Oxidative stress, cardiomyocytes premature senescence and contractile dysfunction in in vitro and in vivo experimental models of Chagas disease.

AIMS: The relationship between redox imbalance and cardiovascular senescence in infectious myocarditis is unknown. Thus, the aim of this study was to investigate whether cardiomyocytes parasitism, oxidative stress and contractile dysfunction can be correlated to senescence-associated ß-galactosidase (SA-ß-Gal) activity in Trypanosoma cruzi-infection in vitro and in vivo. METHODS: Uninfected, T. cruzi-infected untreated and benznidazole (BZN)-treated H9c2 cardiomyocytes and rats were investigated. Parasitological, prooxidant, antioxidant, microstructural, and senescence-associated markers were quantified in vitro and in vivo. RESULTS: T. cruzi infection triggered intense cardiomyocytes parasitism in vitro and in vivo, which was accompanied by reactive oxygen species (ROS) upregulation, lipids, proteins and DNA oxidation in cardiomyocytes and cardiac tissue. Oxidative stress was parallel to microstructural cell damage (e.g., increased cardiac toponin I levels) and contractile dysfunction in cardiomyocytes in vitro and in vivo, whose severity accompanied a premature cellular senescence-like phenotype revealed by increased senescence-associated ß-galactosidase (SA-ß-Gal) activity and DNA oxidation (8-OHdG). Cellular parasitism (e.g., infection rate and parasite load), myocarditis and T. cruzi-induced prooxidant responses were attenuated by early BZN administration to interrupt the progression of T. cruzi infection, protecting against SA-ß-gal-based premature cellular senescence, microstructural damage and contractile deterioration in cardiomyocytes from T. cruzi-infected animals. CONCLUSION: Our findings indicated that cell parasitism, redox imbalance and contractile dysfunction were correlated to SA-ß-Gal-based cardiomyocytes premature senescence in acute T. cruzi infection. Therefore, in addition to controlling parasitism, inflammation and oxidative stress; inhibiting cardiomyocytes premature senescence should be further investigated as an additional target of specific Chagas disease therapeutics.

Challenges of immunosuppressive and antitrypanosomal drug therapy after heart transplantation in patients with chronic Chagas disease: A systematic review of clinical recommendations.

BACKGROUND: Although contraindicated for decades, heart transplantation (HT) has finally become a feasible therapeutic option for the treatment of Chagasic patients with end-stage heart failure. Part of the success in achieving acceptable survival rates after HT is due to the enhancement of the pharmacological management of allograft rejection and reactivation of Trypanosoma cruzi infection. METHODS: By using the framework of a systematic review, we investigated if Chagasic patients who have undergone a HT are treated with similar immunosuppressive and antitrypanosomal regimens in endemic and non-endemic countries and exhibits similar T. cruzi reactivation, allograft rejection and survival rates. From a structured search in PubMed/Medline, Scopus, and Web of Sciences databases, 30 clinical studies were reviewed. RESULTS AND CONCLUSION: Although immunosuppressive regimens are variable in endemic and non-endemic countries, the current evidence supports the administration of lower doses of corticosteroids, adjusted cyclosporine levels (100-150 ng/mL) 3 months after HT, and azathioprine rather than mycophenolate mofetil to reduce the risk of T. cruzi reactivation and rejection episodes. Antitrypanosomal therapy exclusively based on benznidazole, nifurtimox, and allopurinol was consistent in endemic and non-endemic countries, achieving effective results in the control of infection reactivation. The evidence that supports prophylactic antitrypanosomal therapy or administration of allopurinol alone is limited. By highlighting the main sources of research bias, we hope that our critical analysis can help to expedite clinical research and to reduce methodological bias, thereby improving the quality of evidence in new research initiatives.