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Marfan syndrome (MFS) is a systemic connective tissue disorder caused by mutations in the fibrillin-1 (FBN1) gene, and cardiovascular involvement is the leading cause of mortality. We sought to examine the genotype/phenotype realtionship in 61 consecutive patients with a phenotype and genotype compatible with MFS. The FBN1 gene was analyzed by massive sequencing using a hybridization capture-based target enrichment custom panel. Forty-three different variants of FBN1 were identified, of which 17 have not been previously reported. The causal variants of MFS were grouped into mutations resulting in haploinsufficiency (HI group; 23 patients) and mutations producing a dominant-negative effect (DN group; 38 patients). Patient information was collected from electronic medical records and clinical evaluation. While no significant differences were found between the two groups, the HI group included more cases with aortic dissection and occurring at a younger age that the DN group (34.7% vs. 15.8%; p = 0.160). Irrespective of the mutation group, males presented with a higher probability of aortic involvement (4-fold higher risk than females) and aortic dissections events occurred at younger ages. Patients with DN variants carrying a cysteine substitution had a higher incidence of ectopia lentis.

ResumenIntroducciónLa elección la solución cardiopléjica óptima sigue siendo motivo de debate en la actualidad. La cardioplejía Del Nido (diseñada originariamente para la población pediátrica) está ganando popularidad en el campo de la cirugía cardiaca del adulto.MétodosSerie consecutiva de 30 pacientes que recibieron cardioplejía Del Nido como estrategia de protección miocárdica. Se registraron parámetros demográficos y de perfil de riesgo quirúrgico, tipo de procedimiento realizado, supervivencia perioperatoria; así como los principales parámetros de perfusión, variación de hematocrito intraoperatorio y liberación de enzimas de daño miocárdico durante el postoperatorio. Se determinaron los costes de elaboración de la formulación con respecto a los preparados comerciales convencionales.ResultadosLa serie presentó una supervivencia hospitalaria del 100%. La parada electromecánica del corazón fue efectiva en todos los casos. Los grupos de procedimientos realizados fueron cirugía combinada valvular/coronaria (43,34%), cirugía valvular simple (30%), cirugía coronaria aislada (13,34%) e intervenciones de más de 2 procedimientos (13,34%). Tras la reperfusión del miocardio se observó una tasa de desfibrilación espontánea del corazón del 83,34%. El destete de circulación extracorpórea se realizó con éxito en el 100%, sin necesidad de soporte circulatorio mecánico y con dosis bajas de soporte inotrópico con dobutamina. El coste estimado de elaboración se situó en 7,39 euros por cada unidad.ConclusionesLa cardioplejía Del Nido es de uso habitual en la práctica clínica tanto en la población pediátrica como en la adulta en centros de elevado volumen quirúrgico. Podría constituir una estrategia de protección miocárdica segura, eficaz y económica de aplicación universal en cirugía cardiaca. Son necesarios estudios adicionales de corte prospectivo para corroborar estos datos.AbstractIntroductionThe choice of the optimal cardioplegic solution is still under debate. Del Nido cardioplegia (originally designed for the paediatric population) is gaining popularity in the field of adult cardiac surgery.MethodsA study was conducted on a consecutive series of 30 patients who received Del Nido cardioplegia as myocardial protection strategy. Demographic and risk profile parameters, procedure performed, and surgical survival were registered, as well as main the perfusion variables, intraoperative haematocrit variation, and myocardial injury enzymatic release during the postoperative period. Formulation costs compared with conventional commercial solutions were determined.ResultsSurvival of the series was 100%. Electromechanical arrest of the heart was achieved in all cases. The group of procedures performed were combined valvular/coronary surgery (43.34%), isolated valve surgery (30.00%), coronary artery bypass graft surgery (13.34%), and interventions with more than 2 procedures (13.34%). After myocardial reperfusion, spontaneous defibrillation of the heart occurred in 83.34%. Weaning from cardiopulmonary bypass was successful in 100% with no mechanical circulatory support, and low-dose inotropic support with dobutamine. The estimated preparation costs were set at 7.39 euros per unit.ConclusionsDel Nido cardioplegia is routinely used in clinical practice both in paediatric and adult population in high volume centres. It could be a safe, effective and cheap myocardial protection strategy of universal implementation in cardiac surgery. Additional prospective studies are needed to confirm these data.

