The aim of the present study was to evaluate the effects of changes to the autonomic nervous system in mice during the acute phase of Chagas disease, which is an infection caused by the parasite Trypanosoma cruzi. The following types of mice were inoculated with T. cruzi (CHG): wild-type (WT) and vesicular acetylcholine transporter knockdown (KDVAChT) C57BL/6j mice; wild-type non-treated (NT) FVB mice; FVB mice treated with pyridostigmine bromide (PYR) or salbutamol (SALB); and β 2 -adrenergic receptor knockout (KOβ2) FVB mice. During infection and at 18-21 days after infection (acute phase), the survival curves, parasitaemia, electrocardiograms, heart rate variability, autonomic tonus and histopathology of the animals were evaluated. Negative control groups were matched for age, genetic background and treatment. The KDVAChT-CHG mice exhibited a significant shift in the electrocardiographic, autonomic and histopathological profiles towards a greater inflammatory immune response that was associated with a reduction in blood and tissue parasitism. In contrast, the CHG-PYR mice manifested reduced myocardial inflammation and lower blood and tissue parasitism. Similar results were observed in CHG-SALB animals. Unexpectedly, the KOβ2-CHG mice exhibited less myocardial inflammation and higher blood and tissue parasitism, which were associated with reduced mortality. These findings could have been due to the increase in vagal tone observed in the KOβ2 mice, which rendered them more similar to the CHG-PYR animals. In conclusion, our results indicate a marked immunomodulatory role for the parasympathetic and sympathetic autonomic nervous systems, which inhibit both the inflammatory immune response and parasite clearance during the acute phase of experimental Chagas heart disease in mice.

The aim of the present study was to assess the effects of an anticholinesterase agent, pyridostigmine bromide (Pyrido), on experimental chronic Chagas heart disease in mice. To this end, male C57BL/6J mice noninfected (control:Con) or chronically infected (5 months) with Trypanosoma cruzi (chagasic:Chg) were treated or not (NT) with Pyrido for one month. At the end of this period, electrocardiogram (ECG); cardiac autonomic function; heart histopathology; serum cytokines; and the presence of blood and tissue parasites by means of immunohistochemistry and PCR were assessed. In NT-Chg mice, significant changes in the electrocardiographic, autonomic, and cardiac histopathological profiles were observed confirming a chronic inflammatory response. Treatment with Pyrido in Chagasic mice caused a significant reduction of myocardial inflammatory infiltration, fibrosis, and hypertrophy, which was accompanied by a decrease in serum levels of IFNγ with no change in IL-10 levels, suggesting a shift of immune response toward an anti-inflammatory profile. Lower nondifferent numbers of parasite DNA copies were observed in both treated and nontreated chagasic mice. In conclusion, our findings confirm the marked neuroimmunomodulatory role played by the parasympathetic autonomic nervous system in the evolution of the inflammatory-immune response to T. cruzi during experimental chronic Chagas heart disease in mice.

Systemic arterial hypertension (SAH), a clinical syndrome characterized by persistent elevation of arterial pressure, is often associated with abnormalities such as microvascular rarefaction, defective angiogenesis, and endothelial dysfunction. Mesenchymal stem cells (MSCs), which normally induce angiogenesis and improve endothelial function, are defective in SAH. The central aim of this study was to evaluate whether priming of MSCs with endothelial growth medium (EGM-2) increases their therapeutic effects in spontaneously hypertensive rats (SHRs). Adult female SHRs were administered an intraperitoneal injection of vehicle solution (n = 10), MSCs cultured in conventional medium (DMEM plus 10% FBS, n = 11), or MSCs cultured in conventional medium followed by 72 hours in EGM-2 (pMSC, n = 10). Priming of the MSCs reduced the basal cell death rate in vitro. The administration of pMSCs significantly induced a prolonged reduction (10 days) in arterial pressure, a decrease in cardiac hypertrophy, an improvement in endothelium-dependent vasodilation response to acetylcholine, and an increase in skeletal muscle microvascular density compared to the vehicle and MSC groups. The transplanted cells were rarely found in the hearts and kidneys. Taken together, our findings indicate that priming of MSCs boosts stem cell therapy for the treatment of SAH.

