives: Several trials have tested the diagnostic and prognostic value of stress cardiac magnetic resonance (CMR) in ischemic heart disease. However, scientific evidence is lacking in the older population, and the available techniques have limitations in this population. The aim of this study was to evaluate the usefulness of stress CMR in the elderly. Methods: We prospectively studied consecutive patients referred for stress CMR to rule out myocardial ischemia. The cutoff age for the elderly population was 70 years. Stress CMR study was performed according to standardized international protocols. Hypoperfusion severity was classified according to the number of affected segments: mild (1-2 segments), moderate (3-4 segments), or severe (> 4 segments). We analyzed the occurrence of major events during follow-up (death, acute coronary syndrome, or revascularization). Survival was studied with the Kaplan-Meier method and multivariate Cox regression models. Results: Of an initial cohort of 333 patients, 110 were older than 70 years. In 40.9% patients, stress CMR was positive for ischemia. The median follow-up was 26 [18-37] months. In elderly patients there were 35 events (15 deaths, 10 acute coronary syndromes, and 10 revascularizations). Patients with moderate or severe ischemia were at a higher risk of events, adjusted for age, sex, and cardiovascular risk (HR, 3.53 [95%CI, 1.41-8.79]; P=.01). Conclusions: Moderate to severe perfusion defects in stress CMR strongly predict cardiovascular events in people older than 70 years, without relevant adverse effects.

Objective: To determine the safety of regadenoson for vasodilation in cardiac MRI stress tests to detect myocardial ischemia. Material and methods: We retrospectively analyzed cardiac MRI studies done in 120 patients (mean age, 67 11.6 years; 88 men) with suspected ischemic heart disease or known coronary disease who had clinical indications for cardiac MRI stress tests. All studies were done on a 1.5 T scanner (MAGNETOM Aera, Siemens Healthineers) using regadenoson (5 ml, 0.4 mg) for vasodilation. We recorded cardiovascular risk factors, medications, and indications for the test as well as vital signs at rest and under stress and the symptoms and adverse effects induced by the drug. Results: No symptoms developed in 52.6% of patients. The most common symptoms were central chest pain (25%) and dyspnea (12%). At peak stress, the mean increase in heart rate was 23.9 + 11.4 beats per minute and the mean decreases in systolic and diastolic blood pressure were 7.1+18.8 mmHg and 5.3 9.2 mmHg, respectively (p '0.O01). The response to regadenoson was less pronounced in obese and diabetic patients. The increase in heart rate was greater in symptomatic patients (27.4 11.2 bpm vs. 20.6 + 10.7 bpm in asymptomatic patients, p =0.001). No severe adverse effects were observed. Conclusion: Regadenoson is welt tolerated and can be safety used for cardiac MRI stress tests. 0Z0/9 SERAM. Published by Elsevier Espana, S.L.U. All rights reserved.

Coronavirus disease 2019 (COVID-19) has become a worldwide pandemic, affecting humans of all ages. Clinical features of the pediatric population have been published, but there is not yet enough information to make a definitive description. Fever is typical, as it is respiratory symptom. Rarely are the infection and complications severe, and, when they are, it is almost always in a patient with another underlying disease. However, some otherwise healthy children with COVID-19 do suffer critical organ injury, such as acute myocarditis, heart failure and gastrointestinal inflammation. The mechanism of these organ damages remains unclear. An otherwise normally healthy 13-year-old male was admitted to the pediatric intensive care unit with acute abdomen pain, possible myocarditis and a suspected diagnosis of COVID-19. Noteworthy basal findings were ventricular extrasystoles in the electrocardiogram (EKG) and moderate left ventricular systolic dysfunction. Chest X-ray was normal. Blood tests revealed altered levels of inflammation factors (C-reactive protein (CRP), D-dimer, fibrinogen, interleukin 6 (IL-6)), lymphopenia and elevated cardiac enzymes. The first test for polymerase chain reaction (PCR) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was negative. The patient¿s condition worsened, and he entered cardiogenic shock (hypotension, tachycardia and oliguria). He was vomiting continuously, which made pain control difficult; imaging of his abdomen was ...