ResumenIntroducciónLa naturaleza heterogénea de la válvula aórtica bicúspide (VAB) y su asociación con la dilatación de la aorta ascendente ha sido reconocida en muchos estudios observacionales. El objetivo de nuestro estudio es valorar la asociación que tiene el patrón de aortopatía con la morfología y lesión valvular primaria de esta valvulopatía.MétodosDesde febrero del 2007 hasta noviembre del 2013, 107 pacientes con VAB y aneurisma de aorta ascendente fueron derivados a cirugía. Identificamos la morfología valvular intraoperatoriamente y la lesión valvular primaria por ecocardiografia. Con la tomografía preoperatoria realizamos mediciones en varios sectores de la aorta ascendente.ResultadosLa edad media al momento de la cirugía fue significativamente menor en enfermos con insuficiencia frente a estenosis aórtica (51 vs. 64 años, p

Changes in cardiomyocyte cytoskeletal components, a crucial scaffold of cellular structure, have been found in heart failure (HF); however, the altered cytoskeletal network remains to be elucidated. This study investigated a new map of cytoskeleton-linked alterations that further explain the cardiomyocyte morphology and contraction disruption in HF. RNA-Sequencing (RNA-Seq) analysis was performed in 29 human LV tissue samples from ischemic cardiomyopathy (ICM; n=13) and dilated cardiomyopathy (DCM, n=10) patients undergoing cardiac transplantation and six healthy donors (control, CNT) and up to 16 ICM, 13 DCM and 7 CNT tissue samples for qRT-PCR. Gene Ontology analysis of RNA-Seq data demonstrated that cytoskeletal processes are altered in HF. We identified 60 differentially expressed cytoskeleton-related genes in ICM and 58 genes in DCM comparing with CNT, hierarchical clustering determined that shared cytoskeletal genes have a similar behavior in both pathologies. We further investigated MYLK4, RHOU, and ANKRD1 cytoskeletal components. qRT-PCR analysis revealed that MYLK4 was downregulated (-2.2-fold; P

Insufficient vessel growth associated with ischemia remains an unresolved issue in vascular medicine. Mesenchymal stem cells (MSCs) have been shown to promote angiogenesis via a mechanism that is potentiated by hypoxia. Overexpression of hypoxia inducible factor (HIF)-1α in MSCs improves their therapeutic potential by inducing angiogenesis in transplanted tissues. Here, we studied the contribution of exosomes released by HIF-1α-overexpressing donor MSCs (HIF-MSC) to angiogenesis by endothelial cells. Exosome secretion was enhanced in HIF-MSC. Omics analysis of miRNAs and proteins incorporated into exosomes pointed to the Notch pathway as a candidate mediator of exosome communication. Interestingly, we found that Jagged1 was the sole Notch ligand packaged into MSC exosomes and was more abundant in HIF-MSC than in MSC controls. The addition of Jagged1-containing exosomes from MSC and HIF-MSC cultures to endothelial cells triggered transcriptional changes in Notch target genes and induced angiogenesis in an in vitro model of capillary-like tube formation, and both processes were stimulated by HIF-1α. Finally, subcutaneous injection of Jagged 1-containing exosomes from MSC and HIF-MSC cultures in the Matrigel plug assay induced angiogenesis in vivo, which was more robust when they were derived from HIF-MSC cultures. All Jagged1-mediated effects could be blocked by prior incubation of exosomes with an anti-Jagged 1 antibody. All together, the results indicate that exosomes derived from MSCs stably overexpressing HIF-1α have an increased angiogenic capacity in part via an increase in the packaging of Jagged1, which could have potential applications for the treatment of ischemia-related disease.

Mesenchymal stem cells (MSCs) are effective in treating several pathologies. We and others have demonstrated that hypoxia or hypoxia-inducible factor 1 alpha (HIF-1 alpha) stabilization improves several MSC functions, including cell adhesion, migration, and proliferation, thereby increasing their therapeutic potential. To further explore the mechanisms induced by HIF-1 alpha in MSCs, we studied its relationship with Notch signaling and observed that overexpression of HIF-1 alpha in MSCs increased protein levels of the Notch ligands Jagged 1-2 and Delta-like (Dll) 1, Dll3, and Dll4 and potentiated Notch signaling only when this pathway was activated. Crosstalk between HIF and Notch resulted in Notch-dependent migration and spreading of MSCs, which was abolished by gamma-secretase inhibition. However, the HIF-1-induced increase in MSC proliferation was independent of Notch signaling. The ubiquitin family member, small ubiquitin-like modifier (SUMO), has important functions in many cellular processes and increased SUMO1 protein levels have been reported in hypoxia. To investigate the potential involvement of SUMOylation in HIF/Notch crosstalk, we measured general SUMOylation levels and observed increased SUMOylation in HIF-1-expressing MSCs. Moreover, proliferation and migration of MSCs were reduced in the presence of a SUMOylation inhibitor, and this effect was particularly robust in HIF-MSCs. Immunoprecipitation studies demonstrated SUMOylation of the intracellular domain of Notch1 (N1ICD) in HIF-1-expressing MSCs, which contributed to Notch pathway activation and resulted in increased levels of N1ICD nuclear translocation as assessed by subcellular fractionation. SUMOylation of N1ICD was also observed in HEK293T cells with stabilized HIF-1 alpha expression, suggesting that this is a common mechanism in eukaryotic cells. In summary, we describe, for the first time, SUMOylation of N1ICD, which is potentiated by HIF signaling. These phenomena could be relevant for the therapeutic effects of MSCs in hypoxia or under conditions of HIF stabilization. This work was supported, in part, by grants from the Instituto de Salud Carlos III PI13/00414, PI16/0107, RE-TICS RD12/0019/0025 to P.S. and RETICS RD12/0019/0003 (TERCEL) to J.L.D.L.P cofunded by FEDER ``una manera de hacer Europa. It was also supported by the Regenerative Medicine Program of Instituto de Salud Carlos III and Valencian Community to Centro de Investigacion Principe Felipe. The authors are grateful to Dr. A. Dorronsoro for critical review of the work and Dr. K McCreath for manuscript editing. Sí

