ABC | Volume 112, Nº2, February 2019

Brief Communication Analysis of Iron Metabolism in Chronic Chagasic Cardiomyopathy Carla Paixão Miranda, 1 Fernando Antônio Botoni, 1 Maria do Carmo Pereira Nunes, 2 Manoel Otávio da Costa Rocha 1 Universidade Federal de Minas Gerais, 1 Belo Horizonte, MG – Brazil Hospital das Clínicas - Universidade Federal de Minas Gerais, 2 Belo Horizonte, MG – Brazil Keywords Iron Metabolism Disorders; Chagas Disease; Chagas Cardiomyopathy; Inflammation; Anemia. Mailing Address: Carla Paixão Miranda • Avenida Alfredo Balena, 190, 4° Andar Sala 4070. Postal Code 30130-100, Santa Efigênia, Belo Horizonte, MG – Brazil E-mail: carlanutribio@gmail.com Manuscript received March 20, 2018, revised manuscript August 13, 2018, accepted September 05, 2018 DOI: 10.5935/abc.20190006 Abstract Changes in iron metabolism in heart failure (HF) have been described as an important prognostic marker. To check if the markers of iron kinetics are related to the morbidity and etiology of chagasic cardiomyopathy. Patients with Chronic Chagasic Cardiomyopathy (CCC, n = 40), with indeterminate form (IND, n = 40), besides non-chagasic cardiomyopathy (NCh, n = 40). The mean age was 50.98 ± 5.88 in CCC, 50% were male, 49.68 ± 5.28 in IND, 52.2%were male, and 49.20 ± 10.09 in NCh, 12.5%weremale. Lower levels of iron (FeSe) wereobserved in the CCC groups (93.15 ± 36.53), when compared to IND (125.30 ± 22.79) and NCh (114.77 ± 18.90) (p = 0.0004), lower IST transferrin saturation index in CCC (29.48 ± 6.59), when compared to IND (30.95 ± 7.06) and in the NCh group (39.70 ± 7.54) p = 0.0001), total binding capacity of the lower CTLF iron in the CCC group (297.30 ± 36.46), when compared to the IND group (196.52 ± 56.95) and the NCh group (275.18 ± 33, 48) (p = 0.0001), lower ferritin in the CCC group (134.55, 1.56‑42.36), when compared to the IND group (156,25, 1,72‑42,20) and the NCh group (112.95, 2.88-42.66) (p = 0.0004). It was also observed that FeSe (95% CI 1.00‑1.04, p = 0.0014), IST (95% CI 1.02‑1.22) (p = 0.0012) and gender (95% CI 1.07-14.43 p = 0.0038) were independently associated with the degree of ventricular dysfunction in chagasic cardiomyopathy. CCC patients showed greater change in iron metabolism regarding the indeterminate form and other forms of cariomyopathies. Introduction Functional iron deficiency (Fe) can be defined as the imbalance between the required amount of Fe for hemoglobin synthesis and its supply. 1 It occurs in the absence of Fe stock, a characteristic of iron deficiency anemia (FA), and in the presence of blockade of Fe homeostasis, as in anemia of inflammation. In AI, cytokines and reticuloendothelial system cells induce alterations that interfere in different pathways of erythropoiesis leading to anemia. 2 Pro- and anti-inflammatory cytokines, derived from macrophages or T cells, as well as acute phase proteins, are believed to be involved in AI Fe homeostasis disorders. The demonstration of the importance of IL-1 and TNF- α in Fe homeostasis occurred from experiments with rats, where the administration of these cytokines was associated with hypoferremia, and induction of ferritin synthesis by SRW. It is now known that IL-1 and IL-6 are able to modulate the translation of ferritin acting on the 5'-untranslated portion of the ferritin messenger RNA. 3,4 IL-6 appears to play a key role in the stimulation of HAMP transcription, although IL-1 α and IL-1 β also play a role in the transcription of this gene. IL-6 has the ability to bind to the cell membrane through specific receptors, and to activate the signal transducer and transcriptional activator 3 ( Stat3 ), the JAK/STAT signaling pathway, which acts on the gene promoter region by stimulating hepcidin transcription. Excessive production of hepcidin occurs in individuals with inflammatory and infectious diseases, particularly Chagas disease, and this excess explains the sequestration of Fe in macrophages, and the inhibition of intestinal absorption of Fe, two hallmarks of AI. 5 The expression of ferroportin is decreased in SRE cells due to inflammation; it is not only due to the internalization and degradation of ferroportin by the action of hepcidin, but also by a negative regulation of its expression. Alterations in the differentiation and proliferation of erythroid precursors (BFU-E and CFU-E): a blockade is observed due to the inhibitory effect of several cytokines, in particular: interferon- α , β e γ , α tumoral necrosis factor (TNF- α ), and interleukin 1 (IL-1). The related mechanism appears to be the induction of apoptosis; however, cytokines also exert a direct toxic effect on progenitor cells by inducing the formation of free radicals. 6 Chronic chagasic cardiomyopathy (CCC) is the most severe manifestation of Chagas disease (Chd), in which intense and extensive inflammatory and fibrotic action is observed on the myocardium, 1 causing structural and autonomic alterations that affect approximately 20% to 30% of the infected people. 7,8,9 In addition, CCC presents, as a fundamental morphological substrate, a chronic, progressive and fibrosing and, consequently, clinical myocarditis, ranging from silent to more severe forms, such as refractory heart failure (HF), complex arrhythmias, ventricular aneurysms, and sudden death. 10 The impairment of cardiac function, as well as the progression of neurohormonal and inflammatory compensation mechanisms, can either alter iron metabolism by simply reducing its intestinal absorption, or dynamically change its distribution in the reticuloendothelial and hematopoietic system. 7,8,9,6,11,12 Anemia is known to be the last compensatory stage when there is iron bioavailability impairment for the erythropoietic processes from complex pathophysiological mechanisms. The objective of this study was to check if the iron kinetics 189