Associations between clinical features and therapy with macrophage subpopulations and T cells in inflammatory lesions in the aorta from patients with Takayasu arteritis.

Takayasu arteritis (TAK) is a large-vessel granulomatous vasculitis; the inflammatory infiltration in arteries comprises macrophages, multi-nucleated giant cells, CD4+ and CD8+ T cells, γδ T cells, natural killer (NK) cells and neutrophils. However, it is unknown which subtype of macrophages predominates. This study aims to evaluate macrophages subpopulations in the aorta in TAK. Immunohistochemistry was performed in the aorta from TAK patients (n = 22), patients with atherosclerotic disease (n = 9) and heart transplant donors (n = 8) using the markers CD68, CD86, CD206, CD3, CD20 and CD56. Active disease was observed in 54·5% of patients and active histological lesions were found in 40·9%. TAK patients presented atherosclerotic lesions in 27·3% of cases. The frequency of macrophages, M1 macrophages, T, B and NK cells was higher in the aorta from TAK and atherosclerotic patients compared to heart transplant donors. In TAK, macrophages and T cells were the most abundant cells in the aorta, and the expression of CD206 was higher than CD86 (P = 0·0007). No associations were found between the expression of cell markers and active disease or with atherosclerotic lesions. In TAK patients, histological disease activity led to higher T cell counts than chronic fibrotic lesions (P = 0.030), whereas prednisone use was associated with lower T cell counts (P = 0·035). In conclusion, M1 macrophages were more frequent in TAK and atherosclerotic patients compared to heart transplant donors, while M2 macrophages dominated M1 macrophages in TAK. T cells were associated with histological disease activity and with prednisone use in TAK.

Role of cooperative binding on noise expression.

The origin of stochastic fluctuations in gene expression has received considerable attention recently. Fluctuations in gene expression are particularly pronounced in cellular systems because of the small copy number of species undergoing transitions between discrete chemical states and the small size of biological compartments. In this paper, we propose a stochastic model for gene expression regulation including several binding sites, considering elementary reactions only. The model is used to investigate the role of cooperativity on the intrinsic fluctuations of gene expression by means of master-equation formalism. We found that the Hill coefficient and the level of noise increase as the interaction energy between activators increases. Additionally, we show that the model allows one to distinguish between two cooperative binding mechanisms.

Coronary fat content evaluated by morphometry in patients with severe atherosclerosis has no relation with serum lipid levels.

The relationship between lipid serum levels and coronary atherosclerotic plaque fat content was studied in 51 necropsy patients. Serum lipids were measured by standard techniques, during life, in the absence of lipid-lowering drugs. Intima, intimal fat and media areas were measured using a computerized system in cryosections of the odd segments of the right, anterior descending and circumflex coronary arteries stained with Sudan-IV. Mean intimal and lipid areas were 5.74 +/- 1.98 and 1.22 +/- 0.55 mm2 (22.12 +/- 8.48%) in 26 cases with high cholesterol (>or=200 mg/dL) and 4.98 +/- 1.94 and 1.16 +/- 0.66 mm2 (22.75 +/- 9.06%) in 25 cases with normal cholesterol (<200 mg/dL; P > 0.05). Patients with high levels of low-density lipoprotein (>or=130 mg/dL, N = 15) had a higher intima/media area ratio than those with normal levels of low-density lipoprotein (<130 mg/dL, N = 13, P < 0.01). No significant difference in the morphometrical variables was found in groups with high or low serum levels of triglycerides (>or=200 mg/dL, N = 13 vs <200 mg/dL, N = 36) or high-density lipoprotein (>or=35 mg/dL, N = 11 vs <35 mg/dL, N = 17). The association between the morphological measurements and serum levels of cholesterol, its fractions, and triglycerides was also tested and the correlation coefficients were low. Although high cholesterol is a risk factor, we show here that in patients with severe atherosclerosis blood cholesterol and triglyceride levels seem to have little influence on coronary lipid content, indicating that other factors may contribute to arterial lipid deposition and plaque formation.