Mesenchymal stem cells are often transplanted into inflammatory environments where they are able to survive and modulate host immune responses through a poorly understood mechanism. In this paper we analyzed the responses of MSC to IL-1β: a representative inflammatory mediator. Microarray analysis of MSC treated with IL-1β revealed that this cytokine activateds a set of genes related to biological processes such as cell survival, cell migration, cell adhesion, chemokine production, induction of angiogenesis and modulation of the immune response. Further more detailed analysis by real-time PCR and functional assays revealed that IL-1β mainly increaseds the production of chemokines such as CCL5, CCL20, CXCL1, CXCL3, CXCL5, CXCL6, CXCL10, CXCL11 and CX3CL1, interleukins IL-6, IL-8, IL23A, IL32, Toll-like receptors TLR2, TLR4, CLDN1, metalloproteins MMP1 and MMP3, growth factors CSF2 and TNF-α, together with adhesion molecules ICAM1 and ICAM4. Functional analysis of MSC proliferation, migration and adhesion to extracellular matrix components revealed that IL-1β did not affect proliferation but also served to induce the secretion of trophic factors and adhesion to ECM components such as collagen and laminin. IL-1β treatment enhanced the ability of MSC to recruit monocytes and granulocytes in vitro. Blockade of NF-κβ transcription factor activation with IκB kinase beta (IKKβ) shRNA impaired MSC migration, adhesion and leucocyte recruitment, induced by IL-1β demonstrating that NF-κB pathway is an important downstream regulator of these responses. These findings are relevant to understanding the biological responses of MSC to inflammatory environments. Electronic supplementary material The online version of this article (doi:10.1007/s12015-012-9364-9) contains supplementary material, which is available to authorized users.

La técnica quirúrgica óptima para el tratamiento de la enfermedad aneurismática extensa de la aorta torácica no está claramente establecida. Las opciones incluyen un procedimiento en estadios, por esternotomía media, habitualmente incorporando una trompa de elefante, en el primero, seguido por toracotomía izquierda para completar el procedimiento. Una segunda opción es un procedimiento en un estadio realizado mediante ester-notomía media exclusivamente, o bien, esternotomía media extendida mediante incisión a través de un espacio intercostal, o bien, toracotomía anterior bilateral (incisión clamshell).The optimal surgical technique for the treatment of extensive aneurysmal disease of the thoracic aorta is not clearly established. Options include a staged approach, commonly incorporating an elephant trunk in the first stage performed through a median sternotomy, followed by a left thoracotomy to complete the procedure. A second option is a one-stage procedure performed through a median sternotomy alone, a median sternotomy with an extension through a left intercostal space, or a bilateral anterior thoracotomy (clamshell incision). The surgical techniques are described.

Background Intercalated disks are unique structures in cardiac tissue, in which adherens junctions, desmosomes, and GAP junctions co-localize, thereby facilitating cardiac muscle contraction and function. Protocadherins are involved in these junctions; however, their role in heart physiology is poorly understood. We aimed to analyze the transcriptomic profile of adhesion molecules in patients with ischemic cardiomyopathy (ICM) and relate the changes uncovered with the hemodynamic alterations and functional depression observed in these patients. Methods and Results Twenty-three left ventricular tissue samples from patients diagnosed with ICM (n = 13) undergoing heart transplantation and control donors (CNT, n = 10) were analyzed using RNA sequencing. Forty-two cell adhesion genes involved in cellular junctions were differentially expressed in ICM myocardium. Notably, the levels of protocadherin PCDHGA3 were related with the stroke volume (r = -0.826, P = 0.003), ejection fraction (r = -0.793, P = 0.004) and left ventricular end systolic and diastolic diameters (r = 0.867, P = 0.001; r = 0.781, P = 0.005, respectively). Conclusions Our results support the importance of intercalated disks molecular alterations, closely involved in the contractile function, highlighting its crucial significance and showing gene expression changes not previously described. Specifically, altered PCDHGA3 gene expression was strongly associated with reduced stroke volume and ventricular dysfunction in ICM, suggesting a relevant role in hemodynamic perturbations and cardiac performance for this unexplored protocadherin.

