José A Montero

Centro de Investigación Príncipe Felipe, Valenza, Valencia, Spain

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Publications (39)131.87 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The development of biomaterials for myocardial tissue engineering requires a careful assessment of their performance with regards to functionality and biocompatibility, including the immune response. poly(3-hydroxybutyrate) (PHB), poly(e-caprolactone) (PCL), silk, poly-lactic acid (PLA), and polyamide (PA) scaffolds were generated by electrospinning, and cell compatibility in vitro, and immune response and cardiac function in vitro and in vivo was compared with a non-crosslinked collagen membrane (Col) control material. Results showed that cell adhesion and growth of mesenchymal stem cells (MSCs), cardiomyocytes and cardiac fibroblast in vitro was dependent on the polymer substrate, with PHB and PCL polymers permitting the greatest adhesion/ growth of cells. Additionally, polymer substrates triggered unique expression profiles of anti- and pro-inflammatory cytokines in human pheripheral blood mononuclear cells (PBMNCs). Implantation of PCL, silk, PLA and PA patches on the epicardial surface of healthy rats induced a classical foreign body reaction pattern, with encapsulation of polymer fibers and induction of the non-specific immune response, whereas Col and PHB patches were progressively degraded. When implanted on infarcted rat heart, Col, PCL and PHB reduced negative remodelling, but only PHB induced significant angiogenesis. Importantly, Col and PHB modified the inflammatory response to an M2 macrophage phenotype in cardiac tissue, indicating a more beneficial reparative process and remodelling. Collectively, these results identify PHB as a superior substrate for cardiac repair.
    Stem cells and development 02/2014; · 4.15 Impact Factor
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    ABSTRACT: 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-1α) is a master regulator of the adaptative response to hypoxia, we hypothesized that HIF-1α 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-1α 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-1α on MSC biology and suggests the stabilization of HIF-1α as a novel strategy for cellular therapies.
    Stem cells and development 08/2012; · 4.15 Impact Factor
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    ABSTRACT: 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 CX(3)CL1, 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.
    Stem cell reviews 03/2012; 8(3):905-16. · 5.08 Impact Factor
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    ABSTRACT: 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.
    Stem cell reviews 02/2012; · 5.08 Impact Factor
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    ABSTRACT: 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 novo 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 α-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 30days 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.
    Journal of Molecular and Cellular Cardiology 11/2010; 49(5):771-80. · 5.15 Impact Factor
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    ABSTRACT: 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. 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. 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. 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. 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.
    Journal of the American College of Cardiology 05/2010; 55(20):2244-53. · 14.09 Impact Factor
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    ABSTRACT: 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.
    Journal of Cardiovascular Translational Research 02/2010; 3(1):61-5. · 3.06 Impact Factor
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    ABSTRACT: 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.
    Stem cells and development 12/2008; 18(6):907-18. · 4.15 Impact Factor
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    ABSTRACT: Liquid nitrogen is the most common medium used by tissue banks for the storage of cryopreserved heart valves. This study evaluates the effect of the length of storage on human cryopreserved heart valves. Human tissues (14 aortic and 13 pulmonary) were frozen in a controlled-rate freezer (1 degrees C/min) and stored in the liquid phase of a nitrogen tank for 9.1+/-1.6 years. The preservative solution was medium M199 containing 5% human serum albumin and 10% Me(2)SO. After thawing in a water bath at 42 degrees C, the cryoprotectant was removed. Then, fragments from vascular wall and leaflet were dissected. Explant cultures and histological studies were performed in order to assess cell viability and structural integrity. CD90 and CD31 expression was analysed in cultured cells using flow cytometry. Light microscopy, immunofluorescence staining and laser scanning confocal microscopy were used to evaluate cell viability and extracellular matrix components. Electron microscopy was used for ultrastructural study. Cell cultures could be obtained from all the specimens assayed. Cells grew from explants showing a fibroblastic phenotype. CD90 expression was common in cultured cells but a low percentage of cells expressed CD31. Histological results showed a good preservation estructure in both leaflets and vascular walls. Morphological features of cellular irreversible damage were very rare. No differences which could be due to length of allograft storage period were observed. We concluded that allografts stored in liquid nitrogen up to 13 years did not significantly undergo loss of cell viability other than that due to disinfection, freezing and thawing protocols.
    Cryobiology 08/2008; 57(2):113-21. · 2.14 Impact Factor
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    ABSTRACT: 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 x 10(6) 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.
