Biomarkers in <i>Trypanosoma cruzi</i>-Infected and Uninfected Individuals with Varying Severity of Cardiomyopathy in Santa Cruz, Bolivia

<div><p>Background</p><p>Twenty to thirty percent of persons with <i>Trypanosoma cruzi</i> infection eventually develop cardiomyopathy. If an early indicator were to be identified and validated in longitudinal studies, this could enable treatment to be prioritized for those at highest risk. We evaluated cardiac and extracellular matrix remodeling markers across cardiac stages in <i>T. cruzi</i> infected (Tc+) and uninfected (Tc−) individuals.</p><p>Methods</p><p>Participants were recruited in a public hospital in Santa Cruz, Bolivia and assigned cardiac severity stages by electrocardiogram and echocardiogram. BNP, NTproBNP, CKMB, troponin I, MMP-2, MMP-9, TIMP-1, TIMP-2, TGFb1, and TGFb2 were measured in specimens from 265 individuals using multiplex bead systems. Biomarker levels were compared between Tc+ and Tc− groups, and across cardiac stages. Receivers operating characteristic (ROC) curves were created; for markers with area under curve>0.60, logistic regression was performed.</p><p>Results</p><p>Analyses stratified by cardiac stage showed no significant differences in biomarker levels by Tc infection status. Among Tc+ individuals, those with cardiac insufficiency had higher levels of BNP, NTproBNP, troponin I, MMP-2, TIMP-1, and TIMP-2 than those with normal ejection fraction and left ventricular diameter. No individual marker distinguished between the two earliest Tc+ stages, but in ROC-based analyses, MMP-2/MMP-9 ratio was significantly higher in those with than those without ECG abnormalities.</p><p>Conclusions</p><p>BNP, NTproBNP, troponin I, MMP-2, TIMP-1, and TIMP-2 levels rose with increasing severity stage but did not distinguish between Chagas cardiomyopathy and other cardiomyopathies. Among Tc+ individuals without cardiac insufficiency, only the MMP-2/MMP-9 ratio differed between those with and without ECG changes.</p></div

Comparison of biomarkers and biomarker ratios in <i>T. cruzi</i>-infected (Tc+) vs uninfected (Tc−) subjects by stage.

<p>Bolded values represent a significant difference between Tc+ or Tc− individuals at a p<0.05.</p><p>Comparison of biomarkers and biomarker ratios in <i>T. cruzi</i>-infected (Tc+) vs uninfected (Tc−) subjects by stage.</p

Results of ROC analysis of selected markers for discrimination between Stage AB and CD among <i>T. cruzi</i>-infected individuals.

<p>Results of ROC analysis of selected markers for discrimination between Stage AB and CD among <i>T. cruzi</i>-infected individuals.</p

Demographic, electrocardiographic, and echocardiographic findings by stage in <i>T. cruzi</i>-infected (Tc+) and uninfected (Tc−) individuals.

<p>Bolded values represent a significant difference between Tc+ or Tc− individuals at a p<0.05.</p><p>*Not all individuals had echocardiography performed; Ns shown in <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0003227#pntd-0003227-g001" target="_blank">Figure 1</a>.</p><p>bpm = beats per minute, ms = millisecond, AV = atrio-ventricular, RBBB = right bundle branch block, LAFB = left anterior fascicular block, LBBB = left bundle branch block, EF = ejection fraction. LVEDD = left ventricular end diastolic diameter. na = not applicable.</p><p>Demographic, electrocardiographic, and echocardiographic findings by stage in <i>T. cruzi</i>-infected (Tc+) and uninfected (Tc−) individuals.</p

Logistic regression comparing biomakers and biomarker ratios by cardiac stage among <i>T-cruzi</i> infected (Tc+) individuals. Cutoffs were determined by ROC analysis.

<p>*Multivariate analyses adjusted for age, sex, and presence of comorbidities (hypertension, diabetes, and coronary artery disease).</p><p>Logistic regression comparing biomakers and biomarker ratios by cardiac stage among <i>T-cruzi</i> infected (Tc+) individuals. Cutoffs were determined by ROC analysis.</p