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MULTI-THERAPEUTIC STRATEGY TARGETING PARASITE AND INFLAMMATION-RELATED ALTERATIONS TO IMPROVE PROGNOSIS OF CHRONIC CHAGAS CARDIOMYOPATHY: A HYPOTHESIS-BASED APPROACH
Cardiomiopatia chagásica crônica
Testes pré-clínicos
Benznidazol
Pentoxifilina
Multiterapia
Chronic chagasic cardiomyopathy
Preclinical tests
Benznidazole
Pentoxifylline
Multi-therapy
Lannes-Vieira, Joseli | Fecha del documento:
2022
Autor
Afiliación
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia das Interações. Rio de Janeiro, RJ, Brasil.
Resumen en ingles
Chagas disease (CD), caused by infection by the protozoan parasite Trypanosoma cruzi, presents as main clinical
manifestation the chronic chagasic cardiomyopathy (CCC). CCC afflicts millions of people, mostly in Latin America, and vaccine and effective therapy are still lacking. Comprehension of the host/parasite interplay in the chronic phase of T. cruzi infection may unveil targets for rational trait-based therapies to improve CCC prognosis. In the present viewpoint, I critically summarise a collection of data, obtained by our network of collaborators and other groups on CCC and preclinical studies on pathogenesis, targeting identification for intervention and the use of drugs with immunomodulatory properties to improve CCC. In the last two decades, models combining mouse lineages and T. cruzi strains allowed replication of crucial clinical, histopathological, and immunological traits of CCC. This condition includes conduction changes (heart rate changes, arrhythmias, atrioventricular blocks, prolongation of the QRS complex and PR and corrected QT intervals), ventricular dysfunction and heart failure, CD8-enriched myocarditis, tissue remodeling and progressive fibrosis, and systemic inflammatory profile, resembling “cytokine storm”. Studies on Chagas’ heart disease pathogenesis begins to unveil the molecular mechanisms underpinning the inflammation-related cardiac tissue damage, placing IFNγ, TNF and NFκB signaling as upstream regulators of miRNAs and mRNAs associated with critical biological pathways as cell migration, inflammation, tissue remodeling and fibrosis, and mitochondrial dysfunction. Further, data on preclinical trials using hypothesis-based tools, targeting parasite and inflammationrelated alterations, opened paths for multi-therapeutic approaches in CCC. Despite the long path taken using experimental CD models replicating relevant aspects of CCC and testing new therapies and therapeutic schemes, these findings may get lost in translation, as conceptual and economical challenges, underpinning the valley of death across preclinical and clinical trials. It is hoped that such difficulties will be overcome in the near future.
Palabras clave en portugues
Doença de ChagasCardiomiopatia chagásica crônica
Testes pré-clínicos
Benznidazol
Pentoxifilina
Multiterapia
Palabras clave en ingles
Chagas diseaseChronic chagasic cardiomyopathy
Preclinical tests
Benznidazole
Pentoxifylline
Multi-therapy
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