Effect of Posaconazole in an in vitro model of cardiac fibrosis induced by Trypanosoma cruzi.

Posaconazole (POS) is an inhibitor of ergosterol biosynthesis in clinical use for treating invasive fungal infections. POS has potent and selective anti-Trypanosoma cruzi activity and has been evaluated as a possible treatment for Chagas disease. Microtissues are a 3D culture system that has been shown to reproduce better tissue architecture and functionality than cell cultures in monolayer (2D). It has been used to evaluate chemotropic response as in vitro disease models. We previously developed an in vitro model that reproduces aspects of cardiac fibrosis observed in Chagas cardiomyopathy, using microtissues formed by primary cardiac cells infected by the T. cruzi, here called T. cruzi fibrotic cardiac microtissue (TCFCM). We also showed that the treatment of TCFCM with a TGF-ß pathway inhibitor reduces fibrosis. Here, we aimed to evaluate the effect of POS in TCFCM, observing parasite load and molecules involved in fibrosis. To choose the concentration of POS to be used in TCFCM we first performed experiments in a monolayer of primary cardiac cell cultures and, based on the results, TCFCM was treated with 5 nM of POS for 96 h, starting at 144 h post-infection. Our previous studies showed that at this time the TCFCM had established fibrosis, resulting from T. cruzi infection. Treatment with POS of TCFCM reduced 50 % of parasite load as observed by real-time PCR and reduced markedly the fibrosis as observed by western blot and immunofluorescence, associated with a strong reduction in the expression of fibronectin and laminin (45 % and 54 %, respectively). POS treatment also changed the expression of proteins involved in the regulation of extracellular matrix proteins (TGF-ß and TIMP-4, increased by 50 % and decreased by 58 %, respectively) in TCFCM. In conclusion, POS presented a potent trypanocidal effect both in 2D and in TCFCM, and the reduction of the parasite load was associated with a reduction of fibrosis in the absence of external immunological effectors.

Cardiac manifestations of parasitic diseases.

The heart may be affected directly or indirectly by a variety of protozoa and helminths. This involvement may manifest in different ways, but the syndromes resulting from impairment of the myocardium and pericardium are the most frequent. The myocardium may be invaded by parasites that trigger local inflammatory response with subsequent myocarditis or cardiomyopathy, as occurs in Chagas disease, African trypanosomiasis, toxoplasmosis, trichinellosis and infection with free-living amoebae. In amoebiasis and echinococcosis, the pericardium is the structure most frequently involved with consequent pericardial effusion, acute pericarditis, cardiac tamponade or constrictive pericarditis. Chronic hypereosinophilia due to helminth infections, especially filarial infections, has been associated with the development of tropical endomyocardial fibrosis, a severe form of restrictive cardiomyopathy. Schistosomiasis-associated lung vasculature involvement may cause pulmonary hypertension (PH) and cor pulmonale Tropical pulmonary eosinophilia, which is characterised by progressive interstitial fibrosis and restrictive lung disease, may lead to PH and its consequences may occur in the course of filarial infections. Intracardiac rupture of an Echinococcus cyst can cause membrane or secondary cysts embolisation to the lungs or organs supplied by the systemic circulation. Although unusual causes of cardiac disease outside the endemic areas, heart involvement by parasites should be considered in the differential diagnosis especially of myocardial and/or pericardial diseases of unknown aetiology in both immunocompetent and immunocompromised individuals. In this review, we updated and summarised the current knowledge on the major heart diseases caused by protozoan and metazoan parasites, which either involve the heart directly or otherwise influence the heart adversely.

Endomyocardial fibrosis (EMF) in a Ugandan child with advanced hepatosplenic schistosomiasis: coincidence or connection?

An association between late-stage hepatosplenic schistosomiasis and endomyocardial fibrosis (EMF) has been suggested but not proven. We present the case of a 12-year-old Ugandan boy with striking comorbidities, including advanced periportal fibrosis caused by Schistosoma mansoni infection and right ventricular EMF, and discuss the possible correlation between both diseases.

Endomyocardial fibrosis associated with Schistosoma haematobium infection.

