Severe mitral regurgitation after radiotherapy.

We present the case of a 69-year-old patient with a history of gynecological neoplasia and a pulmonary metastasis, who in 1996 underwent chemotherapy and mediastinal radiotherapy followed by cancer remission. Ten years later she presented with heart failure and her Doppler echocardiogram showed severe mitral regurgitation with pulmonary hypertension. In 2011, she underwent a mitral valve replacement with a biological prosthesis and the pathology exam revealed valve damage consistent with radiotherapy-induced changes. This unusual mechanism of mitral regurgitation can be demonstrated clearly by echocardiography and should be disseminated among cardiology physicians and in patients who have survived for long periods after radiotherapy, it is important to remember that cardiac complications may indeed occur, and the treating physician is responsible for detecting them.

The heavy chain variable segment gene repertoire in chronic Chagas' heart disease.

Patients chronically infected with Trypanosoma cruzi develop chronic Chagas' heart disease (cChHD). Their Ab response is suspected to be involved in the cardiac pathogenesis. Reactivity of serum Abs from these patients has been extensively studied but little is known about the diversity of the in vivo IgG repertoire. We analyzed 125 variable H chain (VH) genes and compared it to repertoires from healthy individuals, and patients with autoimmune processes and other infections. VH were from plasma cells isolated from heart tissue of three cChHD patients and from a Fab combinatorial library derived from bone marrow of another cChHD patient. The role of the parasite in shaping the Ab repertoire was assessed analyzing VH genes before and after panning against T. cruzi Ag. Among recovered VH genes, a significantly increased representation of VH4 was observed. Plasma cells at the site of cardiac infiltration showed an increased VH1 usage. CDR3 lengths were similar to the ones found in the healthy repertoire and significantly shorter than in other infections. VH derived from anti-T. cruzi Fab and plasma cells showed a higher proportion of hypermutated genes, 46.9% and 43.75%, respectively, vs 30.9% of the cChHD patient repertoire, pointing to the role of parasite Ags in the shaping of the humoral response in Chagas' disease. No histological evidence of germinal center-like structures was observed in heart tissue. In accordance, VH analysis of heart plasmocytes revealed no evidence of clonal B cell expansion, suggesting that they migrated into heart tissue from secondary lymphoid organs.

Advances in coronary heart disease surgery in Latin America.

BACKGROUND: The beginnings of coronary artery bypass graft in Latin America could be set in the year 1971. Since then, improvements in technique and greater experience have resulted in a rapid increase in the rate of interventions performed in the region. METHODS AND RESULTS: Searches through PubMed and Literatura Latinoamericana y del Caribe en Ciencias de la Salud, as well as personal communications from specialists from Latin America, have been the source of information. Articles were selected by their content related to the theme, and the authors' nationality and information is mainly from Latin America. Demographic information of the population of Latin America denotes higher age averages, and this implies an increase in the severity of comorbidities in patients who undergo surgery. Longer life expectancy and improvements in medical therapy have implied that patients survive a first intervention beyond the expected time a bypass persists patent. Wall vessel properties of arterial conduits, plus a better anastomotic technique, seem to be the current solution to worsening in the coronary health of patients who undergo revascularization surgery in Latin America. CONCLUSIONS: Despite scarce economic investment in medical sciences, many academic groups contribute to the exploration of therapeutic pharmacological combinations and inclusively apply genetic strategies.

Expression of the MDR-1 gene-encoded P-glycoprotein in cardiomyocytes of conscious sheep undergoing acute myocardial ischemia followed by reperfusion.

We have recently reported that in chronic myocardial ischemia, adult mammalian cardiomyocytes express P-glycoprotein (P-gp). We now investigate if P-gp is also expressed in acute regional ischemia followed by reperfusion. Adult conscious sheep underwent 12-min occlusion of the mid-left anterior descending artery (inflatable cuff). Successful ischemia-reperfusion was confirmed by monitoring percent systolic left ventricular anterior wall thickening (sonomicrometry) during the whole ischemic period and every 10 min over 2 hr following cuff deflation. At 3, 24, and 48 hr after reperfusion, P-gp expression was investigated by immunohistochemistry and Western blot and MDR-1 mRNA by RT-PCR. Cardiomyocytes in the occluded artery territory (but not those in remote areas) consistently expressed P-gp at their sarcolemma. Whereas at 3 and 24 hr P-gp was mainly observed in the T tubules, at 48 hr it predominated in intercalated discs and gap junctions. RT-PCR and Western blot revealed higher expression in ischemic than in control myocardium. We conclude that in adult sheep with acute myocardial ischemia, the MDR-1 gene-encoded P-gp is expressed at the sarcolemma of the cardiomyocytes from 3 hr up to at least 48 hr after reperfusion.

