Circulating Proteomics to Phenotype the Development and Reversal of Myocardial Remodeling in Aortic Stenosis

循环蛋白质组学对主动脉瓣狭窄心肌重塑的发展和逆转进行表型分析

• 批准号: 10844786
• 负责人: JANE E Freedman
• 金额: $ 53.31万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10844786
• 关键词: Administrative Supplement; Age; Age Years; Aging; Aortic Valve Stenosis; Auscultation; Biological Assay; Biological Markers; Blood; Blood Proteins; Blood Tests; Brain natriuretic peptide; Cessation of life; Chest Pain; Classification; Clinical; Complement; Cost Savings; Custom; Data; Detection; Development; Diagnosis; Discrimination; Disease Progression; Dyspnea; Early Diagnosis; Echocardiography; Elasticity; Functional disorder; Gatekeeping; Goals; Heart; Heart Valve Diseases; Heart failure; Hospitalization; Individual; Injury; Link; Logistic Regressions; Machine Learning; Medical; Morbidity - disease rate; Myocardium; N-terminal; Obstruction; Outcome; Patients; Phenotype; Plasma; Population Heterogeneity; Preparation; Proteins; Proteome; Proteomics; Race; Recording of previous events; Research; Residual state; Sampling; Sensitivity and Specificity; Specificity; Stenosis; Symptoms; Syncope; Testing; Therapy trial; Time; Troponin; Validation; Ventricular Remodeling; aortic valve replacement; biomarker panel; cohort; cost; detection test; follow-up; heart imaging; high dimensionality; hospital readmission; implementation barriers; improved; innovation; machine learning algorithm; mortality; novel; novel strategies; optimism; participant enrollment; pressure; screening; sex

ABSTRACT: Aortic stenosis (AS) carries significant morbidity and mortality and is a highly prevalent heart valve disease of aging (5-10% of those ³65 years). While treatment with aortic valve replacement (AVR) has historically been reserved for symptomatic severe AS, irreversible myocardial remodeling/injury occurs prior to the onset of symptoms, before AS is “severe”, and contributes to death and persistent heart failure (HF) in up to 40% of patients 1 year after AVR. To reduce the morbidity and mortality of AS, there is an invigorated focus on early-stage AS with goals of (1) advancing medical therapy to slow disease progression; and (2) earlier timing of AVR before symptoms and before AS is severe. A major roadblock for operationalizing this paradigm is detecting early-stage pre-symptomatic AS. While an echocardiogram (echo) is the gold standard for AS diagnosis, physical exam (auscultation) and patient history (e.g., dyspnea, chest pain) are the gatekeepers to trigger an echo order, but they are insensitive (missing AS), non-specific (leading to needless echoes), and biased to detect late-stage AS. Universal echo screening for AS would be exceedingly expensive, wasteful, strain capacity, and difficult to disseminate broadly. A widely available and accessible pre-screening strategy— with high sensitivity/specificity—to increase the detection of early-stage AS and efficiently deploy echo in the diagnosis of AS represents a critical unmet need to optimize outcomes for AS. Accordingly, our long-term goal is to develop, validate, and implement a blood-based multi-marker screening test for the detection of AS among those ³65 years of age. Other (pre)screening strategies have substantial real-world implementation barriers, but a blood test is a novel approach to detect AS that would enable widespread deployment in diverse populations and improve the efficiency of echo in AS diagnosis. The central hypothesis of this application is that valve stenosis and myocardial remodeling/dysfunction resulting from pressure overload will be accompanied by alterations in the circulating proteome useful for detecting individuals with AS. To build on our promising pilot data, we propose to discover and prioritize proteins for a multi-marker panel to detect individuals with AS. Existing plasma samples from two discovery cohorts—each with individuals with AS and age/sex/race-matched controls without AS (presence/absence of AS verified by cardiac imaging)—will be used for high-dimensional proteomics. Several statistical approaches, including machine learning, will be utilized to discover a smaller set of known/novel proteins most strongly associated with AS in logistic regression. The proposed project is closely aligned with encouraged avenues of research outlined in the NOSI (NOT-HL-23- 078) and CAROL Act. Completion of the proposed aim in this administrative supplement will pave the way for the development and validation of a custom multiplex panel for the detection of AS.

摘要：主动脉瓣狭窄（AS）具有显著的发病率和死亡率，是一种高度流行的心脏病 老年瓣膜病（其中5-10% ≥ 65岁）。虽然主动脉瓣置换术（AVR）治疗 历史上被保留用于症状性重度AS，不可逆的心肌重塑/损伤发生在 症状发作前AS是“严重的”，并导致死亡和持续性心力衰竭（HF）， AVR后1年，40%的患者。为了降低AS的发病率和死亡率， 早期AS的目标是（1）推进药物治疗以减缓疾病进展;和（2）更早 症状前和AS前AVR的时机是严重的。实施这一模式的主要障碍是 是检测早期症状前AS虽然超声心动图（回声）是AS的金标准 诊断、体格检查（听诊）和患者病史（例如，呼吸困难，胸痛）是 触发回显命令，但它们不敏感（缺少AS），非特定（导致不必要的回显）， 偏向于检测晚期AS。AS的通用回声筛查将是非常昂贵，浪费， 应变能力，难以广泛传播。一个广泛提供和可获得的预先筛选战略- 具有高灵敏度/特异性-提高早期AS的检测能力，并在 AS的诊断代表了优化AS结果的关键未满足的需求。因此，我们的长期目标 是开发、验证和实施一种用于检测AS的基于血液的多标志物筛查试验 其中，65岁以上。其他（预）筛选策略已在现实世界中得到大量实施 障碍，但血液测试是一种检测AS的新方法，可以在各种疾病中广泛部署。 提高超声诊断AS的效率。本申请的中心假设是 压力超负荷导致的瓣膜狭窄和心肌重塑/功能障碍将 伴随着循环蛋白质组的改变，可用于检测AS患者。加强我们 有前途的试点数据，我们建议发现和优先考虑蛋白质的多标记面板检测 个人AS来自两个发现群体的现有血浆样本-每个群体都有患有AS的个体， 将使用年龄/性别/人种匹配的无AS对照组（通过心脏成像证实存在/不存在AS） 用于高维蛋白质组学。将利用包括机器学习在内的几种统计方法， 在逻辑回归中发现一组较小的已知/新的与AS最密切相关的蛋白质。的 拟议的项目与NOSI（NOT-HL-23）中概述的鼓励研究途径密切相关， 078)卡罗尔法案。完成本行政补充文件中提出的目标将为以下方面铺平道路： 开发和验证用于检测AS的定制多重面板。