Methotrexate associated to lipid core nanoparticles improves cardiac allograft vasculopathy and the inflammatory profile in a rabbit heart graft model.

Coronary allograft vasculopathy is an inflammatory-proliferative process that compromises the long-term success of heart transplantation and has no effective treatment. A lipid nanoemulsion (LDE) can carry chemotherapeutic agents in the circulation and concentrates them in the heart graft. The aim of the study was to investigate the effects of methotrexate (MTX) associated to LDE. Rabbits fed a 0.5% cholesterol diet and submitted to heterotopic heart transplantation were treated with cyclosporine A (10 mg·kg-1·day-1 orally) and allocated to treatment with intravenous LDE-MTX (4 mg/kg, weekly, n=10) or with weekly intravenous saline solution (control group, n=10), beginning on the day of surgery. Animals were euthanized 6 weeks later. Compared to controls, grafts of LDE-MTX treated rabbits showed 20% reduction of coronary stenosis, with a four-fold increase in vessel lumen and 80% reduction of macrophage staining in grafts. Necrosis was attenuated by LDE-MTX. Native hearts of both LDE-MTX and Control groups were apparently normal. Gene expression of lipoprotein receptors was significantly greater in grafts compared to native hearts. In LDE-MTX group, gene expression of the pro-inflammatory factors tumor necrosis factor-α, monocyte chemoattractant protein-1, interleukin-18, vascular cell adhesion molecule-1, and matrix metalloproteinase-12 was strongly diminished whereas expression of anti-inflammatory interleukin-10 increased. LDE-MTX promoted improvement of the cardiac allograft vasculopathy and diminished inflammation in heart grafts.

Decrease in sulphated glycosaminoglycans in aortic dissection--possible role in the pathogenesis.

STUDY OBJECTIVE: The aim was to investigate alterations in sulphated glycosaminoglycans in aortic dissection. DESIGN: Aortic fragments were taken from 10 patients within the first 3 d after onset of symptoms of aortic dissection and from nine age matched patients with no aortic disease. Sulphated glycosaminoglycans were analysed and quantified by agarose gel electrophoresis and densitometry after degradation with specific enzymes. MEASUREMENTS AND MAIN RESULTS: The amount of chondroitin sulphate was similar (7.14 v 7.60 mg.g-1 of dry tissue, n = 10, p greater than 0.5) in patients with dissection and in the control group. Total sulphated glycosaminoglycan content was decreased (11.51 v 14.26 mg.g-1 of dry tissue, n = 10, p less than 0.001). This difference was due to heparan sulphate (1.79 v 2.48 mg.g-1 of dry tissue, n = 10, p less than 0.05) and mainly to dermatan sulphate (2.58 v 4.18 mg.g-1 of dry tissue, n = 10, p less than 0.001). The ratio of 6-/4-sulphated disaccharides after chondroitinase ABC digestion was increased in the affected group. No correlation between these biochemical results and a histological evaluation of mucoid content was found. On the other hand, a significant increase in chondroitin sulphate could be observed related to aging. CONCLUSIONS: The diminution in sulphated glycosaminoglycans and its possible relationship with fat, collagen, and other extracellular matrix molecules could lead to a weakness in the aortic wall related to the dissection.

Adventitial layer enlargement correlates with the percentage of medial thickness in peripheral pulmonary arteries from patients with congenital heart defects.

