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Blood Gene Signatures of Chagas Cardiomyopathy With or Without Ventricular Dysfunction.

ABSTRACT: Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, affects 7 million people in Latin American areas of endemicity. About 30% of infected patients will develop chronic Chagas cardiomyopathy (CCC), an inflammatory cardiomyopathy characterized by hypertrophy, fibrosis, and myocarditis. Further studies are necessary to understand the molecular mechanisms of disease progression. Transcriptome analysis has been increasingly used to identify molecular changes associated with disease outcomes. We thus assessed the whole-blood transcriptome of patients with Chagas disease. Microarray analysis was performed on blood samples from 150 subjects, of whom 30 were uninfected control patients and 120 had Chagas disease (1 group had asymptomatic disease, and 2 groups had CCC with either a preserved or reduced left ventricular ejection fraction [LVEF]). Each Chagas disease group displayed distinct gene expression and functional pathway profiles. The most different expression patterns were between CCC groups with a preserved or reduced LVEF. A more stringent analysis indicated that 27 differentially expressed genes, particularly those related to natural killer (NK)/CD8+ T-cell cytotoxicity, separated the 2 groups. NK/CD8+ T-cell cytotoxicity could play a role in determining Chagas disease progression. Understanding genes associated with disease may lead to improved insight into CCC pathogenesis and the identification of prognostic factors for CCC progression.

SUBMITTER: Ferreira LR

PROVIDER: S-EPMC6095079 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Blood Gene Signatures of Chagas Cardiomyopathy With or Without Ventricular Dysfunction.

Ferreira Ludmila Rodrigues Pinto LR Ferreira Frederico Moraes FM Nakaya Helder Imoto HI Deng Xutao X Cândido Darlan da Silva DD de Oliveira Lea Campos LC Billaud Jean-Noel JN Lanteri Marion C MC Rigaud Vagner Oliveira-Carvalho VO Seielstad Mark M Kalil Jorge J Fernandes Fabio F Ribeiro Antonio Luiz P AL Sabino Ester Cerdeira EC Cunha-Neto Edecio E

The Journal of infectious diseases 20170201 3

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, affects 7 million people in Latin American areas of endemicity. About 30% of infected patients will develop chronic Chagas cardiomyopathy (CCC), an inflammatory cardiomyopathy characterized by hypertrophy, fibrosis, and myocarditis. Further studies are necessary to understand the molecular mechanisms of disease progression. Transcriptome analysis has been increasingly used to identify molecular changes associated with disease ou ...[more]

PMID: 28003350

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Project description:AimsWe investigated the effects of mitochondrial reactive oxygen species (mtROS) on nuclear factor (erythroid 2)-like 2 (NFE2L2) transcription factor activity during Trypanosoma cruzi (Tc) infection and determined whether enhancing the mtROS scavenging capacity preserved the heart function in Chagas disease.ResultsC57BL/6 wild type (WT, female) mice infected with Tc exhibited myocardial loss of mitochondrial membrane potential, complex II (CII)-driven coupled respiration, and ninefold increase in mtROS production. In vitro and in vivo studies showed that Tc infection resulted in an ROS-dependent decline in the expression, nuclear translocation, antioxidant response element (ARE) binding, and activity of NFE2L2, and 35-99% decline in antioxidants' (gamma-glutamyl cysteine synthase [γGCS], heme oxygenase-1 [HO1], glutamate-cysteine ligase modifier subunit [GCLM], thioredoxin (Trx), glutathione S transferase [GST], and NAD(P)H dehydrogenase, quinone 1 [NQO1]) expression. An increase in myocardial and mitochondrial oxidative adducts, myocardial interventricular septum thickness, and left ventricle (LV) mass, a decline in LV posterior wall thickness, and disproportionate synthesis of collagens (COLI/COLIII), αSMA, and SM22α were noted in WT.Tc mice. Overexpression of manganese superoxide dismutase (MnSOD) in cultured cells (HeLa or cardiomyocytes) and MnSODtg mice preserved the NFE2L2 transcriptional activity and antioxidant/oxidant balance, and cardiac oxidative and fibrotic pathology were significantly decreased in MnSODtg.Tc mice. Importantly, echocardiography finding of a decline in LV systolic (stroke volume, cardiac output, ejection fraction) and diastolic (early/late peak filling ratio, myocardial performance index) function in WT.Tc mice was abolished in MnSODtg.Tc mice. Innovation and Conclusion: The mtROS inhibition of NFE2L2/ARE pathway constitutes a key mechanism in signaling the fibrotic gene expression and evolution of chronic cardiomyopathy. Preserving the NFE2L2 activity arrested the mitochondrial and cardiac oxidative stress, cardiac fibrosis, and heart failure in Chagas disease. Antioxid. Redox Signal. 27, 550-566.

Project description:BACKGROUND:Right ventricular (RV) dysfunction predicts adverse outcome in peripartum cardiomyopathy (PPCM). We recently demonstrated beneficial effects associated with the prolactin release inhibitor bromocriptine at different doses when added to standard heart failure therapy in PPCM. Here, we evaluated for the first time the therapeutic potential of bromocriptine particularly in PPCM patients with RV involvement. METHODS:In this study, 40 patients with PPCM were included, of whom 24 patients had reduced RV ejection fraction (RVEF?<?45%). We examined the effect of short-term (1W: bromocriptine, 2.5 mg, 7 days, n?=?10) compared with long-term bromocriptine treatment (8W: 5 mg for 2 weeks followed by 2.5 mg for another 6 weeks, n?=?14) in addition to guideline-based heart failure therapy in patients with an initial RVEF?<?45% on the following outcomes: (1) change from baseline (? delta) in RVEF, (2) change from baseline in left ventricular EF (LVEF), and (3) rate of patients with full LV recovery (LVEF???50%) and (4) rate of patients with full RV recovery (RVEF???55%) at 6-month follow-up as assessed by cardiac magnetic resonance imaging. RESULTS:Reduced RVEF at initial presentation was associated with a lower rate of full cardiac recovery at 6-month follow-up (patients with RV dysfunction: 58% vs. patients with normal RV function: 81%; p?=?0.027). RVEF increased from 38?±?7 to 53?±?11% with a delta-RVEF of +?15?±?12% in the 1W group, and from 35?±?9 to 58?±?7% with a ? RVEF of +?23?±?10% in the 8W group (? RVEF 1W vs 8W: p?=?0.118). LVEF increased from 25?±?8 to 46?±?12% with a ? LVEF of +?21?±?11% in the 1W group, and from 22?±?6 to 49?±?10% with a ? LVEF of +?27?±?9% in the 8W group (? LVEF 1W vs 8W: p?=?0.211). Full LV recovery was present in 50% of the 1W group and in 64% of the 8W group (p?=?0.678). Full RV recovery was observed in 40% of the 1W group and in 79% of the 8W group (p?=?0.092). CONCLUSIONS:Despite overall worse outcome in patients with RV dysfunction at baseline, bromocriptine treatment in PPCM patients with RV involvement was associated with a high rate of full RV and LV recovery, although no significant differences were observed between the short-term and long-term bromocriptine treatment regime. These findings suggest that bromocriptine in addition to standard heart failure therapy may be also effective in PPCM patients with biventricular impairment.

Dataset Information

Blood Gene Signatures of Chagas Cardiomyopathy With or Without Ventricular Dysfunction.

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Blood Gene Signatures of Chagas Cardiomyopathy With or Without Ventricular Dysfunction.

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