Endomyocardial fibrosis (EMF) is a form of restrictive cardiomyopathy common in the tropics and subtropics. The aetiology of EMF is unknown but helminth infestations such as schistosomiasis have been implicated. Two boys aged 8 and 10 years with EMF associated with Schistosoma haematobium, are described. The schistosomes in both cases may have been acquired from contact with contaminated water collected and stored in containers and subsequently used for bathing. Both patients were managed conservatively. Overall prognosis of EMF is poor and this report emphasizes the importance of public health interventions in the control of schistosomiasis.

Endomyocardial fibrosis associated with mansoni schistosomiasis.

Endomyocardial fibrosis (EMF) is a neglected tropical disease that affects millions of people worldwide. EMF is the most common cause of restrictive cardiomyopathy, caused by deposition of fibrous tissue on endocardial surfaces. EMF is a major cause of death in areas where it is endemic, but the pathogenesis of the disease is poorly understood. Schistosomiasis mansoni is a parasitic disease endemic in Brazil, where EMF has also been described. The association between EMF and schistosomiasis has been suggested in various publications, seeking a possible correlation between endocardial and periportal fibroses. This report describes a case of EMF associated with schistosomiasis.

Endomyocardial fibrosis associated with mansoni schistosomiasis / Endomiocardiofibrose associada à esquistossomose mansoni

Endomyocardial fibrosis (EMF) is a neglected tropical disease that affects millions of people worldwide. EMF is the most common cause of restrictive cardiomyopathy, caused by deposition of fibrous tissue on endocardial surfaces. EMF is a major cause of death in areas where it is endemic, but the pathogenesis of the disease is poorly understood. Schistosomiasis mansoni is a parasitic disease endemic in Brazil, where EMF has also been described. The association between EMF and schistosomiasis has been suggested in various publications, seeking a possible correlation between endocardial and periportal fibroses. This report describes a case of EMF associated with schistosomiasis.

A endomiocardiofibrose (EMF) é uma doença tropical, negligenciada, que afeta milhões de pessoas no mundo. É considerada a causa mais comum de cardiomiopatia restritiva, causada pela deposição de tecido fibroso em superfícies endocárdicas. Endomiocardiofibrose é uma das principais causas de morte em áreas onde é endêmica, e sua patogênese é pouco conhecida. A esquistossomose mansoni é uma doença parasitária endêmica no Brasil, onde a EMF também tem sido descrita. Tem sido apontada associação entre EMF e esquistossomose em várias publicações, buscando-se uma possível correlação entre a fibrose endocárdica e periportal. Neste relato, descreve-se um caso de EMF associado a esquistossomose.

Fibrosis endomiocárdica tropical e hipertensión pulmonar secundaria a esquistosomiasis / Schistosomiasis and tropical endomyocardial fibrosis with pulmonary hypertension

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Lack of evidence of myocardial damage in children with Plasmodium falciparum severe and complicated malaria from an endemic area for endomyocardial fibrosis.

Malaria is among the factors thought to be involved in the pathogenesis of endomyocardial fibrosis (EMF), a restrictive cardiomyopathy of unclear etiology, with no specific therapy, which affects predominantly children and adolescents. In Africa, regions endemic with EMF are also areas with high prevalence of malaria. We studied 47 consecutive children aged 5- to 15-years old and concluded that myocardial damage and dysfunction are rare in severe and complicated Plasmodium falciparum malaria cases in children.

Cardiac manifestations of parasitic infections part 3: pericardial and miscellaneous cardiopulmonary manifestations.

This is part three of a three-part series discussing parasites of the heart. In this section, we present an overview on parasitic diseases involving predominantly the pericardium and other miscellaneous cardiopulmonary manifestations such as some pulmonary hypertension syndromes and endomyocardial fibrosis.

Aetiology of endomyocardial fibrosis (EMF).