Arterial walls undergo modifications during the course of pulmonary hypertension, particularly in the medial and intimal layers, leading to progressive occlusion of the lumen. Adventitial layer enlargement has been described as being present in the experimental hypoxic model and in the persistent pulmonary hypertension of the newborn. It was suggested that this enlargement may be related to stimulating factors derived from the medial smooth muscle cells. This study was designed to verify if different degrees of medial hypertrophy are correlated to the volume density of the adventitial layer in pulmonary hypertension secondary to congenital heart defects. Reviewing 21 lung biopsies from patients with congenital heart defects, we concluded that there is a statistically significant positive linear correlation between the mean percentage of medial arterial thickness and the volume density of the adventitial layer in the biopsies showing isolated medial hypertrophy. On the other hand, in biopsies showing frequent intimal proliferative lesions and irregular medial layer hypertrophy the correlation coefficient was lower. These findings suggest that the adventitial layer participates in the arterial remodeling process in secondary pulmonary hypertension, and that its enlargement depends on the qualitative degree of pulmonary vaso-occlusive disease.

Atheromas that cause fatal thrombosis are usually large and frequently accompanied by vessel enlargement.

Several lines of clinical evidence show that AMI frequently occurs at sites with mild to moderate degree of coronary stenosis. The degree of luminal stenosis depends on plaque deposition and degree of vessel remodeling, features poorly assessed by coronary angiography. This postmortem study tested the hypothesis that the size of coronary atheroma and the type of remodeling distinguish culprit lesion responsible for fatal AMI from equi-stenotic nonculprit lesion in the same coronary tree. The main coronary branches from 36 consecutive patients with fatal AMI were studied. The culprit lesion (Group 1) and an equi-stenotic nonculprit segment (Group 2) obtained in measurements of another coronary branch from the same patient were compared. Morphometry and plaque composition was assessed in both groups. Compared to Group 2, Group 1 had larger areas of: plaque 9.6 vs. 4.7 mm(2), vessel 12.7 vs. 7.4 mm(2) and lumen 1.7 vs. 1.2 mm(2); (P< .01). Positive remodeling was more frequent in Group 1 than Group 2: 21/30 (70%) vs. 8/26 (31%). Plaque area correlated positively with lipid core and macrophages and negatively with fibrosis and smooth muscle cells. Atherosclerotic plaques that cause fatal thrombosis are more frequently positively remodeled and tend to be larger than nonculprit plaques with the same degree of cross-sectional stenosis. We tested whether arterial remodeling and plaque size vary between segments containing a fatal thrombosed plaque versus an equi-stenotic nonculprit plaque. Culprit vessel segments had higher cross-sectional areas of intimal plaque and of vessel wall than equi-stenotic nonculprit plaques. The cross-sectional area of the vessel correlated positively with both the lipid core area and CD68(+) macrophage content, and negatively with fibrosis area and smooth muscle cell content. These results add elements explaining limitations of angiography in identifying plaques and provide new insights into the role of remodeling in plaque instability.

Association of an increase in CD8+ T cells with the presence of Trypanosoma cruzi antigens in chronic, human, chagasic myocarditis.

The role of Trypanosoma cruzi in the pathogenesis of myocarditis in the chronic phase of Chagas' disease is still controversial, with autoimmune mechanisms frequently being proposed. In the present work, we demonstrate that higher numbers of CD8+ T cells are correlated with the presence of parasite antigens, suggesting an important role for the parasite in the development of myocardial inflammation. Quantification of the mean numbers of CD8+ and CD4+ T cells per 400x microscopic field was performed in myocardial specimens from 33 chronic chagasic patients with heart failures (nine biopsies and 24 necropsies), using an immunoperoxidase technique. The cases were grouped according to a semiquantitative score of the relative amounts of T. cruzi antigens: group 1 = absent (14 cases); group 2 = scarce extracellular or intramacrophagic antigens (12 cases); group 3 = many extracellular or intramacrophagic antigens plus T. cruzi intramyocytic pseudocysts (seven cases). The mean numbers of CD8+ and CD4+ T cells in groups 1,2, and 3 were 6.94 and 3.79, 13.89 and 6.24, and 17.91 and 5.97, respectively. The numbers of CD8+ T cells in groups 2 and 3 were significantly higher compared with group 1 (no T. cruzi antigens), but were not different from each other. Scarce, extramyocytic T. cruzi antigens were associated with an intense inflammatory infiltrate, suggesting that delayed-type hypersensitivity immune mechanism is induced by the parasite; intact myocardiocytes containing parasites did not show an inflammatory reaction around them. A poor inflammatory response was frequently associated with many extramyocytic antigens and myocardial parasite pseudocysts, suggesting that active proliferation and dissemination of the parasites occur when the immunologic response is diminished. The number of CD4+ T cells did not vary significantly among the three groups. We conclude that the CD8+ T cell is the main cell type responsible for immune activation in chronic, human, chagasic myocarditis and is probably activated by the presence of T. cruzi antigens associated with internal myocytic host antigens. The absence of a significant member of CD4+ T cells in the presence of T. cruzi antigens suggests inhibition of CD4+ T cell activation or the lack of a class II major histocompatibility complex molecule presentation mechanism.

