Improved Biomarker and Imaging Analysis for Characterizing Progressive Cardiac Fibrosis in a Mouse Model of Chronic Chagasic Cardiomyopathy

Abstract

BackgroundChronic chagasic cardiomyopathy (CCC), caused by Trypanosoma cruzi infection, is an important public health problem attributable to progressive cardiomyopathy in patients, for which there is no cure. Chronic chagasic cardiomyopathy is characterized by myocarditis and cardiac fibrosis, which leads to life‐threatening arrhythmogenic and circulatory abnormalities. This study aimed to investigate cardiac fibrosis progression in a mouse model of chronic chagasic cardiomyopathy.Methods and ResultsCardiac cells infected with T cruzi produced significantly higher concentrations of transforming growth factor‐β (TGF‐β), connective tissue growth factor, endothelin‐1, and platelet‐derived growth factor‐D than noninfected controls. Female Balb/c mice infected with T cruzi were compared with naïve mice. TGF‐β genes and other TGF‐β superfamily genes, as well as connective tissue growth factor, endothelin‐1, and platelet‐derived growth factor, were upregulated in infected mouse hearts. Serum concentrations of TGF‐β, connective tissue growth factor, and platelet‐derived growth factor‐D were higher in infected mice and correlated with cardiac fibrosis. Strain analysis performed on magnetic resonance images at 111 and 140 days postinfection and echocardiography images at 212 days postinfection revealed significantly elevated left ventricular strain and cardiac fibrosis and concomitantly significantly decreased cardiac output in infected mice.ConclusionsTGF‐β, connective tissue growth factor and platelet‐derived growth factor‐D are potentially useful biomarkers of cardiac fibrosis, as they correlate with cardiac fibrosis. Strain analysis allows for use of noninvasive methods to measure fibrosis in the chronic stages of chagasic cardiomyopathy in a mouse model. These findings can be applied as noninvasive tools to study the effects of interventions and/or therapeutics on cardiac fibrosis development when using a mouse model of chronic chagasic cardiomyopathy.

Alterations to the cardiac metabolome induced by chronicT. cruziinfection relate to the degree of cardiac pathology

“…pericardial segments, in the same animals as above and as in Hoffman et al 22 Figure 2G). However, in accordance with the histological analysis showing worse disease in the pericardial segment ( Figure 1), a significant relationship between inflammation score and cardiac metabolome perturbations was only observed for the pericardial cardiac segment…”

“…Infected groups had an overall mortality of 40% compared with 0% in uninfected age-matched controls. 22 Chronically infected animals exhibited an overall significant increase in both average cardiac inflammation (p<0.05) and fibrosis (p<0.01) compared to naive control animals at study endpoint ( Figure S1). 22 However, that prior work did not investigate spatial aspects of histopathology.…”

“…Given previous reports of acute T. cruzi infection affecting cardiac metabolism, 30 it was necessary to investigate whether these changes were also observed in chronic infection, and whether they were correlated to the severity of disease (as quantified by the circulating biomarkers of cardiac fibrosis that we previously reported). 22 Thus, we performed metabolomic analysis of the right ventricle, divided between endocardial and…”

“…Echocardiography and analysis of images was performed as previously reported and the data from these images were used in the current study, as well. 22 from these prior experiments was used in the current investigations. 22 Each experiment was performed with two technical replicates.…”

TLR4 agonist protects against Trypanosoma cruzi acute lethal infection by decreasing cardiac parasite burdens

“…55 T cruzi induces cardiac fibrosis through two parallel pathways: T cruzi infection induces inflammation which leads to post-inflammatory fibrosis, and T cruzi directly induces host mediators and cytokines that stimulate fibrosis. 55 Importantly, IL-6 has been found to be significantly elevated in the serum of CCC patients and experimental animal models of CCC. [56][57][58] IL-6 is a pleiotropic cytokine that can induce both inflammatory and fibrotic pathways through STAT3 signalling.…”