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，并且 非裔美国人 (AA) 的负担过重，他们的患病率高出 50%，高出约 80% 与美国白人相比，心力衰竭的发生率。左心室射血分数 (HFpEF) 保留的心力衰竭 (HF) 占 70% AA 地区常见 HF，且无有效治疗方法。一种新颖的、有前途的、可修改的潜在途径 HFpEF 涉及炎症、一氧化氮 (NO) 消耗、利钠肽 (NP) 和 cGMP 改变，以及 可能与全身性炎症较严重且 NP 对 LV 反应受损的 AA 尤其相关 与白色相比，壁应力。该应用程序的目的是定义合并症的贡献- 与一氧化氮 (NO) 消耗相关的炎症以及 NP 对左心室壁反应受损 应激、心功能不全的发展以及从无症状心功能不全到心功能不全的转变 AA 中明显的 HF。我们的中心假设是心血管疾病（尤其是高血压，还有冠状动脉） 疾病、心房颤动）、非心脏疾病（糖尿病、肥胖、肾功能不全）和非传统疾病（身体疾病） 不活动）心力衰竭危险因素会激活炎症通路，再加上 NP 反应受损 左室壁压力，夸大与年龄相关的舒张功能障碍的进展，并通过以下途径促进收缩功能障碍： cGMP 活性下降，最终导致心力衰竭。通过利用 PI 正在进行的资助项目来执行 杰克逊心脏研究 (JHS; R01HL135008) 中约 800 名 AA 参与者进行超声心动图检查，该提案将 在计划的第四次研究访问中以高效的方式获得剩余约 2,000 名 JHS 参与者的回声 最大限度地减少参与者学习负担的方式。该项目还将测量约 4,000 米的 LV 变形 JHS 访视 1（20 年前）的回声以及访视 1 和 4 的通路生物标志物可解决以下问题 具体目标： (1) 定义传统和非传统临床危险因素预测舒张压的程度 和 AA 的收缩功能障碍； (2) 将炎症途径和已知影响 cGMP 活性的 NP 联系起来 舒张和收缩功能障碍的关键指标； (3) 确定 LV 舒张压和 收缩功能障碍可预测 AA 中心力衰竭的发生。拟议研究的贡献将是定义 左心室功能障碍的时间进展及其临床预测因素，建立了一种新颖且可修改的药物的作用 该进展中的生物途径，并量化其与心力衰竭事件的关系。这一贡献意义重大 确定一种有希望的生物途径的重要性，该途径是几种现有药物的目标，可以转化 迅速采取预防性干预措施。该提案的根本创新在于：（1）质疑小说 潜在的 HFpEF 的生物学途径和非传统 HF 危险因素； (2) 重点关注 心力衰竭负担过重和危险因素的未充分研究人群； (3) 定义两者的贡献 尽管使用新型成像技术保留了 LVEF 至 HF 的发展，但舒张和收缩功能障碍 和创新的分析方法（例如，包括潜在轨迹分析、结构化方程建模）。