Human dental pulp contains precursor cells termed dental pulp stem cells (DPSC) that show self-renewal and multilineage differentiation and also secrete multiple proangiogenic and antiapoptotic factors. To examine whether these cells could have therapeutic potential in the repair of myocardial infarction (MI), DPSC were infected with a retrovirus encoding the green fluorescent protein (GFP) and expanded ex vivo. Seven days after induction of myocardial infarction by coronary artery ligation, 1.5 × 106 GFP-DPSC were injected intramyocardially in nude rats. At 4 weeks, cell-treated animals showed an improvement in cardiac function, observed by percentage changes in anterior wall thickening left ventricular fractional area change, in parallel with a reduction in infarct size. No histologic evidence was seen of GFP+ endothelial cells, smooth muscle cells, or cardiac muscle cells within the infarct. However, angiogenesis was increased relative to control-treated animals. Taken together, these data suggest that DPSC could provide a novel alternative cell population for cardiac repair, at least in the setting of acute MI. Disclosure of potential conflicts of interest is found at the end of this article.

ResumenPresentamos el manejo quirúrgico para la corrección de un aneurisma gigante de arteria circunfleja con fístula al seno coronario e insuficiencia valvular aórtica, una combinación muy infrecuente. El procedimiento consistió en el cierre epicárdico de la fístula, la resección del aneurisma y plicatura del seno coronario, junto con reemplazo valvular aórtico. Se discuten otras modalidades de manejo quirúrgico.AbstractWe report the surgical management of a giant circumflex artery aneurysm with fistula to the coronary sinus and aortic valve regurgitation, a very rare combination. The surgical correction consisted in epicardial closure of the fistula, coronary aneurysm resection and sinus plication, simultaneously with aortic valve replacement. Other modalities of surgical management are discussed.

Introduction and objectives. There is controversy regarding the risk factors associated with early death in geriatric patients undergoing aortic valve replacement. We analyzed the risks in these patients and established an accurate model for predicting in-hospital mortality. Patients and method. Univariate and multivariate analyses were made of the risk factors associated with early death in a group of 129 patients older than 70 years who underwent aortic valve replacement (May 1994-June 2001). The variables obtained by multivariate logistic regression were combined to produce an equation for the prediction of early death. The equation was tested using a receiver operating characteristic curve. Results. Univariate analysis identified four factors related to early death: NYHA III-IV (p 1.90 m 2 , 20% for < 1.40 m 2 ). The estimated mortality with the predictive model was 7.06%, which was similar to the observed mortality of 7.80% (area under the ROC curve 0.87) and better than estimates obtained with the EuroSCORE (6.5%; area under the ROC curve 0.56). Conclusions. Risk factors associated with early death after aortic valve replacement in geriatric patients include functional status, aortic regurgitation, and small body surface area. Our model based on these factors accurately predicted operative mortality in our patients. Gender, prosthesis size, and pump time were not identified as risk factors.

Introduction and objectives. Myocardial revascularization without cardiopulmonary bypass has been shown to reduce operative morbi-mortality. We report our recent experience with this novel technique in order to evaluate its theoretical advantages in comparison with conventional surgery. Patients and methods. This retrospective analysis included 547 consecutive patients undergoing isolated myocardial revascularization from December 1997 through November 2000. One hundred twenty-one offpump patients were compared to 426 undergoing cardiopulmonary bypass. Logistic regression analysis was performed to find predictors of mortality, transfusion, postoperative atrial fibrillation and length of hospital stay. Results. Off-pump patients were at greater risk: they were older, with a lower ejection fraction and a higher prevalence of unstable angina, heart failure and associated comorbidity. Off-pump surgery reduced transfusions (1 ± 1 vs 1,9 ± 2 blood units; p < 0.0001) and postoperative hospital stays (8.9 ± 5 vs 11,3 ± 7 days; p < 0.001). The off-pump group showed a trend toward reduced morbidity but the technique did not decrease hospital mortality. Cardiopulmonary bypass was an independent predictor of blood transfusion and longer hospital stay. Short-term follow-up revealed no significant differences in recurring angina or patency rates. Conclusions. Off-pump coronary bypass surgery is a good option in high-risk patients because it reduces the incidence of perioperative transfusion and the length of hospitalization. Furthermore, it showed a trend toward reduced morbidity. Mortality was not significantly higher in spite of the higher risk of the patients. Long-term longitudinal follow-up is mandatory to assess the true effectiveness of this technique.

