Systolic & diastolic dysfunction in heart failure and preserved ejection fraction

描述（由申请人提供）：这是Amil Shah博士的K08申请，他是马萨诸塞州波士顿布里格姆妇女医院的心脏病学教员和早期研究员。他的目标是成为一名领先的临床研究者，使用无创心脏结构和功能评估来更好地了解心力衰竭的风险和进展，并为新的治疗干预提供信息。他的近期目标是采用新的超声心动图测量心功能，以确定以前未被认识到的收缩期功能障碍在保留射血分数（HFpEF）心力衰竭中的作用。该申请提供了一个全面的培训计划，包括结构化的指导，一个完善的咨询委员会，以及先进的统计和成像方法的量身定制的教学课程，这些将为Shah博士提供实现这一目标和过渡到一个成功的独立研究者所必需的技能。HFpEF是公认的公共卫生负担。无创舒张功能测量无法将HFpEF患者与无症状患者区分开来，也无法预测HFpEF患者的不良事件，以及对共存的收缩功能障碍的认识不足（使用新型心肌变形成像检测），这些都是有效分型和开发这种异质性综合征治疗方法的关键障碍。该建议的主要假设是，伴随的收缩和舒张功能损害与心血管危险因素的积累同时发生，这些损害是HFpEF的发展和随后的发病率和死亡率的核心。Shah博士将使用最先进的超声心动图数据，这些数据来自两个独特的、互补的、表型良好的人群，具有前瞻性的临床结果——HFpEF的NHLBI TOPCAT临床试验和基于社区的NHLBI ARIC队列——以解决以下具体目标：(1)在大约8000名老年社区ARIC参与者中，确定收缩变形的新测量方法与HF发生的临床和超声心动图风险标志物之间的关系；(2)确定这些新的收缩功能障碍指标与HFpEF发生风险、流行HFpEF患者CV死亡或HF住院风险的关联程度；(3)通过将收缩功能障碍的新指标与心肌应激（NT-pro-BNP）和损伤（高敏感性肌钙蛋白T）的可溶性生物标志物相结合来改善预后，以建立简化的HFpEF事件风险预测模型，并预测流行HFpEF患者的不良结局。提出的早期职业发展奖的结果将(1)为定义病理性舒张和收缩功能障碍提供关键基准，(2)阐明这些异常在HFpEF中的作用

DESCRIPTION (provided by applicant): This is a K08 application for Dr Amil Shah, a cardiology faculty member and early stage investigator at the Brigham and Women's Hospital in Boston, MA. His goal is to become a leading clinical investigator using noninvasive assessments of cardiac structure and function to better understand heart failure risk and progression, and to inform new therapeutic interventions. His near-term goal is to employ novel echocardiographic measures of cardiac function to define the role of previously under-recognized systolic dysfunction in heart failure with preserved ejection fraction (HFpEF). This application presents a comprehensive training plan, including structured mentorship, a well-developed advisory committee, and a tailored didactic curriculum in advanced statistical and imaging methods, which together will provide Dr Shah with the skills necessary to achieve this goal and transition into a successful independent investigator. HFpEF is a well-recognized public health burden. The inability of noninvasive measures of diastolic function to distinguish HFpEF patients from their symptom-free counterparts and to predict adverse events among HFpEF patients, along with the under-appreciation of co-existing systolic dysfunction (detected using novel myocardial deformation imaging) are critical barriers to progress in effectively phenotyping and developing treatments for this heterogeneous syndrome. The main hypothesis of this proposal is that concomitant impairments in systolic and diastolic function occur in parallel with accumulating cardiovascular risk factors and that these impairments are central to the development of HFpEF and subsequent morbidity and mortality. Dr Shah will use state-of-the-art echocardiographic data from two unique, complementary, and well-phenotyped populations with prospectively adjudicated clinical outcomes - the NHLBI TOPCAT clinical trial in HFpEF and the community based NHLBI ARIC cohort - to address the following specific aims: (1) To determine the relationship of novel measures of systolic deformation with clinical and echocardiographic risk markers for incident HF in approximately 8,000 elderly community-dwelling ARIC participants; (2) To determine the extent to which these novel measures of systolic dysfunction associate with risk of developing HFpEF, and risk of CV death or HF hospitalization in prevalent HFpEF; and (3) To improve prognostication by combining novel measures of systolic dysfunction with soluble biomarkers of myocardial stress (NT-pro-BNP) and injury (high sensitivity troponin T) to develop parsimonious risk prediction models for incident HFpEF and for adverse outcomes in patients with prevalent HFpEF. The results of the proposed early career development award will (1) provide key benchmarks for defining pathologic diastolic and systolic dysfunction, (2) clarify the role of these abnormalities in HFpEF to help inform tailored interventions, (3) improve risk assessment to inform future preventative and therapeutic studies, and (4) serve as an ideal vehicle for Dr Shah to transition to an independent investigator.