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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.

Mechanical circulatory support using ventricular assist devices has become commonplace in the treatment of patients suffering from advanced stages of heart failure. While blood damage generated by these devices has been evaluated in depth, their hemodynamic performance has been investigated much less. This work presents the analysis of the complete operating map of a left ventricular assist device, in terms of pressure head, power and efficiency. Further investigation into its hemocompatibility is included as well. To achieve these objectives, computational fluid dynamics simulations of a centrifugal blood pump with a wide-blade impeller were performed. Several conditions were considered by varying the rotational speed and volumetric flow rate. Regarding the device's hemocompatibility, blood damage was evaluated by means of the hemolysis index. By relating the hemocompatibility of the device to its hemodynamic performance, the results have demonstrated that the highest hemolysis occurs at low flow rates, corresponding to operating conditions of low efficiency. Both performance and hemocompatibility are affected by the gap clearance. An innovative investigation into the influence of this design parameter has yielded decreased efficiencies and increased hemolysis as the gap clearance is reduced. As a further novelty, pump operating maps were non-dimensionalized to highlight the influence of Reynolds number, which allows their application to any working condition. The pump's operating range places it in the transitional regime between laminar and turbulent, leading to enhanced efficiency for the highest Reynolds number.

Recent studies show that microvascular injury consists of microvascular obstruction (MVO) and intramyocardial hemorrhage (IMH). In patients with reperfused ST-segment elevation myocardial infarction (STEMI) quantitative assessment of IMH with T2* cardiovascular magnetic resonance imaging (CMR) appears to be useful in evaluation of microvascular damage. The current study aimed to investigate feasibility of this approach and to correlate IMH with clinical and CMR parameters. A single center observational cohort study was performed in reperfused STEMI patients with CMR examination 7 days (IQR: 5 to 8 days) after percutaneous coronary intervention. Infarct size (IS) and MVO were evaluated in short-axis late gadolinium enhancement sequences and IMH with whole LV volume T2* mapping sequences. Of the 94 patients, MVO was identified in 52% of patients and the median size of MVO was 3% of LV mass (IQR: 1.5 to 5.4%). IMH was present in 28% of patients and the median size of IMH was 1.1% of LV mass (IQR: 0.5 to 2.9%). IMH extent was independently associated with anterior myocardial infarction (p = 0.022) and thrombectomy (p = 0.049). IMH was correlated with MVO (R = 0.62, p

Classically clinical evaluation of patients with aortic stenosis (AS) is made using clinical and echocardiographic parameters but recently new imaging techniques as cardiovascular magnetic resonance (CMR ) are being used increasingly in this clinical setting. We aim to assess utility and prognostic value of aortic valve area (AVA) by CMR in patients with AS regarding echocardiographic data. METHODS a retrospective cohort of patients with AS referred to CMR and cardiac echocardiography study for evaluation were included. Patients with known coronary artery disease or another significant valve disease were excluded. Clinical Follow up was performed to asses cardiovascular death, hospital admission or aortic valve replacement at the first year after imaging evaluation. Furthermore symptomatic status was assessed. Echocardiographic severity was estimated used peak and mean gradients . Additionally a CMR study including b-SSFPS for left ventricle ejection fraction (LVEF) quantification and phase-contrast sequences acquired at aortic valve plane to analyze aortic valve area (AVA) by planimetry was performed. RESULTS ninety eight patients, mean age 67+ 15 years, 52(58%) males, 23 (25%) with decreased left ventricular ejection fraction. A significant negative correlation was observed between AVA by CMR and echocardiographic gradients ( -0.49 for mean gradient and -0.58 for peak gradient). AVA was strongly associated to symptomatic status (AUROC curve 0.66, p ( OR:1.02 p = 0.01) and AVA (OR: 0.002 p = 0.001) were shown to be independent predictors of events. Conclusion 1.AVA by planimetry in phase-contrast CMR sequences is a valid tool to asses severity of aortic valve stenosis . 2 AVA was strongly associated to symptomatic status.3. AVA has proven to have additional prognostic value beyond echocardiographic gradients. Abstract P349 Figure. Aortic valve area by planimetry by MR

