Ischemic strokes have been implicated as a cause of death in Chagas disease patients. Inflammation has been recognized as a key component in all ischemic processes, including the intravascular events triggered by vessel interruption, brain damage and repair. In this study, we evaluated the association between inflammatory markers and the death risk (DR) and stroke risk (SR) of patients with different clinical forms of chronic Chagas disease. The mRNA expression levels of cytokines, transcription factors expressed in the adaptive immune response (Th1, Th2, Th9, Th17, Th22 and regulatory T cell), and iNOS were analyzed by real-time PCR in peripheral blood mononuclear cells of chagasic patients who exhibited the indeterminate, cardiac, digestive and cardiodigestive clinical forms of the disease, and the levels of these transcripts were correlated with the DR and SR. Cardiac patients exhibited lower mRNA expression levels of GATA-3, FoxP3, AHR, IL-4, IL-9, IL-10 and IL-22 but exhibited higher expression of IFN-γ and TNF-α compared with indeterminate patients. Digestive patients showed similar levels of GATA-3, IL-4 and IL-10 than indeterminate patients. Cardiodigestive patients exhibited higher levels of TNF-α compared with indeterminate and digestive patients. Furthermore, we demonstrated that patients with high DR and SR exhibited lower GATA-3, FoxP3, and IL-10 expression and higher IFN-γ, TNF-α and iNOS mRNA expression than patients with low DR and SR. A negative correlation was observed between Foxp3 and IL-10 mRNA expression and the DR and SR. Moreover, TNF-α and iNOS expression was positively correlated with DR and SR. Our data suggest that an inflammatory imbalance in chronic Chagas disease patients is associated with a high DR and SR. This study provides a better understanding of the stroke pathobiology in the general population and might aid the development of therapeutic strategies for controlling the morbidity and mortality of Chagas disease.
Chagas disease is caused by Trypanosoma cruzi (T. cruzi), affects 5.7 million people worldwide and causes 12,000 deaths annually. In the chronic phase of Chagas disease the main cause of death is due to heart failure (about 80%), but cerebral vascular accident or stroke (about 10%) contributes to death mechanisms. Strokes are caused by the interruption of the blood supply to the brain and can be ischemic or hemorrhagic. Stroke is the leading cause of death among adults in Latin America and the second in the world. Infectious diseases, such as Chagas disease, malaria, cysticercosis, tuberculosis, brucellosis and neurosyphilis, can also contribute to the development of immunopathogenic mechanisms leading to stroke and death. In this study, we evaluated the association between inflammatory markers (cytokines, transcription factors of the adaptive immune response and iNOS) and the death risk (DR) and stroke risk (SR) of patients with different clinical forms of chronic Chagas disease. Our data suggest that an inflammatory imbalance in chronic Chagas disease patients is correlated with a high DR and SR. The exacerbated inflammatory mechanism that leads to thrombus formation can lead to sudden death in patients with clinical indeterminate form without prior other clinical symptoms. These inflammatory mechanisms are also involved in atherosclerotic-related strokes. An improved understanding of the immunological mechanisms involved in ischemic stroke formation in Chagas disease patients may also contribute to the reduction of stroke-related mortality and morbidity in the general population and may lead to the development of prophylactic or therapeutic therapies.