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

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-ß 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-ß 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.

Familial Aggregation of Endemic Congenital Hypothyroidism Syndrome in Congo (DR): Historical Data.

Familial aggregation of endemic congenital hypothyroidism (CH) in an iodine-deficient population from northern Congo (Democratic Republic (DR)) was analysed on data collected four decades ago (1979-1980). During a systematic survey of 62 families, 46 endemic CH subjects (44 myxedematous and 2 neurological) were identified based on clinical evidence within a village cohort of 468 subjects. A distribution analysis showed that two families presented significant excess of cases versus a random background distribution. Both families were characterised by two healthy parents having all of their five offspring affected by some form of endemic CH. Goitre prevalence in endemic CH was lower than that in the general population, while goitre prevalence in the unaffected part of the cohort (parents and siblings) was similar to that of the general population. Some unidentified genetic/epigenetic factor(s) could contribute to the evolution of some iodine-deficient hypothyroid neonates through irreversible and progressive loss of thyroid functional capacity during early childhood (<5 years old). Besides severe iodine deficiency, environmental exposure to thiocyanate overload and selenium deficiency, factors not randomly distributed within families and population, intervened in the full expression of endemic CH. Further exploration in the field will remain open, as iodine deficiency in Congo (DR) was eliminated in the 1990s.

Nutritional epidemiology and thyroid hormone metabolism.

Severe iodine deficiency was the main cause of endemic goiter and cretinism. Most of the previously iodine-deficient areas are now supplemented, mainly with iodized salt. The geographical distribution of severe endemic areas has been progressively reduced, and at present, approximately 200 million people living in remote places are still at risk of severe iodine deficiency. International public health programs should be focused first on reaching these populations, and second on auditing and monitoring the operational work of supplementation programs. This second point is essential to prevent iodine-induced hyperthyroidism or interruptions of iodine supplement distribution, which could be catastrophic for the fetus and the young infant. Echography brings a complementary tool to clinical assessment of goiter by palpation. Inductively coupled plasma-mass spectrometry brings at least a definitive gold standard for iodine measurement and thyroid hormone measurement. Thiocyanate overload has been clearly documented as a goitrogen in Central Africa, and when associated with selenium deficiency, it may be included as risk factor for endemic myxedematous cretinism. Variable exposure to different environmental risk factors is likely the explanation of the variable distribution of two types of endemic cretinism (neurological and myxedematous), and the clinical overlap of the pathogeny of both syndromes is more important than previously described. It is possible that Kashin-Beck osteoarthropathy is another evanescent endemic disease that will disappear with the correction of iodine deficiency.

Trace elements, innate immune response and parasites.

Micronutrient deficiencies and infectious disease often coexist and show complex interactions leading to mutually reinforced detrimental clinical effects. Such a combination is predominantly observed in underprivileged people of developing countries, particularly in rural regions. Several micronutrients such as trace elements (zinc, iron, selenium) modulate immune function and influence the susceptibility of the host to infection. Nevertheless, the effect of individual micronutrients on components of innate immunity is difficult to design and interpret. Micronutrient deficiency, in general, has a widespread effect on nearly all components of the innate immune response. Chagas' disease is a pertinent model to study interaction of nutrition, immunity and infection, as it implies many components of innate immunity. An important question is whether alterations on micronutrient intake modify the course of infection. Some interactions of trace elements with innate immunity and acute inflammatory response are reviewed in this article with a special focus on selenium deficiency and Trypanosoma cruzi infection.

Selenium supplementation at low doses contributes to the decrease in heart damage in experimental Trypanosoma cruzi infection.

Chagasic patients with cardiomyopathy have low levels of selenium (Se), a fundamental trace element. We evaluated the effect of supplementing infected mice with Se (0.25-16 ppm). Supplementation with 0.25 or 1 ppm Se led to parasitaemia and survival curves similar to those of the control group. Mice treated with 4-16 ppm showed a dose-dependent decrease of parasitaemia, significant for the highest concentration. This was probably due to a direct effect on the parasites, which were lysed after in vitro incubation with Se. Survival rates did not change significantly; however, heart damage was reduced in infected mice supplemented with 4 ppm Se, as indicated by a lower cardiac isoform of creatine kinase levels. Our results imply that Se supplementation does not lead to a general protection during infection, but may help protect the heart from inflammatory damage. The effect of Se supplementation in the course of T. cruzi infection depends on the host-parasite pair employed.