Activated macrophages as a feeder layer for growth of resident cardiac progenitor cells.

The adult heart contains a population of cardiac progenitor cells (CPCs). Growing and collecting an adequate number of CPCs demands complex culture media containing growth factors. Since activated macrophages secrete many growth factors, we investigated if activated isolated heart cells seeded on a feeder layer of activated peritoneal macrophages (PM) could result in CPCs and if these, in turn, could exert cardioprotection in rats with myocardial infarction (MI). Heart cells of inbred Wistar rats were isolated by collagenase digestion and cultured on PM obtained 72 h after intraperitoneal injection of 12 ml thioglycollate. Cells (1 × 10(6)) exhibiting CPC phenotype (immunohistochemistry) were injected in the periphery of rat MI 10 min after coronary artery occlusion. Control rats received vehicle. Three weeks later, left ventricular (LV) function (echocardiogram) was assessed, animals were euthanized and the hearts removed for histological studies. Five to six days after seeding heart cells on PM, spherical clusters composed of small bright and spherical cells expressing mostly c-Kit and Sca-1 antigens were apparent. After explant, those clusters developed cobblestone-like monolayers that expressed smooth muscle actin and sarcomeric actin and were successfully transferred for more than ten passages. When injected in the MI periphery, many of them survived at 21 days after coronary ligature, improved LV ejection fraction and decreased scar size as compared with control rats. CPC-derived cells with cardiocyte and smooth muscle phenotypes can be successfully grown on a feeder layer of activated syngeneic PM. These cells decreased scar size and improved heart function in rats with MI.

Sialic acid as a protective barrier against neointima development.

Arterial sialic acid (SA) has been shown to attenuate the binding of fibrinogen and low-density lipoproteins (LDL) to the vessel wall, presumably protecting against atherosclerosis. This study was aimed to assess the effect of changes in SA content in intimal thickening, an early step in the development of atherosclerosis. New Zealand white rabbits were subjected to bilateral carotid periarterial collaring, followed by in situ-perfusion with neuroaminidase (random artery) and with vehicle (contralateral control artery). The efficiency of SA removal was evaluated in perfusates and arterial homogenates, and arterial tissue samples were obtained 7 and 14 days after the intervention to assess morphological changes. Neuraminidase significantly reduced SA by 16.7%. Arterial desialylation was associated with a significantly increased neointimal formation. Proliferation of smooth muscle cells (SMCs), assessed by incorporation of bromo-2'-deoxyuridine into replicating DNA was also significantly increased in desialylated arteries. In addition, immunohistochemical studies showed a slightly stronger oxidized-LDL (ox-LDL) immunostaining in neointima of desialylated arteries than in control vessels. A mild reduction of SA increases intimal thickening, at least partly due to an enhanced proliferation of SMCs, and may facilitate the accretion of atherogenic lipoproteins, providing evidence for the potential role of SA in the protection against neointimal development.

Cardiomyocytes of chronically ischemic pig hearts express the MDR-1 gene-encoded P-glycoprotein.

The multidrug-resistant (MDR)-1 gene-encoded P-glycoprotein (Pgp-170) is not normally present in the cardiomyocyte. Given that in other tissues Pgp-170 is not found under normoxic conditions but is expressed during hypoxia, we searched for Pgp-170 in chronically ischemic porcine cardiomyocytes. Pgp-170 was detected and localized via immunohistochemistry in ischemic and nonischemic cardiomyocytes of eight adult pigs 8 weeks after placement of an Ameroid constrictor at the origin of the left circumflex artery (Cx). Regional myocardial ischemia in the Cx bed was documented with nuclear perfusion scans. Pgp-170 mass was quantified using Western blot analysis. In all pigs, Pgp-170 was consistently present in the sarcolemma and T invaginations of the cardiomyocytes of the ischemic zone. Pgp-170 expression decreased toward the border of the ischemic zone and was negative in nonischemic regions as well as in the myocardium of sham-operated animals. Western blot analysis yielded significantly higher Pgp-170 mass in ischemic than in nonischemic areas. We conclude that Pgp-170 is consistently expressed in the cardiomyocytes of chronically ischemic porcine myocardium. Its role in the ischemic heart as well as in conditions such as myocardial hibernation, stunning, and preconditioning may have potentially relevant clinical implications and merits further investigation.

