Predictors of cardiomyopathy progression in a Chagas disease cohort in Bolivia

项目摘要 恰加斯病是导致大量心源性猝死和心力衰竭的原因。的 那些感染了致病原虫寄生虫的人，只有20%-30%会患上心肌病，而潜在的 这种选择性进展的原因尚不清楚。作为我们在玻利维亚圣克鲁斯现有RO1的一部分，我们 如果不是最大的持续纵向查加感染队列，也是其中之一。这项研究已经使我们能够 收集多个EKG、超声心动图和血清样本进行生物标志物分析，以及样本 为进行RNA分析而保存。这项续订拨款建议利用这项正在进行的调查来检测 检测早期进展与那些在十年内没有进展的人。这一点在 通过确定哪些人可能进展为疾病来确定对感染者的干预措施。 我们的团队已经证明了进展者与非进展者以及在 炎症体基因，特别是NLRP1、CASP1和CARD，可能与CCC相关。我们也 证明从心脏A期进展到B期最敏感的指标是调整后的 西尔维斯特QRS评分。最后，我们使用全球纵向应变模式演示了早期的变化。我们的 首要目标是继续检查进展为心脏病和不进展为心脏病和 确定区分两组的遗传和致病特征。 具体目标1：比较EKG、QRS评分和超声心动图整体应变作为 查加斯病的心肌病进展。目前监测疾病进展的标准 是EKG，在这笔赠款的前五年，我们发现QRS评分也可能是一个有用的指标。我们 假设QRS评分将提供一个更灵敏的指标来指示那些患上全球心绞痛的人 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……里面 此外，我们将把动态心电图监测添加到随机分组的个体中。 具体目标2：评估与炎症相关的转录组的变化和 随着疾病进展而改变的心脏神经和结构成分。我们假设 查加斯心肌病是对寄生虫的免疫反应的结果，并且是遗传的 受到了影响。具体地说，我们将通过RNAseq识别差异表达的免疫相关基因， 特别关注Th1 T细胞活化、离子通道、心肌重构、中间丝 表达，以及其他炎症相关指标，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.