Predictors of cardiomyopathy progression in a Chagas disease cohort in Bolivia

项目摘要 查加斯病是造成大量心脏性猝死和心力衰竭病例的原因。的 那些感染了致病的原生动物寄生虫的人，只有20-30%的人会患上心肌病， 这种选择性进展的原因尚不清楚。作为我们在玻利维亚的圣克鲁斯现有RO 1的一部分，我们 如果不是最大的纵向查加斯感染队列之一。这项研究已经使我们 收集多个心电图、超声心动图和血清样本用于生物标志物分析，以及标本 用于RNA分析。这项更新补助金建议利用这项正在进行的调查，以检测标记， 与那些在十年内没有进展的人相比，检测早期进展。这是必不可少的， 通过确定那些可能发展为疾病的人来确定对感染者的干预措施。 我们的研究小组已经证明了进展者与非进展者以及进展者中RNA转录组的变化。 炎性小体基因，特别是NLRP 1，CASP 1和CARD，可能与CCC相关。我们也 证明了从心脏分期A进展到B的最敏感指标是调整后的 西尔维斯特QRS波评分。最后，我们使用全局纵向应变模式演示了早期变化。我们 总体目标是继续检查进展和未进展为心脏病的受试者， 确定区分这两个群体的遗传和发病特征。 具体目标1：比较EKG、QRS评分和超声心动图整体应变作为 查加斯病中的心肌病进展。目前监测疾病进展的标准 是心电图，在该资助的前五年，我们发现QRS评分也可能是一个有用的指标。我们 我假设QRS评分将为那些发生贲门整体劳损的患者提供更敏感的指标 将被证明比这两者更敏感，作为最终疾病进展的早期指标。在 此外，我们将增加霍尔特监测的随机分组的个人。 具体目标2：评估与炎性小体相关的转录组的变化， 心脏神经和结构成分随疾病进展而改变。我们假设 查加斯心肌病是由对寄生虫的免疫反应引起的， 影响。具体来说，我们将通过RNAseq鉴定差异表达的免疫相关基因， 特别关注Th 1 T细胞活化、离子通道、心肌重塑、中间丝 表达和其他炎症相关标志物，以评估随时间的差异。

Project Summary 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.