Effects of short-term inhaled nitric oxide on interleukin-8 release after single-lung transplantation in pigs.

BACKGROUND: Lung transplantation has evolved to become an effective treatment for a variety of end-stage lung diseases. However, severe reperfusion injury is still a major cause for postoperative morbidity and mortality. Although lung reperfusion injury is complex and has not been fully comprehended yet, neutrophil infiltration and cytokine activation have been postulated to play a main role. Recent studies showed that nitric oxide (NO) therapy has salutary effects on lung chronic and acute pathologies because it inhibits interleukin-8 (IL-8) release, but no data have been found on its effects during organ harvest. The aim of this study was to assess whether low doses of inhaled NO pre-treatment at the time of harvesting improves allograft function during early reperfusion in a porcine model. METHODS: Twenty-two Landrace pigs were randomly assigned to NO-treated and control groups. In NO-treated pigs, NO at 20 ppm was administered 30 min before harvest. During the early allograft reperfusion period IL-8 content, dynamic and static compliance and gas exchange (Pa/FiO2 and PaO2) were measured in both control and NO-treated lungs. RESULTS: Pre-treatment with NO at the time of harvesting showed improvement of allograft function in terms of dynamic (92 +/- 8% in NO vs 72 +/- 7% in the control group, p < .05) and static (83 +/- 8% in NO vs 63 +/- 7% in the control group, p < 0.05) compliance and gas exchange (PaO2: 96 +/- 4% in NO vs 74 +/- 4.5% in the control group, p < 0.01; Pa/FiO2: 97 +/- 5% in NO vs 74 +/- 5% in the control group, p < 0.01) by diminishing IL-8 (66.5 +/- 4.7 pg/ml in NO versus 208 +/- 43 pg/ml in the control group, p < 0.05) release in pigs. CONCLUSION: These results show for the first time that NO pre-treatment at the time of harvesting reduces allograft reperfusion injury in part due to its effects on IL-8 release.

DNA content and expression of cell cycle proteins in caterpillar nuclei from fetal human cardiac myocytes.

Caterpillar nuclei (CN) are characterized by their peculiar morphology, with chromatin distributed in clusters and running along the longitudinal axis of the nucleus. They can be observed in normal hearts of fetuses as well as in hearts of children and adults with rheumatic heart disease. This study has demonstrated by means of ploidy studies with digital image analysis that in the fetal heart (20.5+/-1.8 weeks) the CN (diploid = 5.6+/-8.4%; tetraploid = 46.2+/-24.2%; hypertetraploid = 46.9+/-26.3%) present higher DNA content than non-caterpillar myocyte nuclei (diploid = 89.4+/-6.2%; tetraploid = 10.0+/-4.1%; hypertetraploid = 1.5+/-1.3%) (P=0.000001, 0.00013, and 0.000038, respectively). Expression of proliferation cell nuclear antigen (PCNA; 30.6+/-11.7% in CN and 13.4+/-7.3% in non-caterpillar myocyte nuclei; P=0.0115) and cyclin B1 (2.8+/-3.8% and 12.6+/-15.6%, respectively; P=n.s.) was also positive in these nuclei. In conclusion, these results suggest that there exists a relationship between CN morphology and myocyte replication phenomena.

Analysis of the presence of Trypanosoma cruzi in the heart tissue of three patients with chronic Chagas' heart disease.

It is still unclear to what extent myocarditis-associated, chronic Chagas' heart disease is due to persisting Trypanosoma cruzi. In the present study, we have analyzed tissue samples from the hearts of three patients with this disease. In situ hybridization provided little evidence for the presence of intact T. cruzi even at sites of strong inflammation. Nevertheless, micromanipulation techniques detected remnants of both T. cruzi kinetoplast DNA and nuclear DNA. Trypanosoma cruzi DNA was also detected in single macrophages dissected directly from frozen heart tissue sections. Thus, this analysis demonstrates that T. cruzi kinetoplast DNA and nuclear DNA are widely dispersed in the heart tissue, although in low amounts. Since we rarely detected intact T. cruzi parasites during the chronic phase of Chagas' heart disease, we can exclude heart tissue as a major parasite reservoir.