BACKGROUND: Cardiac fibroblasts (CFs) have a central role in the ventricular remodeling process associated with different types of fibrosis. Recent studies have shown that fibroblasts do not respond homogeneously to heart injury. Because of the limited set of bona fide fibroblast markers, a proper characterization of fibroblast population heterogeneity in response to cardiac damage is lacking. The purpose of this study was to define CF heterogeneity during ventricular remodeling and the underlying mechanisms that regulate CF function. METHODS: Collagen1 alpha 1-GFP (green fluorescent protein)-positive CFs were characterized after myocardial infarction (MI) by single-cell and bulk RNA sequencing, assay for transposase-accessible chromatin sequencing, and functional assays. Swine and patient samples were studied using bulk RNA sequencing. RESULTS: We identified and characterized a unique CF subpopulation that emerges after MI in mice. These activated fibroblasts exhibit a clear profibrotic signature, express high levels of Cthrc1 (collagen triple helix repeat containing 1), and localize into the scar. Noncanonical transforming growth factor-beta signaling and different transcription factors including SOX9 are important regulators mediating their response to cardiac injury. Absence of CTHRC1 results in pronounced lethality attributable to ventricular rupture. A population of CFs with a similar transcriptome was identified in a swine model of MI and in heart tissue from patients with MI and dilated cardiomyopathy. CONCLUSIONS: We report CF heterogeneity and their dynamics during the course of MI and redefine the CFs that respond to cardiac injury and participate in myocardial remodeling. Our study identifies CTHRC1 as a novel regulator of the healing scar process and a target for future translational studies.

Abstract To evaluate the vasodilator effect of adenosine triphosphate (ATP) compared with adenosine in stress perfusion cardiac magnetic resonance (CMR) examinations. A total of thirty-three patients underwent clinically indicated stress/rest perfusion CMR examination following intravenous injection of a total dose of 0.2 mmol/kg of gadobutrol. Individuals were randomly assigned to ATP (160 mcg/kg/min) or adenosine (140 mcg/kg/min). The vasodilator effect of both drugs was analyzed by comparing differences in heart rate, symptoms during stress, and semiquantitative myocardial and splenic perfusion parameters, including time, time to peak, upslope, myocardial perfusion reserve index, tissue perfusion values, splenic and myocardial signal intensity ratios, and splenic-to-myocardial signal intensity ratios. No significant difference was found in heart rate variation between the stressors (26.1¿±¿19.1 bpm for ATP vs. 21.7¿±¿17.3 bpm for adenosine, p¿=¿0.52). Patients receiving ATP referred less pronounced clinical symptoms. Semiquantitative myocardial perfusion parameters were comparable, and patients in the adenosine and ATP groups showed similar myocardial perfusion reserve index values (2.34 [1.62-2.73] vs 1.63 [1.29-2.10], p¿=¿0.07). Splenic switch off was visually confirmed in all patients and estimated spleen to myocardium ratio was similar (0.92 [0.53-1.09] vs 0.81 [0.53-0.86] with ATP and adenosine, respectively, p¿=¿0.12). Both ATP and adenosine are potent coronary vasodilators that can be safely employed in stress-CMR. Both stressor cause similar hyperemic response. Splenic switch-off can be used to assess stress adequacy in patients undergoing stress-CMR with either adenosine or ATP.

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.

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.

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.

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

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.

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.

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.

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

Patients with heart failure have increased liver stiffness, that appears to be related with the severity of heart failure

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.

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.

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.

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.

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.

The present document reviews various aspects of the current status of cardiac resynchronization therapy: mechanisms of action, current indications and implantation technique.

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.

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

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.

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.

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.

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

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.

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.

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.