Quantifying cardiac structure and function to define the progression to hear failure in African Americans

量化心脏结构和功能以定义非裔美国人听力衰竭的进展

• 批准号: 10886956
• 负责人: Amil M Shah
• 金额: $ 16.23万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10886956
• 关键词: Quantifying; cardiac; structure; function; define

Heart failure (HF) affects 5.7 million Americans, is associated with a 50% 5-year mortality, and disproportionately burdens African Americans (AAs), who have a 50% higher prevalence and ~80% higher incidence of HF compared to white Americans. HF with preserved LVEF (HFpEF) accounts for up to 70% of prevalent HF in AAs and has no efficacious therapy. A novel, promising, modifiable pathway underlying HFpEF involves inflammation, nitric oxide (NO) depletion, natriuretic peptides (NPs), and altered cGMP, and may be especially relevant in AAs who have greater systemic inflammation and an impaired NP response to LV wall stress compared to whites. The objective of this application is to define the contributions of comorbidity- driven inflammation with associated nitric oxide (NO) depletion, and of impaired NP response to LV wall stress, to the development of cardiac dysfunction, and the transition from asymptomatic cardiac dysfunction to overt HF in AAs. Our central hypothesis is that cardiovascular (especially hypertension, but also coronary disease, atrial fibrillation), non-cardiac (diabetes, obesity, renal dysfunction), and non-traditional (physical inactivity) HF risk factors activate inflammatory pathways which, combined with an impaired NP response to LV wall stress, exaggerate age-related progression in diastolic dysfunction and promote systolic dysfunction via depressed cGMP activity, ultimately resulting in HF. By leveraging the PI's ongoing funded project to perform echocardiography in ~800 AA participants in the Jackson Heart Study (JHS; R01HL135008), this proposal will obtain echos in the remaining ~2,000 JHS participants at the planned 4th study visit in a highly efficient manner that minimizes participant study burden. The project will also measure LV deformation on ~4,000 echos from JHS Visit 1 (20 years prior), and pathway biomarkers from Visits 1 and 4 to address the following specific aims: (1) Define the extent to which traditional and non-traditional clinical risk factors predict diastolic and systolic dysfunction in AAs; (2) Relate inflammatory pathways and NPs known to influence cGMP activity to key measures of diastolic and systolic dysfunction; (3) Determine the extent to which LV diastolic and systolic dysfunction predict incident HF in AAs. The contribution of the proposed research will be to define the temporal progression of LV dysfunction and its clinical predictors, establish the role of a novel and modifiable biologic pathway in this progression, and quantify its relation to incident HF. This contribution is significant in defining the importance of a promising biologic pathway targeted by several existing agents that could translate rapidly into preventative interventions. This proposal is fundamentally innovative in: (1) interrogating novel biological pathways and non-traditional HF risk factors as potentially underlying HFpEF; (2) focusing on an understudied population with excess burden of HF and risk factors; and (3) defining contributions of both diastolic and systolic dysfunction despite preserved LVEF to HF development using novel imaging techniques and innovative analytic approaches (e.g. including latent trajectory analysis, structured equation modeling).

心力衰竭（HF）影响570万美国人，与50%的5年死亡率相关， 非洲裔美国人（AAs）的负担不成比例，他们的患病率高出50%， 与白色美国人相比的HF发病率。LVEF保留的HF（HFpEF）占 在AA中普遍存在HF，并且没有有效的治疗。一种新的，有前途的，可修改的途径， HFpEF涉及炎症、一氧化氮（NO）耗竭、利钠肽（NP）和cGMP改变， 可能与全身性炎症更严重和对LV的NP反应受损的AA尤其相关 与白人相比，本申请的目的是确定科摩罗的贡献- 驱动的炎症与相关的一氧化氮（NO）耗竭，以及受损的NP对LV壁的反应 压力，心功能不全的发展，以及从无症状心功能不全到 AA中明显HF。我们的中心假设是心血管（尤其是高血压，但也包括冠状动脉） 疾病、心房颤动）、非心脏性（糖尿病、肥胖、肾功能不全）和非传统性（身体 不活动）HF危险因素激活炎症通路，其与受损的NP反应结合， 左室壁应力，加重舒张功能障碍的年龄相关进展，并通过以下途径促进收缩功能障碍 cGMP活性降低，最终导致HF。通过利用PI正在进行的资助项目来执行 在杰克逊心脏研究（JHS; R 01 HL 135008）中，对约800名AA受试者进行了超声心动图检查，本提案将 在计划的第4次研究访视中，以高效的方式获得剩余约2，000名JHS参与者的回波 最大限度地减少参与者的学习负担。该项目还将测量约4，000个 JHS访视1（20年前）的回声和访视1和4的途径生物标志物，以解决以下问题 具体目标：（1）确定传统和非传统临床危险因素预测舒张压的程度 （2）与已知影响cGMP活性的炎症通路和NP相关 舒张和收缩功能障碍的关键指标;（3）确定LV舒张和收缩功能障碍的程度， 收缩功能不全可预测AA中HF发生率。拟议研究的贡献将是确定 LV功能障碍的时间进展及其临床预测因素，建立了一种新的和可修改的 生物学途径，并量化其与HF事件的关系。这一贡献在 定义一个有前途的生物途径的重要性，这些生物途径被几种现有的药物靶向， 迅速采取预防性干预措施。本文的创新之处在于：（1）讯问小说 生物学途径和非传统HF风险因素作为潜在的基础HFpEF;（2）关注 HF和危险因素负担过重的未充分研究的人群;（3）定义两者的贡献 使用新的成像技术，尽管LVEF保持不变，但舒张和收缩功能障碍发展为HF 和创新的分析方法（例如，包括潜在轨迹分析，结构方程建模）。