Autopsy findings in early and late postoperative death after partial left ventriculectomy.

BACKGROUND: Partial left ventriculectomy (PLV) is an alternative to heart transplantation for patients with severe heart failure. However, this procedure is accompanied by high morbidity and mortality. Therefore, we studied the hearts of 12 patients who underwent this procedure to increase our understanding of the causes of bad outcome. METHODS: We analyzed the autopsy hearts of 11 of 16 patients who died after PLV, and one heart from a patient who underwent heart transplantation. RESULTS: Six patients died less than 30 days postoperatively, 4 of cardiogenic shock, 1 of arrhythmia, and 1 of coagulopathy. Five patients died from 36 to 120 days after the procedure, 4 of cardiogenic shock and 1 of arrhythmia. The patient who underwent heart transplantation had a cardiogenic shock 230 days after PLV. Ten hearts weighed more than 500 g and nine had myocardial infarction that extended to the papillary muscles. Four patients had infarction of both papillary muscles and 3 of them had episodes of arrhythmia, suggesting some relation between these events. CONCLUSIONS: We found several important morphologic clues for bad outcome: infarction of both papillary muscles, which may be associated with the development of arrhythmia, and myocardial infarction and pericardial hemorrhage, which may contribute to the outcome of heart failure.

Cavitary lesions close to heart valve rings. A necropsy study of 13 cases.

Necropsy reports of 13 patients with 15 cavitary lesions situated close aortic or mitral valve rings were studied in patients who ranged in age from 1 month to 57 (mean 24.9) years; 10 patients were male. Infective endocarditis occurred in 7 patients, rheumatic heart disease in 4, congenital heart diseases in 4, previous valve replacement in 4, and syphilis in 1 patient. Diameters of the cavitary lesions ranged between 1.2 and 10.5 cm; the aortic valve ring was involved in 11 patients; cavitary thrombosis occurred in 2 cases; the orifice communicating the cardiac chamber with the cavitary lesions was situated above the aortic leaflet in 5 lesions, below the aortic leaflet in 4 lesions, and above and below the aortic leaflets in 3 lesions. The mitral valve ring was involved in 3 lesions. Thus, different etiologies may be involved in the pathogenesis of these lesions; positions of the lesion may vary in relation to the valve ring, and the lesions may be a morphological expression of the fragility of the fibrous skeleton of the heart.

Emery-Dreifuss muscular dystrophy: anatomical-clinical correlation (case report).

We report on a man that had weakness of humeroperoneal distribution associated with limited range of motion of the cervical spine and elbows since he was 5 years old. At age 26 he developed tachycardia episodes. A complex arrhythmia was discovered, and a nodal ablation was done with a cardiac pacemaker implanted. The patient had an arrhythmia and sudden death followed this. Emery-Dreifuss muscular dystrophy is a rare recessive X-linked muscular disorder where mixed patterns in electromyography and muscle histology (neurogenic and/or myopathic) have caused nosological confusion. The autopsy findings are here described and correlated to the clinical features in an attempt to better understand the ambiguous findings concerning the process etiology.