Successful circumferential free tracheal transplantation in a large animal model.

BACKGROUND: Long segment tracheobronchial stenoses are associated with high morbi-mortality rates and difficult treatment. Transplantation hasn't proved to be useful yet. Currently, the successful results achieved in small animal models couldn't be satisfactorily accomplished or extrapolated in large mammals. We aimed to evaluate the viability of orthotopic tracheal autoimplantation in an ovine model. METHODS: All animals underwent tracheal transplantation of 4 cm (5-7 rings) of the cervical trachea and were divided randomly in two groups: isolated autoimplantation (Group A/6) and autoimplantation with omental wrapping (Group B/6). Clinical follow up and weekly bronchoscopical examinations were performed. The grafts were macroscopically, histologically, and bacteriologically analyzed. RESULTS: In group A, four animals achieved their planed survival and were sacrificed up to 60 days after transplantation with viable grafts. In group B, only two sheep had successful results. Graft failure with infection, necrosis and severe stenosis was observed in the rest of the animals from both groups. Pseudomonas aeruginose was isolated in all cases. The main complication of the omental pedicle was vascular congestion and peritracheal hemorrhage. CONCLUSIONS: Contrary to the data reported to date, we found that tracheal transplantation is viable in a large mammal like the sheep. The main complication observed in this animal model was graft infection. The use of an omental pedicle with the technique applied worsened the grafts survival. The encouraging results obtained in this investigation justify further research in order to manage graft infection, leading us to establish a suitable large animal model for allotransplantation.

Comparison of prevalence, clinical course, and pathological findings of left ventricular systolic impairment versus normal systolic function in patients with hypertrophic cardiomyopathy.

Impaired left ventricular systolic function (ILVSF) in hypertrophic cardiomyopathy (HC) is a risk factor for sudden death and a determinant of high mortality. We determined its prevalence, clinical parameters, long-term outcome, and pathologic findings of explanted hearts. We retrospectively analyzed 382 patients with HC; ILVSF was characterized by LV ejection fraction <50% at rest and was identified in 24 patients (6.3%). Patients with ILVSF were younger than patients with normal SF (43.5 ± 14.1 vs 55.3 ± 20.4 years, p = 0.001) and had larger LV end-diastolic cavity diameter (53.2 ± 12.2 vs 43.8 ± 6.2 mm, p = 0.001), larger left atrium (51.2 ± 6.5 vs 44.3 ± 8 mm, p <0.001), and lower fractional shortening (30.7 ± 11.1% vs 45.5% ± 10.3%, p <0.001). A combined end point (heart failure death or heart transplantation) was considered. Median follow-up was 3 years (1.2 to 6.3). Fourteen patients with ILVSF (58.3%) had the end point compared to 3 (0.8%) with normal SF (p <0.001). In explanted hearts, fibrosis represented 30.5 ± 12.5% of the left ventricle; we observed a direct correlation between fibrosis and ventricular dilation (r = 0.794, p = 0.001) and an inverse correlation between fibrosis and ejection fraction (r = -0.623, p = 0.023). Number and length density of small arterioles (<50 µm in diameter) were significantly decreased. In conclusion, ILVSF in HC has a poor prognosis and is associated with fibrosis and selective decreased development of small arterioles.

Cardiomyocyte hypertrophy, oncosis, and autophagic vacuolization predict mortality in idiopathic dilated cardiomyopathy with advanced heart failure.