Se presenta el caso de un paciente joven asintomatico con anticuerpos antifosfolipidicos (AAF) positivos en el que se detecto la presencia de una masa auricular derecha tras la realizacion de una ecocardiografia transtoracica. Aunque las caracteristicas morfologicas de la masa resultaron altamente sugestivas de mixoma, la presencia de AAF hizo plantear el diagnostico diferencial con un trombo intraauricular. El paciente fue intervenido extirpandose una tumoracion ligeramente lobulada de 3 ´ 4 cm ampliamente adherida al tabique intraauricular. El estudio histopatologico confirmo que se trataba de un mixoma. Durante el seguimiento el paciente no presento sintomas y los AAF se negativizaron.

Introduction Prolonged catecholamine overstimulation of the myocardium in chronic heart failure causes a reduction in the number and functionality of beta1-adrenoceptors (β1-AR) of the heart. Desensitization of β1-AR is mediated by their phosphorylation by a group of cytosolic kinases (G-protein-coupled receptor kinases GRK). In advanced heart failure, an increase in GRK levels associated with the severity of the disease has been observed. Objective The objective of this study was to analyze messenger RNA (mRNA) levels of β1-AR in the myocardium of patients who underwent transplantation for advanced heart failure and their correlation with expression of the major cardiac isoenzymes of GRK. Materials and Methods Myocardial tissue samples were obtained from the left ventricles of 14 explanted hearts of patients who underwent transplantation for dilated (n = 7) and ischemic (n = 7) cardiomyopathy. RT-PCR techniques were used to analyze mRNA levels of β1-AR and the isoenzymes GRK2, GRK3, and GRK5. Results We observed a significant correlation between β1-AR and the 3 subtypes of GRK ( R 2 = 0.668, 0.71, and 0.318, respectively). Conclusions In patients with advanced heart failure pretransplantation, we observed a significant correlation between β1-AR and GRK2 and GRK3 levels. GRK5, the subtype predominantly expressed in the myocardium, showed a lesser correlation with β1-AR levels.

The aim of our study was to analyze the early presence of metabolic syndrome (MS) in heart transplant (HTx) patients, and to assess its long-term impact on survival and renal function. From January 2000 to October 2011, 253 consecutive HTx patients who survived more than 90 days were included. MS was diagnosed if patients met revised NCEP-ATP III criteria at HTx or within 3 months post-HTx. The prevalence of MS was 41.9%. Patients with MS had greater overall mortality after a mean follow-up of 1700 ± 979 days (log-rank test, P = 0.020). In the multivariate analysis, and subject to a minimum survival of 90 days, the only independent predictor variables of long-term mortality were the presence of MS (OR, odds ratio 2.087, P = 0.032), and rejection episodes (OR 1.833, P = 0.001). Patients with MS had worse renal function at baseline both in plasma creatinine (1.19 ± 0.44 vs. 1.03 ± 0.29 mg/dl, P = 0.002) and glomerular filtration rate estimated by modified diet in renal disease (73.60 ± 26.76 vs. 87.30 ± 43.55 ml/min/1.73 m(2) , P = 0.005), whereas progressive impairment of renal function was of equal magnitude in both groups. The presence of MS prior to transplant or its development within the first 3 months identified a subgroup at greater risk of mortality and long-term renal dysfunction.

Diverticula of the left ventricle are rare and only a few cases have been documented in adults. They may be asymptomatic or may present with embolization, pain, endocarditis, or sudden death. We report the case of a 34-year-old woman who presented a cardiac arrest with ventricular fibrillation which required electrical cardioversion. She was found to have a left ventricular diverticulum associated with a subvalvar aortic stenosis. The diverticulum arose from the apex with a narrow connection to the ventricular cavity. A subvalvar fibrous ridge stenosis with a systolic pressure gradient of 115 mmHg was observed. Coronary angiography revealed normal coronary arteries. The diverticulum and the subvalvar fibrous ridge were resected. Histologic examination of the diverticulum wall demonstrated the presence of the three normal layers with marked muscle cell hypertrophy, atypical plexiform structure and fibrous endocardium. The pathophysioloy of diverticula associated with subvalvar aortic stenosis are discussed.

