Selenium, TGF-Beta and Infectious Endemic Cardiopathy: Lessons from Benchwork to Clinical Application in Chagas Disease

Abstract

For over 60 years, selenium (Se) has been known as an essential microelement to many biological functions, including cardiovascular homeostasis. This review presents a compilation of studies conducted in the past 20 years related to chronic Chagas disease cardiomyopathy (CCC), caused by Trypanosoma cruzi infection, a neglected disease that represents a global burden, especially in Latin America. Experimental and clinical data indicate that Se may be used as a complementary therapy to prevent heart failure and improve heart function. Starting from the main questions "Is Se deficiency related to heart inflammation and arrhythmogenesis in CCC?" and "Could Se be recommended as a therapeutic strategy for CCC?", we show evidence implicating the complex and multidetermined CCC physiopathology, discussing its possible interplays with the multifunctional cytokine TGF-β as regulators of immune response and fibrosis. We present two new proposals to face this global public health challenge in vulnerable populations affected by this parasitic disease: fibrosis modulation mediated by TGF-β pathways and the possible use of selenoproteins as antioxidants regulating the increased reactive oxygen stress present in CCC inflammatory environments. We assess the opportunity to consider the beneficial effects of Se in preventing heart failure as a concept to be applied for CCC patients.

Keywords: TGFbeta signaling; infection; myocardiopathy; pathogenesis; selenoproteins; translational research.

Figure 1

Schematic view of the Chagas disease Chronic Cardiopathy (CCC) physiopathology mechanism showing all the possible implications of selenoproteins involvement (marked Se in a yellow diamond) and/or TGF-beta related effects (marked TGF in a blue rectangle) considering experimental and clinical data available in the literature. In immunocompetent mammals, the acquired adaptive and specific immune response commonly develops at a proper level following an acute phase that lasts about 1 to 3 months in humans and triggers a strong innate immune response. Such mechanisms maintain a low parasite load and an adequate IFN-gamma and IL-10 response (low Th1 type) in about 70% of the cases, sustaining seropositive individuals in an indeterminate form in the chronic phase, with a barely detected parasitemia. However, in about 30% of the human cases, an abnormal cardiac form develops in the chronic phase involving at least four main pathogenic mechanisms (marked 1,2,3, and 4 in the figure): (1) direct heart cell damage caused by parasite infection as nests in the myocardium; (2) direct damage caused by focal CD8-driven myocytolysis and muscle cell tissue substitution by fibrosis; (3) a neurogenic disbalance caused by excessive parasympathetic stimulation by neurotransmitter agonist action of muscarinic-like antibodies produced by T. cruzi-infected persons; and (4) endothelial dysfunction with microvascular compromise. The major clinical outcomes are sudden or cardiovascular death, stroke, CCC progression and typical abnormalities in electrocardiograms presented as bradyarrhythmias, tachyarrhythmias, or even complex arrhythmias. The important factors affecting the balance between indeterminate or CCC progression forms are: (i) inflammation x parasite load and (ii) maintenance and repair for homeostasis x stressed or malfunctioning tissue sustaining chronic inflammation. The authors expanded and produced Figure 1.

Figure 2

Changes in left ventricular ejection fraction (LVEF) after 6 and 12 months in Chagas disease patients participating in STCC, after Se (solid lines) or Placebo (traced lines). The effect of Se was statistically significant only in panel (c), in patients starting the trial with a moderate heart disfunction and LVEF lower than 45%. Patients with normal heart function (LVEF ≥ 55%, panel (a) or with mild heart disfunction (LVEF between 45 and 55%, panel (b) did not show a significant effect after Se treatment.

Figure 3

Social legacy from the Selenium Trial for Chagas disease: the project pamphlet (a), translation to English: Selenium project STCC, searching for innovations to the treatment of Chagas disease produced in 2015 to invite patients to diverse types of meetings that used a Trypanosoma cruzi model (b) and education activities that culminated with the organization of a new Chagas disease Association (c)—Rio Chagas Association logomark with affected persons (patients, families, and health professionals). (d–g) show images (d–f) and banners produced for the “Chagas Express 21” (Expresso Chagas 21), in its expedition version (d,e,g) and in the virtual version (f) developed during COVID-19 pandemics (f). (g) (original words in Portuguese are depicted inside the parentheses) shows an expedition banner indicating “food that are sources of Selenium” (alimentos que são fontes de selênio) as natural diet sources: Brazil nuts (castanha-do-Brasil), fish (sardinha, atum), chicken eggs (ovo de galinha), chicken liver (fígado de galinha), cream cheese (requeijão cremoso), black beans (feijão preto), wheat flour (farinha de trigo), bread, corn meal, cream crackers.