Pathogenesis of Heart Failure with Preserved Ejection Fraction in Chronic Kidney Disease

项目摘要 Rupal Mehta，医学博士，是耶鲁大学肾脏病和高血压科的医学助理教授。 西北大学（NU）Feinberg医学院。梅塔医生组织了一个跨学科的 导师团队推进她的独立研究计划，重点是研究心力衰竭（HF） 慢性肾脏病（CKD）患者的发病机制。射血分数保留性心力衰竭 HFpEF是CKD患者心血管疾病（CVD）的常见表现， CKD代表HFpEF异质性综合征中一种独特且高度流行的亚表型。 靶向CVD的传统机制并没有减轻CKD中HFpEF的负担，这表明， 可能存在CKD特异性机制。考虑到肾脏对小分子清除和代谢的影响， 博士Mehta建议研究CKD中代谢组改变有助于 HFpEF发病机制。科学前提是基于不同代谢特征的出现 HFpEF，这表明CKD诱导的代谢变化可能有助于HFpEF的发病机制。在Aim中 1、梅塔博士将利用慢性肾功能不全队列研究（一项基于人群的流行病学研究）， 研究循环代谢物与亚临床和临床HFpEF之间的相关性， CKD。在目标2中的一项以患者为导向（POR）的研究中，Mehta博士将检查剂量-反应关系 循环代谢物和亚临床HFpEF之间的关系，使用2D斑点追踪进行表型分析 超声心动图和心肺运动试验，在有和没有CKD的患者。进行介入性 在目标3的POR研究中，Mehta博士将使用钠葡萄糖协同转运蛋白2抑制作为治疗探针， 研究CKD和亚临床HFpEF患者的代谢组学改变是否与 心脏结构和功能改善超过6个月。结果将提供关键数据， 未来的研究。Mehta博士的职业发展目标是：1）扩大代谢组学测试的知识， 代谢组学数据的解释; 2）加强鉴定HFpEF表型和解释的技能 CKD患者的心脏测试; 3）发展进行POR机制研究的专业知识;以及4） 丰富研究组合，掌握科学管理技能，建立跨学科合作。博士 Mehta的跨学科导师团队包括POR和CKD临床试验专家（主要导师- 博士Tamara Isakova）、心脏表型和HFpEF试验（Co-Mentor - Dr. Sanjiv Shah）和生物统计学 和代谢组学（Denise Scholtens）。两名外部咨询委员会成员还将提供 HF（Ravi V Shah博士）和CKD（Morgan Grams博士）代谢组学导师。通过完成 建议的研究和实现职业发展目标的指导下，经验丰富的导师， 在NU动态科学环境的支持下，Mehta博士将过渡到研究独立， 作为一名致力于推进CKD和HF患者护理的医生-科学家茁壮成长。

Project Summary Rupal Mehta, MD is an Assistant Professor of Medicine in the Division of Nephrology and Hypertension at the Northwestern University (NU) Feinberg School of Medicine. Dr. Mehta has assembled a cross-disciplinary mentorship team to advance her independent research program focused on studying heart failure (HF) pathogenesis in patients with chronic kidney disease (CKD). Heart failure with preserved ejection fraction (HFpEF) is a common manifestation of cardiovascular disease (CVD) in patients with CKD, and patients with CKD represent a distinct and highly prevalent sub-phenotype within the heterogeneous syndrome of HFpEF. Targeting of traditional mechanisms for CVD has not relieved the burden of HFpEF in CKD, suggesting that CKD-specific mechanisms may exist. Given the kidney’s impact on small molecule clearance and metabolism, Dr. Mehta proposes to investigate the central hypothesis that an altered metabolome in CKD contributes to HFpEF pathogenesis. The scientific premise is based on the emergence of distinct metabolic signatures of HFpEF, which suggests that CKD-induced metabolic changes may contribute to HFpEF pathogenesis. In Aim 1, Dr. Mehta will use the Chronic Renal Insufficiency Cohort Study, a population-based epidemiologic study, to investigate the associations between circulating metabolites and subclinical and clinical HFpEF in patients with CKD. In a patient-oriented (POR) study in Aim 2, Dr. Mehta will examine the dose-response relationship between circulating metabolites and subclinical HFpEF, phenotyped using 2D-speckle tracking echocardiography and cardiopulmonary exercise testing, in patients with and without CKD. In an interventional POR study in Aim 3, Dr. Mehta will use sodium glucose cotransporter 2 inhibition as a therapeutic probe to investigate whether modification of the metabolome in patients with CKD and subclinical HFpEF is associated with improved cardiac structure and function over 6 months. The results will provide critical data to inform future studies. Dr. Mehta’s career development goals are: 1) to expand knowledge of metabolomics testing and interpretation of metabolomics data; 2) to strengthen skills in identifying HFpEF phenotypes and interpreting cardiac testing in patients with CKD; 3) to develop expertise in conducting mechanistic POR studies; and 4) to enrich research portfolio, master scientific management skills and build cross-disciplinary collaborations. Dr. Mehta’s cross-disciplinary mentorship team includes experts in POR and CKD clinical trials (Primary mentor - Dr. Tamara Isakova), cardiac phenotyping and HFpEF trials (Co-Mentor - Dr. Sanjiv Shah) and biostatistics and metabolomics (Dr. Denise Scholtens). Two external advisory committee members will also provide mentorship in metabolomics in HF (Dr. Ravi V Shah) and CKD (Dr. Morgan Grams). By completing the proposed studies and attaining career development goals with guidance from experienced mentors and support from the dynamic scientific environment at NU, Dr. Mehta will transition to research independence and thrive as a physician-scientist committed to advancing the care of patients with CKD and HF.