Chagas disease is responsible for a compelling number of cases of sudden cardiac death and heart failure. Of those infected with the causal protozoan parasite, only 20-30% develop cardiomyopathy and the underlying reason of this selective progression remains unknown. As part of our existing RO1 in Santa Cruz, Bolivia, we have one of if not the largest ongoing longitudinal Chagas-infected cohorts. This study has already enabled us to collect multiple EKGs, Echocardiograms, and serum samples for biomarker analysis, as well as specimens preserved for RNA analysis. This renewal grant proposes to utilize this ongoing survey to detect markers for detecting early progression versus those who do not progress over a ten-year period. This is essential in determining interventions in those infected by defining those who are likely advance to disease. Our group has demonstrated RNA transcriptome changes in progressors vs. non-progressors as well as in the inflammasome genes, particularly in NLRP1, CASP1 and CARD, which may be associated with CCC. We also demonstrated that the most sensitive indicator of progression from Cardiac stage A to B is the adjusted Sylvester QRS score. Finally, we demonstrated early changes using Global Longitudinal Strain pattern. Our overarching aim is to continue to examine subjects who progress and don?t progress to cardiac disease and determine genetic and pathogenetic characteristics that differentiate between the two groups.
Specific Aim 1 : To compare EKG, QRS score, and echocardiogram global strain as indicators of cardiomyopathy progression in Chagas disease. The current standard for monitoring disease progression is an EKG, and in the first five years of this grant, we found that QRS score may also be a useful indicator. We hypothesize that the QRS score will provide a more sensitive indicator of those who go to cardia global strain will prove to be more sensitive than both of these as an early indicator of eventual disease progression. In addition, we will add Holter monitoring to a randomized subgroup of individuals.
Specific Aim 2 : To assess changes in the transcriptome associated with the inflammasome and cardiac neural and structural components that are altered with disease progression. We hypothesize that Chagas cardiomyopathy results from an immunological reaction to the parasite and is genetically influenced. Specifically, we will identify differentially expressed immune-related genes through RNAseq, particularly concentrating on Th1 T cell activation, ion channels, myocardial remodeling, intermediate filament expression, and other inflammatory-related markers to evaluate differences over time.

Public Health Relevance

Chagas disease is responsible for a compelling number of cases of sudden cardiac death and heart failure. Of those infected with the causal parasite, only 20-30% develop heart problems, and the underlying reason of this selective progression remains unknown. This renewal grant proposes to utilize our ongoing study to identify ways to detect early progression, which is essential in determining interventions in those infected by defining those who are likely advance to disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI107028-07
Application #
9950975
Study Section
Cancer, Heart, and Sleep Epidemiology A Study Section (CHSA)
Program Officer
Rao, Malla R
Project Start
2014-02-15
Project End
2024-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
7
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Fu, Katherine Yih-Jia; Zamudio, Roxana; Henderson-Frost, Jo et al. (2017) Association of caspase-1 polymorphisms with Chagas cardiomyopathy among individuals in Santa Cruz, Bolivia. Rev Soc Bras Med Trop 50:516-523
Sherbuk, Jacqueline E; Okamoto, Emi E; Marks, Morgan A et al. (2015) Biomarkers and mortality in severe Chagas cardiomyopathy. Glob Heart 10:173-80
Messenger, Louisa A; Miles, Michael A; Bern, Caryn (2015) Between a bug and a hard place: Trypanosoma cruzi genetic diversity and the clinical outcomes of Chagas disease. Expert Rev Anti Infect Ther 13:995-1029
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Clark, Eva H; Marks, Morgan A; Gilman, Robert H et al. (2015) Circulating serum markers and QRS scar score in Chagas cardiomyopathy. Am J Trop Med Hyg 92:39-44
Kaplinski, Michelle; Jois, Malasa; Galdos-Cardenas, Gerson et al. (2015) Sustained Domestic Vector Exposure Is Associated With Increased Chagas Cardiomyopathy Risk but Decreased Parasitemia and Congenital Transmission Risk Among Young Women in Bolivia. Clin Infect Dis 61:918-26
Castillo-Neyra, Ricardo; Chou Chu, Lily; Quispe-Machaca, Victor et al. (2015) The potential of canine sentinels for reemerging Trypanosoma cruzi transmission. Prev Vet Med 120:349-56

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