Abstract
Chagas disease cardiomyopathy (CCC) is an inflammatory dilated cardiomyopathy occurring in 30% of the 6 million infected with the protozoan Trypanosoma cruzi in Latin America. Survival is significantly lower in CCC than ischemic (IC) and idiopathic dilated cardiomyopathy (DCM). Previous studies disclosed a selective decrease in mitochondrial ATP synthase alpha expression and creatine kinase activity in CCC myocardium as compared to IDC and IC, as well as decreased in vivo myocardial ATP production. Aiming to identify additional constraints in energy metabolism specific to CCC, we performed a proteomic study in myocardial tissue samples from CCC, IC and DCM obtained at transplantation, in comparison with control myocardial tissue samples from organ donors. Left ventricle free wall myocardial samples were subject to two-dimensional electrophoresis with fluorescent labeling (2D-DIGE) and protein identification by mass spectrometry. We found altered expression of proteins related to mitochondrial energy metabolism, cardiac remodeling, and oxidative stress in the 3 patient groups. Pathways analysis of proteins differentially expressed in CCC disclosed mitochondrial dysfunction, fatty acid metabolism and transmembrane potential of mitochondria. CCC patients’ myocardium displayed reduced expression of 22 mitochondrial proteins belonging to energy metabolism pathways, as compared to 17 in DCM and 3 in IC. Significantly, 6 beta-oxidation enzymes were reduced in CCC, while only 2 of them were down-regulated in DCM and 1 in IC. We also observed that the cytokine IFN-gamma, previously described with increased levels in CCC, reduces mitochondrial membrane potential in cardiomyocytes. Results suggest a major reduction of mitochondrial energy metabolism and mitochondrial dysfunction in CCC myocardium which may be in part linked to IFN-gamma. This may partially explain the worse prognosis of CCC as compared to DCM or IC.
Highlights
Heart failure can be seen as a progressive disorder resulting from loss of cardiomyocyte function and contractility decline in the ability of the heart, due to molecular and structural modifications, collectively called cardiac remodeling [1]
Patients from the three cardiomyopathy groups included in the analysis displayed cardiomyocyte hypertrophy and fibrosis upon histopathological analysis, but lymphocytic myocarditis was only observed in myocardial samples from chronic Chagas’ disease cardiomyopathy (CCC) patients (Table 1)
Pathway analysis of proteins differentially expressed in CCC showed selective enrichment in the CCC group for pathways involved in the fatty acid metabolism and decreased transmembrane potential of mitochondria
Summary
Heart failure can be seen as a progressive disorder resulting from loss of cardiomyocyte function and contractility decline in the ability of the heart, due to molecular and structural modifications, collectively called cardiac remodeling [1]. About 30% of infected patients develop chronic Chagas’ disease cardiomyopathy (CCC), an inflammatory dilated cardiomyopathy that occurs decades after the initial infection, while 60% remain asymptomatic (ASY) and 10% develop gastrointestinal motility disorders. Chagas disease is the most common cause of non-ischemic cardiomyopathy in Latin America, where 6 million people are infected, causing approximately 10,000 deaths/year, mainly due cardiac compromise [2]. Due to migration to non-endemic countries, Chagas disease cardiomyopathy is a global health problem [7]. Refractory heart failure due to CCC is one of the main indications for heart transplantation in endemic countries. A recent report disclosed 25 cases of heart transplantation due to CCC in the USA, indicating the presence of patients with severe complications from Chagas disease [8]. The absence of alternative specific treatment for CCC is a consequence of limited knowledge about the pathogenesis
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