Resumen Introduccion La incidencia de dilatacion de arco, asi como la necesidad de cirugia sobre arco en la valvula aortica bicuspide, es un tema controvertido. En el presente estudio analizamos los factores predictivos de dilatacion de arco en la valvula bicuspide y la tasa de dilatacion del arco no tratado en la intervencion. Metodos Se analizo a 161 pacientes con aneurismas sobre valvula bicuspide y cirugia electiva. Se considero dilatacion de arco para diametro ≧40 mm o indice ≧2,1 cm/m 2 (angio-TAC). Se analizo la relacion con la lesion y el fenotipo valvular y otros factores. En los pacientes con arco conservado se estudio la tasa de dilatacion anual y la reoperacion. Resultados El 83,2% eran varones, con una edad de 57,1 ± 13 anos. El diametro y el indice de arco fueron 35,6 ± 5,8 mm y 1,9 ± 0,4 cm/m 2 , respectivamente. Un 12,4% tenia arco bovino. La dilatacion de arco fue del 27,4% segun diametro y del 32,3% segun indice. La edad, fusion derecho no coronariano y apertura lateral fueron predictores de dilatacion. La mortalidad hospitalaria fue del 2,5% (EuroSCORE-II 4,4%). En el seguimiento (media 32 meses) la dilatacion del arco fue de 0,3 ± 0,6 mm/ano, con la edad como unico predictor. Un 1,3% fue reintervenido por causa aortica, ninguno sobre arco. Conclusiones Menos de 1/3 de los aneurismas sobre valvula bicuspide presenta afectacion de arco; la progresion de la dilatacion del arco preservado tras la cirugia es lenta y la necesidad de reoperacion, baja. No esta, por tanto, justificada la reparacion de arco de forma sistematica.

In the setting of STEMI, microvascular injury consists of microvascular obstruction (MVO) and intramyocardial hemorrhage (IMH). We aimed to investigate prognostic value and clinical predictors of MR T2* w analysis of IMH in this setting. Methods A single center observational cohort study was performed in patients with reperfused STEMI with CMR examination after percutaneous revascularization. Infarct related CMR characteristics were analyzed in whole LV short-axis late gadolinium enhancement sequences (LGE) for infarct size and MVO and whole volume T2*w sequences for IMH. Extent of MVO and IMH were derived as percentage of LV mass. Kaplan-Meier was used to analyze the incidence of major adverse cardiovascular events, defined as a composite of cardiac death, myocardial re-infarction, and new congestive heart failure. Results 94 reperfused STEMI patients were included in the study. T2*w IMH was present in 26 (28%) patients and the median size of IMH was 1.1% (IQR: 0.5 to 2.9%). MVO was identified in 49 (52%) patients and the median size of MVO was 3% mass (IQR: 1.5 to 5.4%). T2*w IMH extension was independently associated with anterior myocardial infarction (p=0.022) and thrombectomy (p=0.049). IMH was correlated with MVO (R=0.62, p Typical CMR sequences Conclusions Whole LV T2*w proves useful to asses IMH. IMH extension was associated with anterior infarction and thrombectomy. T2*w IMH was associated with higher incidence of MACE regardless preserved or reduced LVEF

Background: Nowadays, evaluation of the need for intervention in patients with aortic coarctation (AC) is based on anatomical and clinical data. The purpose of the study was to analyze the utility of assessing flow in the thoracic descending aorta using magnetic resonance imaging (MRI) in patients with AC. Methods: Patients with a diagnosis or suspicion of AC, who underwent MRI study between 2008-2016 in a single tertiary center, were retrospectively studied. MRI standardized protocol included gadolinium enhanced angiographic 3-D sequences to evaluate relative stenosis (RS) and phase contrast imaging to assess flow in the descending aorta. Results: 106 patients {70 men (66%), mean age 22 ± 17 years} were included. Of these, 28 (26%) required surgical intervention during the first year after evaluation and 9 (9.3%) required percutaneous treatment. AUROC curves were applied to find best cut-off points of imaging variables. Imaging variables were entered into a multivariate logistic regression model including the presence of arterial hypertension. Percentage of flow increase was shown to be an independent predictor of the need for an intervention (OR, 7.2; 95%CI, 1-20; p=0.03) and adding this parameter in the standard work-up represented a significant increase in diagnostic accuracy (S, 85%; Sp, 89%; vs. S, 62%; Sp, 92%). Conclusion: physiological assessment of flow pattern in descending aorta by MRI significantly increases the ability to evaluate the need for invasive treatment in AC patients beyond standard clinical and anatomical study.