Selenium and iodine supplementation of rural Tibetan children affected by Kashin-Beck osteoarthropathy.

BACKGROUND: Kashin-Beck disease is an osteoarthropathy endemic in selenium- and iodine-deficient areas around Lhasa, Tibet. OBJECTIVE: We assessed the efficacy of selenium supplementation on disease progression. DESIGN: A double-blind, randomized controlled trial of selenium supplementation was carried out in 324 children aged 5-15 y who had Kashin-Beck disease. Two hundred eighty children received iodized oil before being randomly assigned to receive selenium or placebo, and a control group of 44 subjects was not supplemented at all. Clinical and radiologic signs, selenium status, urinary iodine, and thyroid function were evaluated at baseline and at 12 mo. RESULTS: The frequencies of joint pain, decreased joint mobility, and radiologic abnormalities were not significantly different between the 3 groups at 12 mo. Height-for-age z scores increased significantly in the subjects who received placebo and iodine or selenium and iodine. In contrast, unsupplemented control subjects did not recover from growth retardation. Serum selenium concentrations at 12 mo were within the reference range and were significantly greater in the selenium-iodine group than in the placebo-iodine group. Serum thyroid hormone concentrations were within the reference ranges after the administration of iodine, and these values were not significantly affected by selenium supplementation. CONCLUSIONS: The results of this study do not rule out the possibility that selenium may help to prevent the occurrence of Kashin-Beck disease. However, selenium supplementation had no effect on established Kashin-Beck disease, growth, or thyroid function once iodine deficiency was corrected. These results suggest that iodine, but not selenium, deficiency should be corrected in Tibetan children with Kashin-Beck disease.

Progressive Chagas' cardiomyopathy is associated with low selenium levels.

Selenium (Se) deficiency is linked with some cardiomyopathies. Its status was determined in 170 patients with chronic Chagas' disease from 2 Brazilian regions (Rio de Janeiro and Belo Horizonte), clinically stratified into groups as follows: indeterminate or asymptomatic (IND); cardiac asymptomatic (CARDa); cardiac symptomatic with moderate to severe heart dysfunction (CARDb); and healthy adults (HA), used for comparison. In most HA, Se levels were normal, excluding an overall Se deficiency. Se was significantly lower in CARDb than in HA, IND, or CARDa patients. This was not associated with a concomitant decrease in activity of glutathione peroxidase. Thyrotropin was normal, excluding iodine deficiency. Se correlated positive and significantly with ventricular ejection fraction (assessed via echocardiography). Asymptomatic children with acute Chagas' disease had normal Se as well as 5 noninfectious cases of cardiomyopathy. Low Se was found in 6 of 10 chagasic patients with digestive megasyndromes. Thus, the decrease in Se in chagasic patients seems to be a biological marker for Trypanosoma cruzi infection and related to the progression of pathology.

Trypanosoma cruzi: host selenium deficiency leads to higher mortality but similar parasitemia in mice.

Selenium is an essential trace element and its deficiency was implicated in heart diseases. We recently showed low Se levels in chronic chagasic patients with cardiomyopathy. Herein, mice were depleted in Se by feeding the mothers with chow containing only 0.005 mg Se/kg and maintaining this diet for offspring, that were further infected with Trypanosoma cruzi. Survival rate was significantly lower in Se deficient than in control mice. Parasitemia was similar in all groups. Necrotic heart lesions were found after infection (high CK-MB levels). No outbreaks of parasite growth were detected in chronic survivors submitted or not to a second Se depletion. The present results confirm our hypothesis that a nutritional deficiency in Se is associated to a higher mortality during T. cruzi infection. The potential beneficial effect of Se supplementation is a perspective. Hypothesis to explain the higher susceptibility of Se-depleted mice to T. cruzi infection are discussed.