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

项目摘要 Rupal Mehta，医学博士，华盛顿大学肾脏病和高血压科医学助理教授 西北大学范伯格医学院。梅塔博士召集了一个跨学科的 导师团队推进她专注于研究心力衰竭(HF)的独立研究计划 慢性肾脏病(CKD)的发病机制。射血分数保留的心力衰竭 (HFpEF)是CKD患者心血管疾病(CVD)的常见表现， 在HFpEF的异质性综合征中，CKD代表着一种独特且高度流行的亚型。 针对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特有的机制。鉴于肾脏对小分子清除和新陈代谢的影响， 梅塔博士建议调查一个中心假设，即CKD中的代谢体改变有助于 HFpEF的发病机制。科学前提是基于不同新陈代谢特征的出现 HFpEF，提示CKD引起的代谢改变可能参与了HFpEF的发病。在AIM 1，梅塔博士将使用慢性肾功能不全队列研究，这是一项基于人群的流行病学研究， 探讨慢性阻塞性肺疾病患者循环代谢产物与亚临床和临床HFpEF的关系 CKD。在Aim 2的一项以患者为中心(POR)的研究中，梅塔博士将研究剂量-反应关系 循环代谢产物和亚临床HFpEF之间的关系，使用2D斑点跟踪进行表型 有无慢性肾脏病患者的超声心动图和心肺运动试验。在一次干预性的 在Aim 3的POR研究中，Mehta博士将使用钠葡萄糖共转运体2抑制作为治疗探针 研究慢性肾脏病患者代谢组的改变是否与亚临床HFpEF相关 6个月以上心脏结构和功能均有改善。结果将提供关键数据以供参考 未来的研究。梅塔博士的职业发展目标是：1)扩大代谢组学测试和 代谢组学数据的解释；2)加强识别HFpEF表型和解释的技能 CKD患者的心脏测试；3)发展进行机械性POR研究的专业知识；4) 丰富研究资料，掌握科学管理技能，建立跨学科合作。Dr。 梅塔的跨学科导师团队包括POR和CKD临床试验方面的专家(主要导师- 、心脏表型和HFpEF试验(共同导师--Sanjiv Shah博士)和生物统计学 和代谢组学(丹尼斯·肖尔滕斯博士)。两名外部咨询委员会成员也将提供 在新陈代谢组学方面的指导：HF(Ravi V Shah博士)和CKD(Morgan Grams博士)。通过填写 在有经验的导师的指导下，建议的研究和实现职业发展目标 在国立大学充满活力的科学环境的支持下，梅塔博士将过渡到研究独立性和 作为一名致力于推进慢性肾脏病和心力衰竭患者护理的内科科学家，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.