    Stem Cells 04/2008; 26(3):638-45. · 7.70 Impact Factor
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    The Journal of thoracic and cardiovascular surgery 03/2006; 131(2):466-7. · 3.41 Impact Factor
  • María Bueno, Óscar Gil, José A. Montero
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    ABSTRACT: Penetrating aortic ulcers (PAU) are lesions caused by rupture of an atherosclerotic plaque. Associated to intramural hematoma are equivalent to a dissection in prognosis. They evolve towards rupture, dissection and aneurysm formation. A 78-year-old male with past history of hypertension and operated colonic cancer. CAT scan showed a descending thoracic aortic aneurysm. MRI showed PAU and aneurysm (Fig. 1). Transfemoral endovascular repair with general anesthesia and monitoring of cerebrospinal fluid pressure was performed. The aneurysm and ulcers were excluded (Fig. 2). He was discharged in 48 h.
    Cirugía Cardiovascular. 01/2006; 13(1):105.
  • The Annals of thoracic surgery 11/2005; 80(4):1528. · 3.45 Impact Factor
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    ABSTRACT: Virtual endoscopy of the aorta is a new three-dimensional reconstruction method from multislice computed tomography or magnetic resonance that offers a virtual navigation through the aorta, and the possibility of having a new preoperative endoluminal vision. We present a case of subacute aortic dissection with a preoperative virtual endoscopy of the aorta.
    The Annals of thoracic surgery 09/2005; 80(2):708-10. · 3.45 Impact Factor
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    ABSTRACT: In the last few years, the percentage of high-risk patients proceeding to coronary artery bypass surgery has increased. The most common risk factors are older age and the presence of comorbid complaints. We carried out a retrospective study to confirm this new risk profile and to evaluate its impact on surgical results. We analyzed the changing risk profile of 1360 patients who underwent coronary artery bypass surgery in our hospital between 1993 and 2001, divided into three historical cohorts: 1993-1996, 1997-1999 and 2000-2001. The main factors associated with morbidity and mortality were analyzed by logistic regression analysis. The introduction of new operative techniques, such as off-pump surgery and arterial grafting, was also evaluated. The patients' risk profile worsened over time: patients were older, comorbid complaints were more common, and ventricular function was poorer. EuroSCORE figures reflected this trend: estimated mortality in the three historical cohorts was 2.0%, 4.0% and 4.2%, respectively (P<.001). However, risk-adjusted mortality, at 3.7%, 2.7% and 1.5%, respectively, decreased (P<.05), and combined overall morbidity and mortality remained stable, at 16.7%, 16.4% and 13.8%, respectively, (P<.39). There was a non-significant tendency for arterial grafting and off-pump surgery to reduce in-hospital morbidity and mortality. The risk profile of patients undergoing surgery has worsened as their mean age has increased and as comorbid complaints have become more prevalent. However, there has been no simultaneous increase in risk-adjusted mortality. The potential benefits of new surgical advances such as off-pump surgery and multiple arterial grafting must be corroborated by future studies.
    Revista Espa de Cardiologia 05/2005; 58(5):512-22. · 3.20 Impact Factor
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    ABSTRACT: In the last few years, the percentage of high-risk patients proceeding to coronary artery bypass surgery has increased. The most common risk factors are older age and the presence of comorbid complaints. We carried out a retrospective study to confirm this new risk profile and to evaluate its impact on surgical results. We analyzed the changing risk profile of 1360 patients who underwent coronary artery bypass surgery in our hospital between 1993 and 2001, divided into three historical cohorts: 1993-1996, 1997-1999, and 2000-2001. The main factors associated with morbidity and mortality were analyzed by logistic regression analysis. The introduction of new operative techniques, such as off-pump surgery and arterial grafting, was also evaluated. The patients' risk profile worsened over time: patients were older, comorbid complaints were more common, and ventricular function was poorer. EuroSCORE figures reflected this trend: estimated mortality in the three historical cohorts was 2.0%, 4.0%, and 4.2%, respectively (P <.001). However, risk-adjusted mortality, at 3.7%, 2.7%, and 1.5%, respectively, decreased (P <.05), and combined overall morbidity and mortality remained stable, at 16.7%, 16.4%, and 13.8%, respectively (P <.39). There was a nonsignificant tendency for arterial grafting and off-pump surgery to reduce in-hospital morbidity and mortality. The risk profile of patients undergoing surgery has worsened as their mean age has increased and as comorbid complaints have become more prevalent. However, there has been no simultaneous increase in risk-adjusted mortality. The potential benefits of new surgical advances such as off-pump surgery and multiple arterial grafting must be corroborated by future studies.