[Ligation of the right coronary artery in dogs. Hemodynamic and pathological effects]. / Ligadura da artéria coronária direita do cão. Efeitos hemodinâmicos e patológicos.

PURPOSE: To assess the hemodynamic and pathologic effects of the right coronary artery occlusion in anesthetized dogs submitted to pericardiotomy. METHODS: Ten mongrel dogs were anesthetized with pentobarbital and submitted to a right thoracotomy, pericardiotomy and ligation of the right coronary artery. The pericardium was kept opened throughout the entire experiment. The circulatory pressures and the cardiac output were determined twice before and three times after the right coronary artery ligation. The hearts were then excised, barium was injected in the coronary arteries and radiographs were taken to confirm the artery occlusion. Three dogs were kept alive to later pathologic examination of the hearts. RESULTS: The observation of the radiographs showed proximal occlusion of the right coronary artery and absence of the right ventricle free wall vascularization. There was ischemic necrosis of about three quarters of this area, whereas the septum was normal. The cardiac index and the systemic mean arterial decreased 14% without significant variation of the central venous and the pulmonary artery pressures, although marked right ventricular dilation was observed. CONCLUSION: The proximal right coronary artery ligation in the dog determines ischemia and infarction of the right ventricular free wall, without affecting the interventricular septum. There are few hemodynamic consequences with open pericardium and at rest.

[Fatal acute myocardial infarction in a young cocaine addict]. / Infarto agudo do miocárdio fatal em jovem viciado em cocaína.

A 28 year-old male cocaine abuser without coronary atherosclerosis suffered fatal myocardial infarction. Necropsy revealed several myocardial infarctions of different ages. Examination of the coronary arteries revealed fibrointimal thickening of the intimal layer of the coronary arteries.

[Right ventricular dysplasia associated with Ebstein type malformation of the tricuspid valve. A case report]. / Displasia ventricular direita associada à malformação "tipo Ebstein" da valva tricúspide. Relato de caso.

Right ventricular dysplasia, also named right ventricular cardiomyopathy, cardiac lipidosis and partial absence of the right ventricular myocardium, is an uncommon disease in which the myocardium is partially replaced by fat and fibrous tissue. The clinical picture is usually characterized by complex arrhythmias, causing sudden death in adolescents and young adults, and cardiac failure. In this report, an association between this disease and "Ebstein-type" tricuspid valve malformation has been diagnosed in a 22 year old female patient with cianosis and dyspnea on exertion.

[Analysis of the composition and spatial disposition of atherosclerotic plaques localized in epicardial coronary artery bifurcations in adults]. / Análise da composição e disposição espacial de placas ateroscleróticas localizadas em bifurcações das artérias coronárias epicárdicas de adultos.

PURPOSE: To analyze macro and microscopic features of atherosclerotic plaques located in bifurcation of coronary arteries, defining their spatial disposition in those sites. METHODS: We studied 38 bifurcations of coronary arteries of patients whose cause of death was related to coronary artery disease. Histologic sections of 0.5mm were sequentially made from the main artery to the secondary branches. They were stained with hematoxilin-eosin technique. Histological analysis evaluated: a) morphologic composition of the plaques, b) degree of obstruction and c) plaque's disposition. RESULTS: a) Plaque's composition: fibrolipid plaques constituted 80% of the cases and mingled focal atrophy of the media at the base of the plaque in 61% with spots of total destruction and rupture of the elastic layers in 30%; b) degree of obstruction: ranged from 20% to 95%, with average 60 +/- 28%; c) disposition of plaques: we verified morphologic variation along the plaque, most of them (71%) being eccentric at bifurcation and not reaching the beginning of flow divider walls. CONCLUSION: Atherosclerotic plaques located in bifurcation of coronary arteries of adults are often fibrolipid plaques, eccentric, and their spatial disposition on those sites spare the beginning of the inner walls, reaching the outer walls.

