Predictive value of novel circulating biomarkers in Chagas disease: The Brazilian Chagas disease cohort

Abstract Introduction Chagas disease, caused by the protozoan Trypanosoma cruzi (T. cruzi), is the leading causes of non-ischemic heart failure and premature cardiac deaths in Latin America. Identifying predictive biomarkers of morbidity and progression of Chagas cardiomyopathy (CCC) is important to deciphering novel pathways and aid in early identification of patients at highest risk for future adverse cardiovascular (CV) outcomes. Objectives To determine the association of novel circulating biomarkers with CCC and disease survival. Methods Serum levels of 184 unique cardiometabolic and inflammation proteins were measured using proximity extension immunoassay using age- and sex- matched patients without history of any other cardiovascular or infectious diseases as well as diabetes mellitus, who were identified and selected at the referral outpatient center for Chagas Disease at a clinical hospital in Brazil. Univariable linear regression using standardized protein levels were compared between patients with and without CCC. All p-values were adjusted for multiple testing and in findings with p value<0.0002 were considered statistically significant. Proteins that reached significance level were further compared between disease mortalities and survival. We also performed network analysis using STRING-DB on overexpressed proteins to determine its interaction. Results We used data from 44 with CCC and 44 with asymptomatic T. cruzi-positive patients (indeterminate). Among individuals with CCC, 22 patients had a fatal cardiovascular event during follow-up period of 4.1 (SD ±1.4) years. In linear regression analyses, we identified 45 candidate biomarkers associated with chronic CC (all p values <0.0002). Among these, only three proteins (IL33, CD40, REG1A) were significantly different between individuals with CCC who died vs survived over a period of 4.1 years. We used 38 overexpressed proteins in network analysis. THBS4, marker of cardiac remodeling, was overexpressed in CCC. CXCL11 were seen co-expressed with CXCL9 and CXCL10, all are known activators of CD4+ Th1 cells in CCC. Conclusion We identified 45 novel cardiometabolic and inflammatory markers that are associated with chronic Chagas cardiomyopathy. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Leading House of Latin America of the Swiss State Secretariat for Education, Research and Innovation (SERI)