Chagas disease is an endemic parasitic disease, caused by the flagellate protozoan Trypanosoma cruzi, with a high prevalence in Latin America. During its chronic phase, chronic chagasic cardiomyopathy is the most apparent clinical form, affecting 25-30% of patients. This clinical form may present as congestive heart failure, thromboembolic phenomena, cardiac arrhythmias and sudden death. Pathological findings in the heart include mononuclear inflammatory infiltrate, focal myocarditis, epicarditis and neuroganglionitis, associated with variable focal fibrosis and widely variable autonomic dysfunction. The immune-inflammatory response has been considered to be the cause of the autonomic dysfunction, which may trigger life-threatening arrhythmias and sudden death. In the last few years, several reports in the literature have described the marked role played by the autonomic nervous system in the modulation of the immune-inflammatory response in some experimental models of infectious, ischaemic and autoimmune diseases. However, nothing is known about this autonomic neural modulation of the immune response in Chagas disease. In the present report, we discuss several sets of evidence suggesting that changes in the autonomic drive directed towards the heart could modify blood and tissue parasitism, as well as inflammatory infiltration, in chagasic cardiomyopathy. The pathogenic implications of these potential neural immune manipulations are also discussed.

No abstract

A destruição de neurônios do sistema nervoso autônomo tem sido há muito descrita em pacientes chagásicos 4 . Esta desnervação autonômica parece exercer um papel preponderante na patogênese da forma digestiva da doença, uma vez que a destruição dos plexos mioentéricos do esôfago e do cólon alteram o funcionamento normal da musculatura lisa destas vísceras, levando ao desenvolvimento dos megas 4 . Enquanto o papel da desnervação autonômica digestiva na patogênese dos megas parece não deixar dúvidas, o papel desta mesma desnervação autonômica na patogênese da cardiopatia ainda é alvo de grande discussão 4 . Koberle 4 propôs a teoria neurogênica para o desenvolvimento da cardiopatia chagásica crônica, no qual a destruição preferencial dos gânglios intra-cardíacos vagais, por contigüidade anatômica com o tecido miocárdico inflamado na fase aguda, levaria a uma disfunção vagal crônica com prevalência a longo prazo do sistema nervoso simpático, reconhecidamente deletério ao coração. Entretanto, vários achados, tais como, corações chagásicos com miocardiopatia e contagem neuronal normal, disfunção autonômica cardíaca importante sem cardiopatia e lesão simultânea do simpático, tem trazido inúmeras dúvidas sobre o papel da desnervação autonômica na gênese da cardiopatia chagásica. Apesar disso, desnervação e consequente disfunção autonômica provavelmente desempenham um papel importante na gênese dos fenômenos arrítmicos e talvez da morte súbita, muito prevalente em pacientes chagásicos 2 . O emprego de modelos experimentais animais, para o estudo da doença de Chagas, tem permitido a aquisição de um enorme corpo de conhecimento sobre a patogênese da doença e poderia ser de grande valor para responder a importantes questionamentos relativos ao sistema nervoso autônomo: Como se dá e em que fase de evolução da doença ocorre a desnervação e disfunção autonômica cardíaca? Quais divisões do sistema nervoso autônomo são preferencialmente acometidos, simpático ou parassimpático? Que estratégias terapêuticas poderiam ser adotadas para minimizar o impacto da disfunção autonômica cardíaca?Desnervação autonômica cardíaca tem sido descrita em modelos experimentais da doença de Chagas no cão, coelho, rato, camundongo e hamster. Porém, tem sido pouco investigado se a desnervação cardíaca descrita nestes modelos traz repercussões sobre a função autonômica cardíaca. Junqueira Jr. e cols.3 demonstraram em ratos cronicamente infectados uma atenuação da resposta vagal cardíaca à estimulação barorreflexa, a qual se correlacionou com a presença de neuroganglionite em gânglios intra-cardíacos 3 . Porém, as repercussões destes achados sobre a evolução da cardiopatia e sobre as alterações do ritmo cardíaco não foram investigados.Nos últimos 20 anos, o emprego de métodos de análise de variabilidade de sinais cardiovasculares no domínio do tempo (métodos estatístico) e no domínio da freqüência (análise espectral) tem trazido grandes avanços no entendimento e na avaliação da função autonômica cardíaca em pacientes e animais experimentais. O emprego d...

O Acidente Vascular Cerebral (AVC) é uma das maiores causas de óbito e/ou incapacidade funcional no Brasil e no mundo. Os cuidados paliativos são uma forma humanizada e diferenciada de assistência ao paciente, e podem ser empregados em diversas doenças que ameaçam a vida, como no AVC. Recentemente, o Ministério da Saúde publicou uma resolução que normatizou a oferta de cuidados paliativos como parte dos cuidados continuados integrados no âmbito do Sistema Único de Saúde (SUS). Esta é uma reflexão sobre conceitos e a abordagem nutricional no cuidado paliativo de pacientes acometidos por AVC.  Embora a terapia nutricional não represente vantagens em abordagens paliativas, para um seleto grupo de acometidos por AVC, a recuperação ou manutenção de um bom estado nutricional podem ser fundamentais para a qualidade de vida, inclusive em situações de desospitalização.