[The biopsy in the diagnosis of pericardial involvement by malignant tumor]. / A biopsia no diagnóstico do comprometimento pericárdico por tumores malignos.

We performed pericardial biopsy by subxiphoid approach in twelve patients (eight men, four women) with cardiac tamponade or pericardial effusion without low cardiac output, in order to search for the underlying disease. Five patients (41%) had pericardial biopsy with malignant neoplastic invasion. In seven patients (59%) the biopsy was nonspecific; in these patients, the diagnosis was made by another methods. We concluded that the pericardial biopsy is a safe method, with high especificity but low sensibility in the diagnosis of malignant pericardial invasion.

Neoplastic pericardial disease. Analysis of 26 patients.

PURPOSE: To characterize patients with neoplastic pericardial disease diagnosed by clinical presentation, complementary test findings, and the histological type of tumor. METHODS: Twenty-six patients with neoplastic pericardial disease were retrospectively analyzed. RESULTS: Clinical manifestations and abnormalities in chest roentgenograms and electrocardiograms were frequent, but were not specific. Most patients underwent surgery. There was a high positivity of the pericardial biopsy when associated with the cytological analysis of the pericardial liquid used to determine the histological type of the tumor, particularly when the procedure was performed with the aid of pericardioscopy. CONCLUSION: The correct diagnosis of neoplastic pericardial disease involves suspicious but nonspecific findings during clinical examination and in screen tests. The suspicious findings must be confirmed through more invasive diagnostic approaches, in particular pericardioscopy with biopsy and cytological study.

[Mitral valve dysfunction caused by papillary muscle necrosis in patients with anomalous origin of the left coronary artery from the pulmonary trunk]. / Disfunção da valva mitral por necrose de músculo papilar em origem anômala de artéria coronária esquerda do tronco pulmonar.

The clinical evolution of mitral valve disfunction caused by papillary muscle necrosis in patients with anomalous origin of the left coronary artery from the pulmonary trunk was analysed in three children (one 42-day-old male, one five-month-old female and one seven-year-old female). Two patients had been submitted to surgical repair of the anomalous origin of the coronary artery; one of them without mitral repair had a bad evolution in the postoperative period, was reoperated for mitral valve replacement and died two days after surgery. The other patient with plastic of mitral valve had a good outcome. The data indicated that the surgical repair of mitral valve should be provided in cases of mitral valve incompetence secondary to anomalous origin of the left coronary artery from the pulmonary trunk.

[Differences between men and women in fatal cases of myocardial infarction: study of 200 necropsies]. / Diferenças entre homens e mulheres em casos fatais de infarto do miocárdio. Estudo de 200 necrópsias.

PURPOSE: To compare morphological characteristics from myocardial infarction (IM) in men and women in 200 consecutive necropsies. MATERIAL AND METHODS: Necropsy heart findings from 62 female cases compared with those from 138 male cases, from patients who died from transmural myocardial infarction. Age ranged from 21 to 82 (mean 60) years. RESULTS: Concerning the coronary arteries, the number of 3 major (right, left anterior descending and left circumflex) epicardial coronary arteries narrowed at some point greater than 70% in cross-sectional area by atherosclerotic plaque was not significantly different; on the other hand, there were more severe lesions in the left main coronary artery in men (10.33%) than in women (1.64%) (p = 0.050). 33.33% of men and 43.55% of women had only recent myocardial infarction (1 month or less); 33.33% of men and 14.52% of women had only old myocardial infarction (more than 1 month); 33.33% of men and 41.94% of women had both recent and old myocardial infarction. 12.90% of women and 2.17% of men showed rupture of the left ventricle (p = 0.0220). 15.22% of men and 6.45% of women had left ventricular aneurysms (p = 0.830). CONCLUSION: There are more deaths during the acute phase of MI, in the first infarction and from rupture of the left ventricle in female patients; in men, there are more deaths occurring in chronic phases of the disease and with previous myocardial infarction; and more severe narrowing from the left main coronary artery.