On epidemiological basis EMF behaves like a vector transmitted disease. The cardiac pathologies of EMF and HES are identical. In some cases of HES, hypereosinophilia may return to normal, leaving residual heart disease that is exactly like EMF. Most temporary residents from Europe and North America who developed EMF while resident in the endemic areas of Africa had hypereosinophilia that was induced by helminths. In our case studies from the EMF endemic areas of Nigeria, most children with acute idiopathic myocarditis associated with helminth induced hypereosinophilia, developed clinical EMF on follow up. We showed also that the rate of decline in the incidence of hypereosinophilia in EMF cases was significantly related to the duration of symptoms. Our studies and other observations show that EMF, like HES is a multiple system disease with similar organ damage. The morphologic evolution of cardiac damage in EMF appears similar to that reported for HES; with a stage of myocarditis/pericarditis, followed by a stage of cardiac necrosis, a stage of thrombosis and by the chronic fibrotic stage. Also during larval migration, all the helminths associated with EMF induce the same spectrum of damage in the central and peripheral nervous system, in the lungs, kidneys and skin, as are reported for HES. The cardiovascular damage reported for these worms (which include hypersensitivity vasculitis, acute myocarditis/ pericarditis) are also similar to what is reported for HES. Acute endomyocardial necrosis and thrombosis that are similar to what is found in HES, have been documented in Trichinella Spiralis and in filariasis. Increased cerium concentrations have been documented in the endocardium of EMF cases from South India. It remains to be established whether cerium excess, which is known to stimulate collagen synthesis does accelerate the process of endomyocardial fibrosis, following cardiac necrosis (which may have been triggered by helminths and the associated hypereosinophilia).

Human chronic chagasic cardiopathy: participation of parasite antigens, subsets of lymphocytes, cytokines and microvascular abnormalities.

This article tries to demonstrate by new pathological findings (with the use of immunohistochemical technique and confocal laser microscopy) that chronic chagasic cardiomyopathy is a result of multiple factors involving myocarditis, immunodepression, severe fibrosis and microvessels dilatation and that all of these alterations are probably directly related with the presence of Trypanosoma cruzi parasites in the host associated with inadequate immunological response of the host.

Endomyocardial fibrosis in Egypt: an illustrated review.

The detailed features of right sided endomyocardial fibrosis are described in 15 out of 10,000 consecutive patients who all had infection with Schistosoma mansoni and came from rural Egypt. Laboratory investigations, 12 lead electrocardiography, chest radiography, and Doppler echocardiography were performed in all patients. Cardiac catheterisation and angiography were performed in eight. Endomyocardial biopsy specimens were obtained from the right ventricles of two patients and pericardial biopsy specimens from two. Pericardiocentesis was performed in all patients. All patients were infected with S mansoni and had schistosomal hepatic fibrosis and ascites. Eleven had splenomegaly. All patients had raised cervical venous pressure with prominent Y descent and atrial fibrillation. Eosinophilia was notably absent. Echocardiography showed apical fibrosis in the right ventricle, obliteration of the ventricle, and moderate to massive exudative pericardial effusion in all patients. Calcification and fibrosis extended into the right ventricular outflow tracts in two patients. Huge right atrial thrombi occurred in five patients. Tricuspid regurgitation (grades I-II) was detected in 11 patients by Doppler ultrasonography. Haemodynamic and angiographic data confirmed the pure right sided restrictive pathophysiology. Pericardial biopsy specimens showed perivascular inflammatory infiltrates in two patients and a schistosomal granuloma in one. Endocardial biopsy specimens showed dense fibrosis with many fibroblasts. Endomyocardial fibrosis in Egypt is unique in several aspects. It always affected only the right side of the heart. Calcification and fibrosis extended to the right ventricular outflow tract. Pericardial inflammatory reaction was present. The relation to schistosomiasis and the link to periportal hepatic fibrosis in these patients is intriguing.

Reversibility of cardiac fibrosis in mice chronically infected with Trypanosoma cruzi, under specific chemotherapy.