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

ResumenIntroducción y objetivosLos modelos predictivos de mortalidad hospitalaria, EuroSCORE logístico y EuroSCORE II, ofrecen un rendimiento razonable en cirugía cardíaca. Sin embargo, su aplicación en la cirugía de aorta es motivo de controversia. El objeto del presente estudio es el diseño de un modelo de estimación de riesgo específico ajustado a pacientes con cirugía de aorta torácica.MétodosSe recogieron retrospectivamente 310 pacientes consecutivos con cirugía de aorta proximal (raíz, aorta ascendente y/o arco) entre 2006 y 2013. Se elaboró un modelo predictivo mediante regresión logística múltiple con las variables que resultaron significativas en el análisis univariado. La capacidad discriminatoria se calculó mediante el área bajo la curva ROC y se comparó con las obtenidas aplicando el EuroSCORE logístico y el EuroSCORE II.ResultadosLa mortalidad hospitalaria observada fue de un 8,1%. Las variables relacionadas con muerte hospitalaria fueron la clase NYHA, el aclaramiento de creatinina, el estado crítico preoperatorio y la endocarditis activa. La mortalidad predicha por el EuroSCORE logístico, el EuroSCORE II y el modelo elaborado fueron de 14,98, 8,12 y 8,06%, respectivamente. El área bajo la curva ROC fue de 0,665 (0,541-0,789) para el EuroSCORE logístico, de 0,718 (0,588-0,848) para el EuroSCORE II y de 0,775 (0,675-0,876) para el modelo elaborado (Hosmer-Lemeshow, p=0,405).ConclusionesEl modelo predictivo elaborado predice la mortalidad hospitalaria de manera más ajustada, y con mayor discriminación que el EuroSCORE logístico y el EuroSCORE II para pacientes sometidos a cirugía de aorta torácica, aportando además una mayor sencillez de cálculo al basarse únicamente en 4 parámetros preoperatorios.AbstractIntroduction and objectivesPredictive stratification scores of hospital mortality, logistic EuroSCORE and EuroSCORE II are reasonable tools in cardiac surgery. However, its utility in aortic procedures is controversial. The aim of this study is to design a new specific mortality risk model adjusted to patients undergoing thoracic aortic surgery.MethodsWe analyzed retrospectively 310 consecutive patients who underwent surgery of proximal aorta (root, ascending and/or arch) between 2006 and 2013. A predictive model was developed using multiple logistic regression, entering variables that were significant in univariate analysis. Discriminatory performance was calculated by area under ROC curve and was compared with those of the logistic EuroSCORE and EuroSCORE II.ResultsThe observed death in-hospital mortality was 8.1%. Hospital mortality related variables were NYHA class, creatinine clearance, critical preoperative status, and active endocarditis. Logistic EuroSCORE, EuroSCORE II and new model predicted mortality were 14.98, 8.12, and 8.06, respectively. Area under ROC curve was 0.665 (0.541-0.789) for logistic EuroSCORE, 0.718 (0.588-0.848) for EuroSCORE II and 0.775 (0.675-0.876) for the new developed model (Hosmer-Lemeshow P=.405).ConclusionsThe new developed model predicts hospital mortality more accurate and with more discriminatory power than logistic EuroSCORE and EuroSCORE II in thoracic aortic surgery, also offering an easier method for the calculation based on only 4 preoperative parameters.

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

Background Acute renal dysfunction (ARD) may appear in heart transplant (HTx) patients both in the early postoperative period and during follow-up, even after several years. CD25 is a subunit of the interleukin-2 receptor which is found exclusively on activated CD4 T lymphocytes. CD25 is crucial for clonal expansion of anti-allograft host lymphocytes that mediate in acute rejection. There are experiences supporting the use of Anti-CD25 monoclonal antibodies (MAb) immediately after HTx in patients with ARD as a bridge to renal function recovery, allowing the temporary suspension of treatment with CNI. Methods In this study we report two cases of successful use of weekly MAb (basiliximab) in HTx patients who developed late ARD after HTx. Conclusions In coclusion, we think that in cases of ARD where CNI therapy plays a key role, the use of weekly doses of basiliximab allows CNI discontinuation until the restoration of renal function is achieved.

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

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.

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.

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.