OBJECTIVES: The aim of this study was to identify the remodeling parameters cardiomyocyte (CM) damage or death, hypertrophy, and fibrosis that may be linked to outcomes in patients with advanced heart failure (HF) in an effort to understand the pathogenic mechanisms of HF that may support newer therapeutic modalities. BACKGROUND: There are controversial results on the influence of fibrosis, CM hypertrophy, and apoptosis on outcomes in patients with HF; other modalities of cell damage have been poorly investigated. METHODS: In endomyocardial biopsy specimens from 100 patients with idiopathic dilated cardiomyopathy and advanced HF, CM diameter and the extent of fibrosis were determined by morphometry. The proportion of CMs with evidence of apoptosis, autophagic vacuolization (AuV), and oncosis was investigated by immunohistochemical methods and by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling. Those parameters were correlated with mortality in 3 years of follow-up by univariate analysis and with multivariate models incorporating the clinical variables more relevant to the prediction of outcomes. RESULTS: CM AuV occurred in 28 patients (0.013 ± 0.012%) and oncosis in 41 (0.109 ± 0.139%). Nineteen patients showed both markers. Apoptotic CM nuclei were observed in 3 patients. In univariate analysis, CM diameter and AuV, either alone or associated with oncosis, were predictors of mortality. In multivariate analysis, CM diameter (hazard ratio: 1.37; 95% confidence interval: 1.12 to 1.68; p = 0.002) and simultaneous presence in the same endomyocardial biopsy specimen of AuV and oncosis (hazard ratio: 2.82; 95% confidence interval: 1.12 to 7.13; p = 0.028) were independent predictors of mortality. CONCLUSIONS: CM hypertrophy and AuV, especially in association with oncosis, are predictors of outcome in patients with idiopathic dilated cardiomyopathy and severe HF.

Cardiac regeneration: the gene therapy approach.

BACKGROUND: Ischemic heart disease often results in myocardial infarction, after which surviving tissue undergoes remodeling. Unfortunately, the regenerative capacity of adult cardiomyocytes is poor. Repopulating myocardium with contractile cells is an objective of regenerative medicine. The most investigated strategy is implantation of stem cells. An alternative approach is stimulating cardiomyocytes to re-enter the cell cycle and progress to mitosis and cytokinesis through gene-mediated interventions targeting cell cycle regulators, or by injecting genes coding for mitotic cytokines. OBJECTIVE/METHODS: To summarize work done and examine postnatal growth of the heart in small rodents and large mammals to emphasize the need for caution when extrapolating results from mice and rats to humans. RESULTS/CONCLUSIONS: Today we have evidence that under certain circumstances adult cardiomyocytes re-enter the cell cycle and advances to mitosis, The problem is that our current knowledge of the triggering phenomena and the cascade of events leading to cardiomyocyte mitosis is poor.

Endurance training in the spontaneously hypertensive rat: conversion of pathological into physiological cardiac hypertrophy.

The effect of endurance training (swimming 90 min/d for 5 days a week for 60 days) on cardiac hypertrophy was investigated in the spontaneously hypertensive rat (SHR). Sedentary SHRs (SHR-Cs) and normotensive Wistar rats were used as controls. Exercise training enhanced myocardial hypertrophy assessed by left ventricular weight/tibial length (228+/-7 versus 251+/-5 mg/cm in SHR-Cs and exercised SHRs [SHR-Es], respectively). Myocyte cross-sectional area increased approximately 40%, collagen volume fraction decreased approximately 50%, and capillary density increased approximately 45% in SHR-Es compared with SHR-Cs. The mRNA abundance of atrial natriuretic factor and myosin light chain 2 was decreased by the swimming routine (100+/-19% versus 41+/-10% and 100+/-8% versus 61+/-9% for atrial natriuretic factor and myosin light chain 2 in SHR-Cs and SHR-Es, respectively). The expression of sarcoplasmic reticulum Ca(2+) pump was significantly augmented, whereas that of Na(+)/Ca(2+) exchanger was unchanged (93+/-7% versus 167+/-8% and 158+/-13% versus 157+/-7%, sarcoplasmic reticulum Ca(2+) pump and Na(+)/Ca(2+) exchanger in SHR-Cs and SHR-Es, respectively; P<0.05). Endurance training inhibited apoptosis, as reflected by a decrease in caspase 3 activation and poly(ADP-ribose) polymerase-1 cleavage, and normalized calcineurin activity without inducing significant changes in the phosphatidylinositol 3-kinase/Akt pathway. The swimming routine improved midventricular shortening determined by echocardiography (32.4+/-0.9% versus 36.9+/-1.1% in SHR-Cs and SHR-Es, respectively; P<0.05) and decreased the left ventricular free wall thickness/left ventricular cavity radius toward an eccentric model of cardiac hypertrophy (0.59+/-0.02 versus 0.53+/-0.01 in SHR-Cs and SHR-Es, respectively; P<0.05). In conclusion, we present data demonstrating the effectiveness of endurance training to convert pathological into physiological hypertrophy improving cardiac performance. The reduction of myocardial fibrosis and calcineurin activity plus the increase in capillary density represent factors to be considered in determining this beneficial effect.

Development of mild aortic valve stenosis in a rabbit model of hypertension.

OBJECTIVES: This study was designed to investigate the association between hypertension and aortic valve stenosis (AVS) in a rabbit model. BACKGROUND: Degenerative AVS is a prevalent disease in elderly persons. Its molecular mechanisms remain unclear, in part because of the absence of experimental models. Epidemiologic data suggest a link between hypertension and AVS. However, there has been no evidence of a cause-effect relationship. METHODS: New Zealand White rabbits were divided into two groups: 1) animals (n = 20) instrumented according to one-kidney/one-clip hypertensive model; and 2) control animals (n = 10) sham operated. Echocardiography (S12 MHz) was used to assess aortic valve (AV) morphology and function as well as left ventricular mass at baseline and after two and four months of hypertension. RESULTS: Blood pressure and left ventricular mass increase were highly significant in the animal model but not in controls at two months, without noticeable AV function abnormalities. After 4 months, however, 14 hypertensive survived animals showed a 14.6% reduction of AV area (0.240 +/- 0.063 cm2 vs. 0.205 +/- 0.060 cm2, p < 0.05), a 19.6% increase of AV thickness (0.056 +/- 0.011 cm vs. 0.067 +/- 0.010 cm, p < 0.001), a 40.4% increase of transvalvular mean gradient (5.35 +/- 2.26 mm Hg vs. 7.51 +/- 3.73 mm Hg, p < 0.05) and a 63.6% increase of transvalvular maximal gradient (10.56 +/- 3.68 mm Hg vs. 17.28 +/- 10.95 mm Hg, p < 0.05). Control animals did not show significant changes. CONCLUSIONS: We report a novel experimental model of AVS in rabbits that may prove useful in studying the progression of the disease and the efficacy of new treatments. The present findings support the hypothesis of a causal link between hypertension and AVS.

Dilated cardiomyopathy in Erb-b4-deficient ventricular muscle.

The neuregulin receptor tyrosine kinase Erb-b4, initially linked to early cardiac development, is shown here to play a critical role in adult cardiac function. In wild-type mice, Erb-b4 protein localized to Z lines and to intercalated disks, suggesting a role in subcellular and intercellular communications of cardiomyocytes. Conditional inactivation of erb-b4 in ventricular muscle cells led to a severe dilated cardiomyopathy, characterized by thinned ventricular walls with eccentric hypertrophy, reduced contractility, and delayed conduction. This cardiac dysfunction may account for premature death in adult erb-b4-knockout mice. This study establishes a critical role for Erb-b4 in the maintenance of normal postnatal cardiac structure and function.

Reducción del tamaño del infarto de miocardio mediante la transferencia génica de VEGF en ovejas / Myocardial infarct size reduction after VEGF gene transfer in sheep

La transferencia génica de plásmido codificante para VEGF (pVEGF) induce angiogénesis, incremento del índice mitótico e hiperplasia miocítica en cerdos con isquemia miocárdica crónica. El presente trabajo se realizó con el objetivo de estudiar el efecto del pVEGF sobre el tamaño del infarto de miocardio. Una hora después de la ligadura de la descendente anterior, 28 ovejas de 23 ± 0,5 kg se agruparon al azar para recibir 10 inyecciones intramiocárdicas de 3,8 mg de pVEGF (n = 14) o placebo (n= 14) distribuídas en la periferia del infarto. La función miocárdica se estudió con SPECT gatillado y los animales se sacrificaron 7, 10 y 15 días después del tratamiento. El tamaño del infarto fue el 34 por ciento menor en el grupo tratado que en el placebo (placebo: 17,1 ± 2,1 por ciento, VEGF: 11,2 ± 1,5 por ciento, p < 0,05) a los 15 pero no a los 10 días. Aunque hubo una leve tendencia a favor del grupo tratado, la mejoría de la función miocárdica no fue diferente entre grupos (placebo: 3,3 ± 1,4; VEGF: 3,8 ± 2,4; p = NS). El estudio histológico mostró que los mecanismos involucrados fueron la respuesta angiogénica a los 7 días (placebo: 676 ± 31 capilares / mm²: VEGF: 1925 ± 262; p <0,05), la menor fibrosis periinfarto a los 10 días (contenido de colágeno; placebo: 70, 1 ± 1,7 por ciento; VEGF: 43,5 ± 4,4 por ciento; p < 0,05); la proliferación de mioblastos a los 7 y 10 días. La expresión del pVEGF fue positiva a los 3 (ARNm), 7 y 10 días. La expresión del pVEGF fue positiva a los 3 (ARNm), 7 y 10 días (proteína) posadministración. Conclusión: A los 15 días la transferencia génica de VEGF humano reduce el tamaño de infarto en ovejas mediante angiogénesis, disminución de la fibrosis e inducción de proliferación de mioblastos (miocardiogénesis).