UNLABELLED: This investigation was performed to verify the effect of specific chemotherapy (Benznidazole or MK-436) on the inflammatory and fibrotic cardiac alterations in mice chronically infected with the strains 21 SF (Type II) and Colombian (Type III) of Trypanosoma cruzi. To obtain chronically infected mice, two groups of 100 Swiss mice each, were infected with either the 21 SF or the Colombian strain (2 x 10(4) and 5 x 10(4) blood forms respectively). The rate of mortality in the acute phase was of 80% for both groups. Twenty surviving mice chronically infected with the 21 SF strain and 20 with the Colombian strain were then divided in treated and untreated groups. Excluding those that died during the course of treatment, 14 mice chronically infected with the 21 SF strain and 15 with the Colombian strain were finally evaluated in the present study. Chemotherapy was performed with Benznidazole (N-benzil-2-nitro-1-imidazolacetamide) in the dose of 100 mg/k.b.w/day, for 60 days, or with the MK-436 (3(1-methyl-5 nitroimidazol-2-yl) in two daily doses of 250 mg/k.b.w, for 20 days. Parasitological cure tests were performed (xenodiagnosis, haemoculture, subinoculation of the blood into newborn mice), and serological indirect immunofluorescence test. The treated and untreated mice as well as intact controls were killed at different periods after treatment and the heart were submitted to histopathological study with hematoxilineosin and picrosirius staining; ultrastructural study; collagen immunotyping, fibronectin and laminin identification by immunofluorescence tests. RESULTS: the untreated controls either infected with 21 SF or Colombian strain, showed inflammatory and fibrotic alterations that were mild to moderate with the 21 SF strain and intense with the Colombian strain. Redpicrosirius staining showed bundles of collagen in the interstitial space and around cardiac fibers. Increased deposits of matritial components and collagen fibers, macrophages and fibroblasts appeared at the ultrastructural examination. Deposits of fibronectin, laminin, pro-III and IV collagens were seen, most intense in those infected with the Colombian strain. Treated mice, parasitologically cured, presented clear-cut regression of the inflammatory lesions and of the interstitial matrix thickening. Mice infected with the Colombian strain and treated with MK-436, was parasitologically cured in 5/6 cases and showed mild inflammatory infiltration and fibrosis. The mice treated with Benznidazole (Colombian strain) did not cure and showed moderate fibrosis and inflammation. Treatment of the mice infected with the 21 SF with Benznidazole determined parasitological cure of all animals, that showed mild inflammation and fibrosis of the myocardium.(ABSTRACT TRUNCATED AT 400 WORDS)

Controversies and advances in endomyocardial fibrosis: a review.

Controversial aspects of, and recent advances in endomyocardial fibrosis are reviewed. Available data indicate that the disease has a worldwide distribution but is most prevalent in tropical Africa. Several factors have been incriminated in different parts of the world in its aetiopathogenesis but in tropical Africa subclinical viral myocarditis and eosinophilia caused by parasitic infections appear to be the most likely causes. Despite diversity in its aetiology, however, the clinicopathological manifestations are fairly uniform. This has facilitated the recognition of characteristic electrocardiographic and echocardiographic signs as well as the use of similar surgical techniques for its treatment in different countries.

Endomyocardial fibrosis and eosinophilia.

Absolute eosinophil counts were assessed in 15 African patients with proven endomyocardial fibrosis. Though the mean eosinophil count in patients with endomyocardial fibrosis was higher compared with the normals reported from Kampala (1-13 vs 0.72X10(9)/1), the absolute range was comparable. A high percentage of patients with endomyocardial fibrosis had malarial parasites, high malarial antibody titres, hookworms, or strongyloides, but the correlation of eosinophilia to various parasitic infections was poor. Both eosinophilia and parasitic infections are common in the tropics and they effect patients with endomyocardial fibrosis no more than the population at large. Other aetiological factors, genetic, environmental, and immunological, are felt to be important in the causation of endomyocardial fibrosis in Uganda and evidence for this is reviewed. Though there is a similarity in pathological features, African endomyocardial fibrosis is a distinct entity from Löffler's endocarditis and cardiac lesions seen in eosinophilic leukaemia or reactive eosinophilia. There is no hard evidence to suggest that African endomyocardial fibrosis is a variant of Löffler's endocarditis caused by parasitic infections via eosinophilia.