Heart failure (HF) induces alterations in nucleocytoplasmic transport, which is essential to the cardiomyocyte biology. The objective of this study was to analyze the changes in gene expression in human HF, particularly focusing on nucleocytoplasmic transport-related genes.29 RNA heart samples from dilated cardiomyopathy (DCM, n = 12) and ischemic cardiomyopathy (ICM, n = 12) patients undergoing heart transplantation and control donors (CNT, n = 5) were extracted to perform a microarray profiling using Affymetrix Human Gene® 1.0 ST arrays. We focused on the study of 5 nucleocytoplasmic transport-related genes, since this functional category has not previously been studied in HF. XPO1, GABPB2, and RANBP17 were upregulated, while KALRN was downregulated in both DCM and ICM, and XPO5 only in DCM. Validation of the results by RT-qPCR increasing the total heart samples up to 41 showed a high degree of consistency with microarray results. Moreover, we observed a strong relationship between the XPO1 mRNA and robust left ventricular function parameters in ICM: left ventricular end-systolic (r = 0.81, p0.0001) and end-diastolic diameters (r = 0.80, p0.0001), and ejection fraction (r = -0.57, p0.05).We show that the expression of nucleocytoplasmic transport-related genes is altered in HF. Furthermore, XPO1 mRNA level is closely related with robust left ventricular function parameters in ICM patients. These changes may help to distinguish DCM and ICM in HF at the level of the transcriptome and provide a base for novel therapeutic approaches.

Acute myocardial infarction is a major problem of world public health and available treatments have limited efficacy. Cardiac cell therapy is a new therapeutic strategy focused on regeneration and repair of the injured cardiac muscle. Among different cell types used, mesenchymal stem cells (MSC) have been widely tested in preclinical studies and several clinical trials have evaluated their clinical efficacy in myocardial infarction. However, the beneficial effects of MSC in humans are limited due to poor engraftment and survival of these cells, therefore ways to overcome these obstacles should improve efficacy. Different strategies have been used, such as genetically modifying MSC, or preconditioning the cells with factors that potentiate their survival and therapeutic mechanisms. In this review we compile the most relevant approaches used to improve MSC therapeutic capacity and to understand the molecular mechanisms involved in MSC mediated cardiac repair.

Left ventricular free wall rupture is a dramatic complication after myocardial infarction. We present our experience with the simple, expedient technique of patch glue repair without extracorporeal circulation. Access is obtained via median sternotomy. Evacuation of blood and haematoma is undertaken and a Goretex® patch exceeding the size of infarct is fashioned. The patch is applied to the epicardium using enbrucrilate surgical glue instilled with gentle pressure against the beating heart. We performed this technique on 17 patients from 1993 to 2001, with a operative (30-day) mortality of 23.5% with a post-discharge survival of 85% at 2.2 years.

12 p.-6 fig.-1 tab., Mesenchymal stem cells (MSC) are effective in treating myocardial infarction (MI) and previous reports demonstrated that hypoxia improves MSC self-renewal and therapeutics. Considering that hypoxia-inducible factor- 1 alpha (HIF-1a) is a master regulator of the adaptative response to hypoxia, we hypothesized that HIF-1a overexpression in MSC could mimic some of the mechanisms triggered by hypoxia and increase their therapeutic potential without hypoxia stimulation. Transduction of MSC with HIF-1a lentivirus vectors (MSC-HIF) resulted in increased cell adhesion and migration, and activation of target genes coding for paracrine factors. When MSC-HIF were intramyocardially injected in infarcted nude rats, significant improvement was found (after treatment of infarcted rats with MSC-HIF) in terms of cardiac function, angiogenesis, cardiomyocyte proliferation, and reduction of fibrotic tissue with no induction of cardiac hypertrophy. This finding provides evidences for a crucial role of HIF-1a on MSC biology and suggests the stabilization of HIF-1a as a novel strategy for cellular therapies., This work was supported in part by grants from the Instituto de Salud Carlos III for the Regenerative Medicine Program of Valencian Community to Centro de Investigación Principe Felipe, KUTXA founding and from the FIS (PI07/784, CP08/80 and PI10/00743).