    Revista Espanola de Cardiologia 05/2005; 58(5):512-22. · 3.20 Impact Factor
  • María Bueno, Fernando Hornero, José A. Montero
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    ABSTRACT: In the surgical treatment of rheumatic tricuspid disease with leaflet fibrosis and retraction, valve replacement is often performed. Patch enlargement of the leaflets with a pericardial patch is an alternative. A 71-year-old female with rheumatic polivalvular valve disease. At operation, the tricuspid valve is found to have thickened leaflets and subvalvular apparatus with no coaptation (Fig. 1). The anterior and posterior leaflets were enlarged with an autologous pericardial patch treated with glutaraldehide (Fig. 2) and mitral and aortic valve replacement with bioprostheses performed. Postoperative echocardiogram showed normal function of the tricuspid valve and bioprostheses.
    Cirugía Cardiovascular. 01/2005; 12(3):254.
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    ABSTRACT: Introducción y objetivos. En los últimos años se ha producido un aumento del riesgo en los pacientes en los que se realiza una derivación coronaria. La mayor edad y comorbilidad son las causas involucradas con más frecuencia. Se ha realizado un estudio retrospectivo para constatar este nuevo perfil y valorar su impacto. Pacientes y método. Se ha analizado la tendencia de riesgo de 1.360 pacientes en los que se realizó una derivación coronaria consecutivamente entre 1993 y 2001 en nuestro centro. Se han considerado 3 cohortes históricas: en los años 1993-1996, 1997-1999 y 2000-2001. Se ha estudiado la morbimortalidad y sus principales factores asociados mediante un análisis de regresión logística. Se ha valorado la influencia de nuevas técnicas, como la revascularización con injertos arteriales o la cirugía sin circulación extracorpórea. Resultados. Se ha constatado un riesgo quirúrgico creciente: mayor edad, mayor frecuencia de morbilidad asociada y peor función ventricular. El EuroSCORE ha ratificado esta tendencia (el 2,0, el 4,0 y el 4,2% de mortalidad estimada en las cohortes respectivas; p < 0,001). Pese a ello, la mortalidad ajustada al riesgo ha descendido (el 3,7, el 2,7 y el 1,5%; p < 0,05) y la morbimortalidad global se ha mantenido (el 16,7, el 16,4 y el 13,8%; p = 0,39). El empleo de injertos arteriales y la cirugía sin circulación extracorpórea han mostrado una tendencia hacia una menor morbimortalidad hospitalaria. Conclusiones. Ha empeorado el riesgo quirúrgico de los pacientes coronarios debido a una mayor edad y comorbilidad. Pese a ello, no se ha producido un aumento de la mortalidad ajustada al riesgo. El probable efecto beneficioso de la cirugía sin circulación extracorpórea y el empleo de injertos arteriales debe ser corroborado por futuros estudios.
    Revista española de cardiología, ISSN 0300-8932, Vol. 58, Nº. 5, 2005, pags. 512-522. 01/2005;
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    Rafael García Fuster, Jordi Estornell, Oscar Gil, José Anastasio Montero
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    ABSTRACT: 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.
    European Journal of Cardio-Thoracic Surgery 11/2004; 26(4):839-41. · 2.67 Impact Factor
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    ABSTRACT: The maze procedure can be performed surgically with radiofrequency, generating transmural ablation lines. We report our experience with a biatrial pattern of lesions based on the use of epicardial and endocardial radiofrequency ablation in an effort to minimize maze procedure. In 85 patients undergoing cardiac surgery for established permanent atrial fibrillation (>3 months), a biauricular pattern of epicardic-endocardic maze lesions was performed. The main surgical procedures were diverse: 42 mitral valve surgeries, 7 mitrotricuspid valves, 18 mitroaortics, 4 mitroaortic and tricuspids, 2 aortic valves, 3 CABGs, 5 CABG and valve procedures, and 4 atrial septal defects. The mean age of the patients was 61 +/- 12 (range 39-78). The mean duration of atrial fibrillation was 5.8 years (range 0.3 to 24). Sixty-two (72.9%) patients presented postoperative supraventricular arrhythmia. Hospital mortality was seen in five patients (5.8%). Two patients died after a 12-month mean follow-up (range 2 to 32). A total of 14.1% of patients remained with their previous atrial fibrillation and 85.9% recovered and maintained sinus rhythm, with two patients having a permanent pacemaker. A total of 56% patients have been followed-up for a period of more than 6 months, and among them prevalence of sinus rhythm is 87.5%. Echocardiography detected biauricular contraction in 65% of them. After analyzing the data, factors involved in postoperative recurrence of atrial fibrillation after radiofrequency surgery were oldness of the atrial fibrillation (p < 0.01) and pre and postoperative left auricle volume (p < 0.04). Intraoperative radiofrequency has permitted us to perform the maze procedure in a simple way, with a low surgical morbid-mortality. We have obtained an 85.9% electrographic effectiveness and a 65% recovery of atrial contraction. Postoperative incidence of arrhythmia is the main postoperative problem.
    Journal of Cardiac Surgery 09/2004; 19(5):383-8. · 1.35 Impact Factor