Objectives The purpose of this study was to compare the ability of human CD34(+) hematopoietic stem cells and bone marrow mesenchymal stem cells (MSC) to treat myocardial infarction (MI) in a model of permanent left descendent coronary artery (LDA) ligation in nude rats. Background Transplantation of human CD34(+) cells and MSC has been proved to be effective in treating MI, but no comparative studies have been performed to elucidate which treatment prevents left ventricular (LV) remodelling more efficiently. Methods Human bone marrow MSC or freshly isolated CD34(+) cells from umbilical cord blood were injected intramyocardially in infarcted nude rats. Cardiac function was analyzed by echocardiography. Ventricular remodelling was evaluated by tissue histology and electron microscopy, and neo-formed vessels were quantified by immunohistochemistry. Chronic local inflammatory infiltrates were evaluated in LV wall by hematoxylin-eosin staining. Apoptosis of infarcted tissue was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Results Both cell types induced an improvement in LV cardiac function and increased tissue cell proliferation in myocardial tissue and neoangiogenesis. However, MSC were more effective for the reduction of infarct size and prevention of ventricular remodelling. Scar tissue was 17.48 +/- 1.29% in the CD34 group and 10.36 +/- 1.07% in the MSC group (p < 0.001 in MSC vs. CD34). Moreover, unlike MSC, CD34(+)-treated animals showed local inflammatory infiltrates in LV wall that persisted 4 weeks after transplantation. Conclusions Mesenchymal stem cells might be more effective than CD34(+) cells for the healing of the infarct. This study contributes to elucidate the mechanisms by which these cell types operate in the course of MI treatment. (J Am Coll Cardiol 2010;55:2244-53) (C) 2010 by the American College of Cardiology Foundation

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.

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.

Cardiopulmonary bypass (CPB) is associated with oxidative stress. This study examined antioxidant levels in adults undergoing CPB surgery and their correlation with clinical variables. Arterial blood samples were obtained from 27 patients undergoing CPB. The time-course variation of vitamin C (spectrofluorimetry), alpha-tocopherol and retinol (HPLC) levels were determined. Plasma vitamin C rose initially but gradually decayed during reperfusion until 60% reduction of baseline values post-surgery. alpha-Tocopherol and retinol were reduced along CPB with post-operative values approximately 25% lower than baseline. No significant changes were found for selenium and glutathione peroxidase. PaO(2) values rose steadily throughout CPB. A correlation existed for alpha-tocopherol and retinol depletion vs maximal PaO(2) throughout CPB but no correlation was found for antioxidant consumption vs duration of ischaemia and reperfusion and hypothermia level. In conclusion, consumption of arterial blood antioxidant vitamins occurs with CPB in relation with PaO(2) levels but not for other clinical variables measured in this study.

Background The amount of epicardial adipose tissue (EAT) has been associated with the presence of atherosclerotic disease but its role in assessing the risk of obstructive coronary artery disease (CAD) and its relationship with other cardiovascular risk factors is not fully established. We hypothesized that EAT quantified by cardiac magnetic resonance (CMR) is greater in patients with obstructive CAD and could be a new cardiovascular risk marker. Methods To assess the hypothesis, EAT was quantified in patients with ischemia detected in CMR vasodilator stress test and evidence of obstructive CAD in coronary angiogram and also in a group of control patients with similar risk profile but absence of ischemia in CMR stress test and also without diagnosis of obstructive CAD in follow up. Volume of EAT was quantified in 8-10 end-diastolic short axis slices of steady state free precession sequences, derived by Simpson method and indexed by body surface area. Results Seventy patients were included, 46 males (66%), mean age of 60 years (sd: 11.21) of them 42 had obstructive CAD in coronary angiogram. Volume of EAT indexed by body surface area was significantly greater in patients with obstructive CAD :42.43ml/m2 vs 34.35ml/m2, odds ratio: 1,034 [1,001- 1-069 ] p=0.04. Demographic data including cardiovascular risk factors are shown in the table. Conclusions

