Multi-Omic Markers of Cardiac Function and Structure within the Pressure Overloaded Heart

项目摘要/摘要 这项拟议的研究是基于主动脉瓣狭窄(AS)对公共健康的重要性，AS是一种常见的 与大量发病率和死亡率相关的瓣膜心脏病。一旦出现症状，生存就是 如果不进行治疗，1年期的死亡率为50%，令人沮丧。临床症状发生一次心脏代偿机制 失败，表明需要进行主动脉瓣置换术(AVR)，但因为AS主要影响老年人， 症状经常被错误地归因于合并症、高龄或两者兼而有之--导致延迟 治疗。虽然大多数最终接受AVR的患者在症状和 存活，近一半的患者在AVR后第一年内死亡或未能获得症状和健康状况 他们接受了AVR的改善。我们的研究表明，不可逆转的心脏重塑和 与延迟治疗相关的损伤导致了这些不良的临床结果，突显了未得到满足的 客观和敏感的措施，为临床决定动静脉动静脉瘘的时机提供信息。我们的长期目标是 开发和实施一种基于组学的精准医学方法来识别重症AS患者 面临不可逆转的心脏重构和损伤的风险谁将受益于早期的AVR，以及我们的中心 假说是，反映心脏结构和功能维度的多组特征将识别 不可逆的心脏重构，因此可以预测对AVR的临床反应。我们之前的工作和 初步研究为我们的假设提供了强有力的支持，并证明了我们的经验 多学科团队是唯一有资格完成拟议研究的团队。我们已经确定了新陈代谢 与心脏功能和结构测量密切相关的信号，并预测AVR后的死亡率， 以及与心脏功能有关的蛋白质组学特征，这些特征可以区分严重的AS并与 死亡率。在这项建议中，我们采用纵向系统生物学方法，利用最新的 蛋白质组和代谢组(多组)科学：发现、测试和交叉验证多组签名 重症强直性脊柱炎患者的心功能和结构(目标1)；纵向多组体特征 AVR后心脏结构和功能改变的征象和相关性(目标2)； 多组特征预测AVR反应的准确性(目标3)。我们的方法将使我们能够 确定重症AS患者心脏不可逆重构和损伤的多组学特征。这些 数据将支持开发新的基于精确医学的策略，以识别哪些患者 将受益于早期临床干预，以努力降低死亡率和最大限度地提高AVR后的健康水平。

PROJECT SUMMARY/ABSTRACT This proposed study is motivated by the public health importance of aortic stenosis (AS), a common form of valvular heart disease that is associated with substantial morbidity and mortality. Once symptomatic, survival is a dismal 50% at 1-year if left untreated. Clinical symptoms develop once cardiac compensatory mechanisms fail, indicating the need for aortic valve replacement (AVR), but because AS primarily affects the elderly, symptoms are often incorrectly attributed to comorbid conditions, advanced age, or both—resulting in delayed treatment. While most patients that eventually undergo AVR experience improvements in symptoms and survival, nearly half of patients die within the first year after AVR or fail to reap the symptom and health status improvements for which they underwent AVR. Our research suggests that irreversible cardiac remodeling and injury related to delayed treatment contribute to these poor clinical outcomes, highlighting the unmet need for objective and sensitive measures to inform clinical decisions regarding the timing of AVR. Our long-term goal is to develop and implement an omics-based precision medicine approach for identifying patients with severe AS at-risk for irreversible cardiac remodeling and injury who would benefit from earlier AVR, and our central hypothesis is that multi-omic signatures reflective of dimensions of cardiac structure and function will identify irreversible cardiac remodeling and therefore predict the clinical response to AVR. