RESUMO
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.
RESUMO
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.
Assuntos
Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/etiologia , Insuficiência da Valva Mitral/diagnóstico por imagem , Insuficiência da Valva Mitral/etiologia , Lesões por Radiação/diagnóstico por imagem , Lesões por Radiação/etiologia , Radioterapia/efeitos adversos , Idoso , Ecocardiografia/métodos , Feminino , Insuficiência Cardíaca/cirurgia , Humanos , Insuficiência da Valva Mitral/cirurgia , Órgãos em Risco/efeitos da radiação , Órgãos em Risco/cirurgia , Lesões por Radiação/cirurgia , Resultado do TratamentoRESUMO
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.
Assuntos
Traqueia/transplante , Animais , Broncoscopia , Masculino , Modelos Animais , Pseudomonas aeruginosa/isolamento & purificação , Ovinos , Traqueia/patologia , Transplante AutólogoRESUMO
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.
Assuntos
Cardiomiopatia Hipertrófica/patologia , Cardiomiopatia Hipertrófica/fisiopatologia , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/fisiopatologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Fatores de Risco , Sístole , Disfunção Ventricular Esquerda/epidemiologiaRESUMO
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.
Assuntos
Cardiomiopatia Dilatada/patologia , Insuficiência Cardíaca/patologia , Miócitos Cardíacos/patologia , Remodelação Ventricular , Adulto , Cardiomiopatia Dilatada/complicações , Cardiomiopatia Dilatada/mortalidade , Feminino , Fibrose , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
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.
Assuntos
Anticorpos Antiprotozoários/genética , Cardiomiopatia Chagásica/imunologia , Rearranjo Gênico do Linfócito B/genética , Cadeias Pesadas de Imunoglobulinas/biossíntese , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/biossíntese , Região Variável de Imunoglobulina/genética , Adulto , Sequência de Aminoácidos , Anticorpos Antiprotozoários/biossíntese , Antígenos de Protozoários/imunologia , Linfócitos B/imunologia , Linfócitos B/parasitologia , Linfócitos B/patologia , Cardiomiopatia Chagásica/parasitologia , Cardiomiopatia Chagásica/patologia , Doença Crônica , Regiões Determinantes de Complementaridade/biossíntese , Regiões Determinantes de Complementaridade/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Hipermutação Somática de Imunoglobulina/genética , Trypanosoma cruzi/imunologiaRESUMO
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.
Assuntos
Terapia Genética/métodos , Miócitos Cardíacos/patologia , Regeneração/fisiologia , Animais , Terapia Genética/tendências , Humanos , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/terapia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/transplanteRESUMO
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.
Assuntos
Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Hipertensão/patologia , Hipertensão/fisiopatologia , Resistência Física/fisiologia , Animais , Apoptose/fisiologia , Calcineurina/metabolismo , Cardiomegalia/terapia , Regulação para Baixo/fisiologia , Expressão Gênica/fisiologia , Hipertensão/terapia , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , Transdução de Sinais/fisiologia , Trocador de Sódio e Cálcio/genética , Natação/fisiologiaRESUMO
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.
Assuntos
Ponte de Artéria Coronária/métodos , Doença das Coronárias/cirurgia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Angioplastia Coronária com Balão , Aterosclerose/epidemiologia , Soluções Cardioplégicas , Terapia Combinada , Comorbidade , Ponte de Artéria Coronária/economia , Ponte de Artéria Coronária/mortalidade , Ponte de Artéria Coronária/estatística & dados numéricos , Ponte de Artéria Coronária/tendências , Doença das Coronárias/epidemiologia , Doença das Coronárias/terapia , Reestenose Coronária/epidemiologia , Reestenose Coronária/cirurgia , Diabetes Mellitus/epidemiologia , Dieta , Feminino , Fibrinolíticos/uso terapêutico , Terapia Genética , Humanos , Hiperlipidemias/epidemiologia , América Latina/epidemiologia , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/cirurgia , Obesidade/epidemiologia , Inibidores da Agregação Plaquetária/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Reoperação , Fatores de Risco , Fatores SocioeconômicosRESUMO
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.