Objective: Although the first pulmonary autograft operations were performed in Spain in 1991, this procedure has gained substantial interest and has been consolidated since 1997. The establishment of the Spanish Registry of the Ross Operation pretends to evaluate the results of this option in aortic valve disease patients in our setting. Methods: In a yearly fashion, the cardiac surgery departments in Spain currently performing this intervention send data from new patients or follow-ups to the reference center. Preoperative, intraoperative and postoperative data are included in the registry, with special attention to morbidity, mortality, autograft and homograft dysfunction and need for reintervention. Results: Since February 1991 to May 2002, 169 patients have been treated with this technique. The most prevalent aortic disease was regurgitation (72; 42.59%), congenital being the most frequent etiology (108; 63.9%). Four (2.36%) patients required intraoperative aortic counterpulsation. Operative mortality was 2.36% (n ¼ 4). Follow-up is 98.7% complete, with an average of 36.08 ^ 31.09 months (range 1 –135), 84 patients (49.7%) were followed for more than 2 years. The autograft remains competent or with trivial to mild regurgitation in 161 patients (95.6%), presenting two (1.18%) with severe regurgitation. The homograft was normal or with mild stenosis in 159 patients (94.07%), presenting five (2.95%) with severe stenosis. Three (1.77%) required reintervention (surgical or interventional) on the right ventricular outflow tract and four (2.36%) required autograft replacement for a mechanical prosthesis. Actuarial survival is 95.99 ^ 1.65% at 36 months, remaining 92.44 ^ 2.55% free from reintervention in the same period. Conclusions: The Ross operation is an increasingly popular surgical option in Spain, and although the number of patients and length of follow-up are still limited, initial results are at least as good as those reported internationally. It is important to continue a close follow-up of these patients to assess the long-term function of auto and homograft. With the available data, we believe that this therapeutic approach is a valid option for selected groups of patients with surgical aortic valve disease in Spain. q 2003 Published by Elsevier B.V.

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.

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.

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.

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.

Introduccion y objetivo La mediastinitis poscirugia cardia-ca, aunque infrecuente, continua siendo una patologia con una elevada mortalidad pese a su manejo de forma agresiva. Segun algunas series publicadas previamente, la mortalidad se situa en torno al 30–40% de los afectados que son tratados de forma convencional. En este estudio queremos mostrar nuestros resultados y experiencia en el manejo de esta patologia con la utilizacion de la terapia vacuum assisted closure (VAC). Material y metodos Desde abril de 2006 - diciembre de 2011 se utilizo la terapia VAC en 63 pacientes con diagnostico establecido de mediastinitis. De forma retrospectiva se recogieron datos pre, intra y postoperatorio que se analizaron en SPSS. Resultados La edad media fue de 64 anos (19–82), siendo el 73% varones. El 58,9% eran diabeticos y el 45% eran obesos. La media de dias con tratamiento VAC fue de 28. La distribucion por etiologias fue: cirugia coronaria (BPAC) 48%, cirugia valvular 18%, combinado 12%, trasplante 10%, congenitos 6%, y aorta ascendente 6%. En el 80% de los pacientes la infeccion fue polimicrobiana, destacando el S. aureus, que se aislo hasta en el 65% de los cultivos. La estancia media hospitalaria fue de 59 dias. La mortalidad hospitalaria fue de 9 pacientes (14,2%). Conclusiones En nuestro estudio evidenciamos que la terapia VAC disminuye significativamente la mortalidad y estancia hospitalaria de las mediastinitis poscirugia cardiaca comparada con las series publicadas con el tratamiento convencional. Estos resultados nos animan a continuar con este tratamiento.

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.

Of a total number of 288 patients with mitral stenosis treated by percutaneous balloon valvuloplasty, 21 patients had a basal mitral area equal to or greater than 1.5 cm2, as measured hemodynamically. The immediate hemodynamic results of this particular group of patients with mild mitral stenosis are described, as well as the clinical and echo doppler findings at follow-up (22 +/- 12 mo). Patients with mild mitral stenosis (group I) had more pliable valves (p less than 0.01), as assessed by echo, and higher incidence of sinus rhythm (p less than 0.02) than that observed in the remaining 267 patients (group II). After valvuloplasty the valve area increased in group I from 1.7 +/- 0.2 to 3.1 +/- 0.7 cm2 (p less than 0.0001). This mean final area was significantly different (p less than 0.0001) than that observed in group II (1.98 +/- 0.6 cm2). No patients with mild mitral stenosis developed progression of mitral regurgitation, and none had any other major complications. Most of them reached a grade I final functional status. At echo doppler follow-up studies we did not observe significant changes in the mean mitral gradient as compared with the immediate hemodynamic results. These findings suggest that early mitral balloon valvuloplasty could be an alternative in trying to favorably influence the natural course of the rheumatic mitral disease in selected patients.