Myocardial infarction caused by vascular occlusion results in the formation of nonfunctional fibrous tissue. Cumulative evidence indicates that cell therapy modestly improves cardiac function; thus, novel cell sources with the potential to repair injured tissue are actively sought. Here, we identify and characterize a cell population of cardiac adipose tissue-derived progenitor cells (ATDPCs) from biopsies of human adult cardiac adipose tissue. Cardiac ATDPCs express a mesenchymal stem cell-like marker profile (strongly positive for CD105, CD44, CD166, CD29 and CD90) and have immunosuppressive capacity. Moreover, cardiac ATDPCs have an inherent cardiac-like phenotype and were able to express de nova myocardial and endothelial markers in vitro but not to differentiate into adipocytes. In addition, when cardiac ATDPCs were transplanted into injured myocardium in mouse and rat models of myocardial infarction, the engrafted cells expressed cardiac (troponin I, sarcomeric alpha-actinin) and endothelial (CD31) markers, vascularization increased, and infarct size was reduced in mice and rats. Moreover, significant differences between control and cell-treated groups were found in fractional shortening and ejection fraction, and the anterior wall remained significantly thicker 30 days after cardiac delivery of ATDPCs. Finally, cardiac ATDPCs secreted proangiogenic factors under in vitro hypoxic conditions, suggesting a paracrine effect to promote local vascularization. Our results indicate that the population of progenitor cells isolated from human cardiac adipose tissue (cardiac ATDPCs) may be valid candidates for future use in cell therapy to regenerate injured myocardium. (C) 2010 Elsevier Ltd. All rights reserved.

Differentiation of human bone marrow mesenchymal stem cells (hBMSC) into the cardiac lineage has been assayed using different approaches such as coculture with cardiac or embryonic cells, treatment with factors, or by seeding cells in organotypic cultures. In most cases, differentiation was evaluated in terms of expression of cardiac-specific markers at protein or molecular level, electrophysiological properties, and formation of sarcomers in differentiated cells. As observed in embryonic stem cells and cardiac progenitors, differentiation of MSC towards the cardiac lineage was preceded by translocation of NKX2.5 and GATA4 transcription factors to the nucleus. Here, we induce differentiation of hBMSC towards the cardiac lineage using coculture with neonatal rat cardiomyocytes. Although important ultrastructural changes occurred during the course of differentiation, sarcomerogenesis was not fully achieved even after long periods of time. Nevertheless, we show that the main cardiac markers, NKX2.5 and GATA4, translocate to the nucleus in a process characteristic of cardiac specification.

Myocardial infarction is a major public health problem that causes significant mortality despite recent advances in its prevention and treatment. Therefore, approaches based on adult stem cells represent a promising alternative to conventional therapies for this life-threatening condition. Mesenchymal stem cells (MSCs) are self-renewing pluripotent cells that have been isolated from multiple tissues and differentiate to various cell types. Here we have analyzed the capacity of MSCs from human bone marrow (BMSC), adipose tissue (ATSC), and dental pulp (DPSC) to differentiate to cells with a cardiac phenotype. Differentiation of MSCs was induced by long-term co-culture with neonatal rat cardiomyocytes (CMs). Shortly after the establishment of MSC-CM co-cultures, expression of connexin 43 and the cardiac-specific markers troponin I, beta-myosin heavy chain, atrial natriuretic peptide, and alpha-sarcomeric actinin was detected in BMSCs, ATSCs, and DPSCs. Expression of differentiation markers increased over time in the co-cultures, reaching the highest levels at 4 weeks. Translocation of the transcription factors NKX2.5 and GATA4 to the nucleus was observed in all three cultures of MSCs during the differentiation process; moreover, nuclear localization of NKX2.5 and GATA4 correlated with expression of alpha-sarcomeric actinin. These changes were accompanied by an increase in myofibril organization in the resulting CM-like cells as analyzed by electron microscopy. Thus, our results provide novel information regarding the differentiation of tissue-specific MSCs to cardiomyocytes and support the potential use of MSCs in cell-based cardiac therapies.

Introduction and Objectives. The immediate postoperative period is a critical phase in heart transplantation. Severe complications occur that may influence short-term and medium-term morbidity and mortality in these patients. The aim of this study was to analyze the incidence of severe complications in emergency and nonemergency transplantations. Materials and Methods. We studied 152 patients who underwent heart transplantation between 2001 and 2007. Combined transplantations and retransplantations were excluded. Two groups were considered: emergency transplantations (36 patients, 24%) and elective transplantations. We compared survival and occurrence of infection, primary graft failure (PGF), renal and hepatic failure, respiratory complications, cardiac tamponade, arrhythmias, reoperation, and intensive care unit (ICU) stay. Results. The emergency transplantation group had a greater number of ischemic patients, with a more prolonged cardiopulmonary bypass time, and a larger proportion of donors were women. Overall mortality in the intensive care unit was 2.6%, with no differences between groups. However, emergency procedures were significantly associated with a higher incidence of PGF, need for intraaortic balloon pump, and a more prolonged mechanical ventilation time, as well as a greater number of bacterial infections and a significantly longer ICU stay. Conclusions. In our series, emergency transplantation showed no greater perioperative mortality. We observed a greater number of severe complications, such as PGF, bacterial infection, and more prolonged mechanical ventilation time.

