Low Doses of Simvastatin Therapy Ameliorate Cardiac Inflammatory Remodeling in Trypanosoma cruzi-Infected Dogs

Abstract

Abstract. Chagas cardiomyopathy remodeling is based on the presence of Trypanosoma cruzi in heart tissue and on the complex inflammatory response leading to a myocardium fibrosis and alterations in conductive and functional heart parameters. This study aims to evaluate Simvastatin on the inflammatory response and heart functionality using dogs infected with Y strain of T. cruzi . Animals were treated daily with Simvastatin (20 mg) for 6 months and submitted to clinical and immunopathological evaluations. Simvastatin reduced heart expression and serum levels of interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) but not interleukin-10 (IL-10), possibly favoring blood parasitism but reducing inflammation and fibrosis in the left ventricle and right atrium. Simvastatin also ameliorated ejection fraction, diastolic diameter, and mass index of the left ventricle 6 months after infection. This study suggests that more investigation should be performed on the use of statins as a prophylactic therapy against cardiac remodeling because of their effects on modifying immune response and benefiting functional parameters in dogs with T. cruzi -induced ventricular dysfunctions.

Enalapril in Combination with Benznidazole Reduces Cardiac Inflammation and Creatine Kinases in Mice Chronically Infected with Trypanosoma cruzi

“…In this context, well-known cardiovascular therapeutic options (e.g., ACE-inhibitors, β-blockers, statins) have gained new interest because of their more recently described modulatory properties over the release of inflammatory cytokines and chemokines, the cellular infiltration, and fibrosis leading to improvements in ventricular cardiac function in experimental and human T. cruzi studies. 8,[10][11][12] Our group previously described, in an experimental model of acute infection by T. cruzi, a relevant role for the enalapril using the Colombian strain of the parasite whose characteristic feature is to cause high systemic and cardiac inflammation in C57BL/6 mice. In this study, the short treatment with 25 mg/kg/day of enalapril was capable to reduce circulating parasites, heart tissue inflammation and plasma IFN-γ, TNF-α, and CCL5/ RANTES, suggesting a protective effect to this ACE inhibitor to the chronic stage of the infection.…”

“…[2][3][4] Since the presence of T. cruzi is the switch for inducing and maintaining the inflammatory process running in the heart tissue, three cardinal therapeutic strategies are proposed: 1) an antiparasitic drug, where benznidazole is considered a standard treatment but still ineffective to those symptomatic individuals in chronic stage of Chagas cardiopathy 5 ; 2) drugs that act direct on the cardiac dysfunction avoiding progressive failure of the organ-for example, diuretics, digitals, β-blockers, and angiotensin-converting enzyme (ACE) inhibitors 6,7 and, more recently, 3) drugs that act in controlling the over-reactivity of the immune system avoiding severe destruction in the heart during chronic stage of the infection-for example, statins and ACE inhibitors. [8][9][10][11][12] ACE inhibitors have been shown to be efficacious not only as therapies against hypertension and protection against left ventricular hypertrophy but also in the regulation of the immune system related to distinct diseases, including the T. cruziinduced pathologies. 9,[13][14][15] Their actions are based on the angiotensin II, a key factor in the renin-angiotensin system that plays an essential role in the regulation of blood pressure, and that also interferes in the cardiac inflammatory activity through the activation of the nuclear factor kappaB (NF-κB) and in the production of inflammatory cytokines and chemokines.…”

Short-term therapy with simvastatin reduces inflammatory mediators and heart inflammation during the acute phase of experimental Chagas disease

“…Based on our previous experience, an early anti-inflammatory intervention with simvastatin could be essential for the treatment of long-term cardiac inflammation and to reduce heart architectural and functional changes in experimental Chagas disease (Melo et al 2011). A daily dose of simvastatin (20 mg) was capable of reducing pro-inflammatory IFN-γ and TNF-α, but not regulatory IL-10 and did not ameliorate the clinical parameters (left ventricle ejection fraction and diastolic diameter of left ventricle) of dogs infected with T. cruzi during the chronic phase of disease.…”

Genome profiling of sterol synthesis shows convergent evolution in parasites and guides chemotherapeutic attack

“…For terbinafi ne and its presumed target squalene epoxidase (enzyme no. 22), there was even a signifi cant positive correlation between profi le score and IC 50 ( r S = 0.89, P < 0.05; Fig. 5 ).…”