Identificacion de un antigeno tumoral asociado al receptor estrogenico en ganglios linfaticos axilares de pacientes con cancer mamario / Identification of a tumor antigen associated to the estrogen receptor in axillary lymph nodes of breast cancer patients

Dieciseis ganglios linfáticos axilares fueron enfrentados con suero de pacientes portadoras de cáncer mamario, encontrándose que dichos sueros reconocían determinantes antigénicos en células foliculares dendríticas (CFD) de los centros germinativos. Este hecho fue corroborado con CFD aisladas y cultivadas a las que se enfretó con los sueros experimentales. Con sueros normales, los resultados fueron negativos. Posteriormente sobre los mismos ganglios y las CFD aisladas, se realizó técnica de inmunoperoxidasa con anticuerpos monoclonales anti-proteína asociada al receptor estrogénico (ERAP). En el 75 por ciento de los casos, los ganglios mostraron células anti-ERAP+ en el seno subcapsular, sinusoides corticales y centros germinativos. El fenotipo de las células correspondió a macrófagos y células foliculares dentríticas respectivamente. Controles utilizando ganglios que drenan otros tumores malignos fueron negativos. Estoshallazgos sugieren que el antígeno tumoral podría corresponder a la proteína asociada al receptor de estrógenos o tal vez al mismo receptor, capaz de ser captado y transportado por células presentadoras de antígenos desde el tumor a los ganglios linfáticos regionales donde se produce la respuesta inmune del huésped. El posible reconocimiento de un antígeno tumoral mamario abre una perspectiva futura para el manipuleo terapéutico de esta enfermedad.

Patogenia de la miocarditis chagasica cronica humana / Pathogenesis of human chronic chagasic myocarditis

Durante las últimas décadas se publicaron numerosos estudios tendientes a demostrar la posibilidad de una patogenia autoinmune de la miocarditis chagásica crónica. Durante ese tiempo se demostró que: 1) existe mimetismo molecular entre el parásito y los antígenos del huésped, 2) aparecen autoanticuerpos que reconocen epítopes cardiácos durante la fase crónica de la infección; 3) la inmunización de animales con la totalidad del parásito, con fragmentos del mismo o con antígenos bioquímicamente definidos provoca miocarditis y alteraciones electrocardiográficas, 4) los linfocitos B de los infiltrados inflamatorios del corazón elaboran anticuerpos contra antígenos miocárdicos, 5) de esas mismas lesiones se aíslan clones de linfocitos T que reaccionan con epítopes cardíacos, 6) es posible inducir alteraciones tisulares en el corazón y en nervios mediante la transferencia de linfocitos de animales infectados en animales singeneicos virgenes de infección. Sin embargo, las características del infiltrado inflamatorio en la miocarditis humana, conteniendo una gran variedad de células, muchas de las cuales no están comprometidas en el proceso de autorreactividad, como la presencia de granulomas con células gigantes y abundantes eosinófilos, su ficalidad y asincronismo, y la frecuente asociación con pericarditis, crean dudas acerca de la posibilidad que la autoinmunidad sea por sí misma responsible de la perpetuación de la miocarditis. Estas dudas se ven reforzadas por la demostración reciente que en pacientes asintomáticos el tratamiento con drogas tradicionales previene el desarrollo de cardiopatía y que componentes del parásito, sean antígenos o fragmentos del mismo, siguen presentes en el sitio de las lesiones inflamatorias. Bajo estas nuevas evidencias se deberían postular otros mecanismos patogénicos alternativos para explicar la aparición de una miocarditis polimorfa y prolongada en el tiempo, que necesita para desarrollarse de la presencia de pequeños fragmentos del parásito. De esta manera, una nueva explicación patogénica debería conciliar la información inmunológica disponible en la actualidad y vincularla con la relación entre la presencia de pequeñas trazas de parásito, por debajo de la posibilidad de detección microscópica, y la formación del extenso infiltrado inflamatorio...