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

心力衰竭(HF)影响着570万美国人，与50%的5年死亡率有关，以及 非洲裔美国人(AA)的负担不成比例，他们的患病率高出50%，高出约80% 与美国白人相比，心力衰竭的发病率。保留左心室射血分数(HFpEF)的高频占高达70% AAS中普遍存在HF，目前尚无有效的治疗方法。一种新的、有希望的、可修改的途径 HFpEF涉及炎症、一氧化氮(NO)耗竭、利钠肽(NPs)和改变的cGMP，以及 可能与有较大全身炎症和左心室受损的NP反应的AA特别相关 与白人相比，墙面的应力。本申请的目的是定义共病的贡献- 与一氧化氮(NO)耗竭相关的炎症以及左室壁NP反应受损 应激，到心功能障碍的发展，以及从无症状的心功能障碍到 腹主动脉硬化中明显的心力衰竭。我们的中心假设是心血管疾病(尤其是高血压，但也包括冠状动脉疾病 疾病、房颤)、非心脏疾病(糖尿病、肥胖症、肾功能不全)和非传统疾病(身体 不活动)心衰危险因素激活炎症通路，与受损的NP反应相结合 左室壁应激，夸大舒张期功能障碍的年龄相关进展，并通过 抑制cGMP活性，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)约800名AA参与者的超声心动图，这项建议将 在计划的第4次考察访问中高效地在其余约2,000名JHS参与者中获得回声 将参与者的学习负担降至最低的方式。该项目还将测量~4,000的LV形变 来自JHS的回声访问1(20年前)，以及访问1和4的路径生物标记物，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 和收缩功能障碍；(2)与炎症通路和已知影响cGMP活性的NPs有关 对舒张期和收缩期功能障碍的关键指标；(3)确定左室舒张和收缩功能障碍的程度 心脏收缩功能障碍可预测腹主动脉硬化患者发生心衰的可能性。拟议研究的贡献将是定义 左心功能障碍的时间进展及其临床预测指标，建立了一种新的和可修改的作用 在这一进程中的生物途径，并量化其与发生心力衰竭的关系。这一贡献在以下方面意义重大 确定了几种现有药物靶向的有希望的生物途径的重要性，这些药物可以翻译 迅速转变为预防性干预。这一建议的根本创新之处在于：(1)审问小说 作为潜在的HFpEF的生物途径和非传统的心力衰竭危险因素；(2)关注 未充分研究心力衰竭超负荷人群和危险因素；以及(3)界定两者的贡献 使用新的成像技术，尽管保留了LVEF到HF的发展，但舒张期和收缩期功能障碍 以及创新的分析方法(例如，包括潜在轨迹分析、结构化方程建模)。

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).