Radiofrequency energy applied by means of surgical probes permits the ablation of atrial fibrillation (AF). This study presents our initial experience on 55 consecutive cardiac patients with permanent AF with radiofrequency ablation through biatrial epicardial and endocardial surgical approach. At discharge, 8.1% of the patients had persistent AF-atrial flutter. Hospital incidence of arrhythmias were, 9% of paroxysmal atrial fibrillation, 10.9% of atrial flutter, and 34.5% of persistent atrial fibrillation. After a mean follow-up of 7 months, 83.6% patients have recovered sinus rhythm, and echocardiographic biatrial contraction was re-established in 73%. Biatrial radiofrequency ablation applied from the endocardium and the epicardium has achieved satisfactory results, without increasing the surgical risk.

Background: Mitral valve pathology is frequently associated with auricular dilatation and atrial fibrillation. Mitral surgery allows an immediate surgical auricular remodeling and besides in those cases in which sinus rhythm is reached, it is followed by a late remodeling. The aim of this study is to investigate the process of postoperative auricular remodeling in patients with permanent atrial fibrillation undergoing mitral surgery. Methods: In a prospective randomized trial, 50 patients with permanent atrial fibrillation and dilated left atrium, submitted to surgical mitral repair, were divided into two groups: Group I contained 25 patients with left auricular reduction and mitral surgery, and Group II contained 25 patients with isolated valve surgery. Both groups were considered homogeneous in the preoperative assessment. Results: After a mean follow-up of 31 months, 46% of patients included in Group I versus 18% of patients included in Group II restarted sinus rhythm (p = 0.06). An auricular remodeling with size regression occurred in those patients who recovered from sinus rhythm, worthy of remark in Group II (–10.8% of left auricular volume reduction in Group I compared to –21.5% in Group II; p < 0.05). A new atrial enlargement took place in those patients who remained with atrial fibrillation (+16.8% left auricular volume in Group I vs. +8.4% in Group II; p < 0.05). Conclusions: Mitral surgery produces an atrial postoperative volume that decrease especially when reduction techniques are employed. Late left atrial remodeling depended on the type of atrial rhythm and postoperative surgical volume.

A method of total arterial revascularization is presented. This technique is based on the extension of a semi-skeletonized right internal thoracic artery graft with an entire radial artery in an end to end fashion. A complete arterial revascularization is achieved with a bilateral in situ internal thoracic artery strategy preserving the left internal thoracic artery to the left anterior descending artery bypass as an isolated graft. In our experience, this pattern of revascularization has been especially important in patients with atheromatous disease of the ascending aorta, a difficult situation in which a 'no-touch technique' is mandatory.

Background The atrium is the major site of ANP synthesis, which has been said to increase in heart failure as a result of increased production in the left ventricular (LV) myocardium. This is a key issue related to its diagnostic and prognostic capabilities. We aimed to evaluate protein levels of proANP and ANP and the enzymes that cleave the natriuretic peptides, corin and furin, in the LV tissue of heart transplant patients with dilated (DCM) and ischemic (ICM) cardiomyopathy compared with control donors (CNT). We also evaluate mRNA levels of ANP gene (NPPA) by RNA sequencing in the same tissue. Methods and Results Seventy-three human LV tissue samples from ICM (n = 30) and DCM (n = 33) patients and CNT (n = 10) were analyzed by Western blot and RNA sequencing. Comparing protein levels according to etiology, neither DCM nor ICM showed levels of proANP or ANP different from those of CNT. However, NPPA was increased in both groups compared to CNT (DCM 32 fold, p

ResumenLas fistulas congénitas desde los senos aórticos a las cavidades cardíacas son lesiones infrecuentes, la mayoría provocadas por la rotura de un aneurisma previo. Las fístulas desde senos normales son aún más raras. Tras el diagnóstico, las fístulas grandes deben corregirse pronto, pero el tratamiento en el caso de fístulas pequeñas asintomáticas está peor establecido. Presentamos el caso de un paciente asintomático con fístula de seno aórtico no coronariano no aneurismático a ventrículo derecho. Se describen los hallazgos del diagnóstico así como la técnica quirúrgica usada para su corrección.AbstractCongenital fistulas from aortic sinuses to cardiac chambers are unusual lesions, most of them caused by a rupture of a previous aneurysm. Fistulas from normal sinuses are even rarer. Once diagnosed, large fistulas have to be corrected as soon as possible, but treatment in case of small asymptomatic fistulas is less established. A fistula from a non aneurysmatic non coronary aortic sinus to the right ventricle was diagnosed in an asymptomatic patient. Diagnostic features as well as the surgical technique used in its correction are described.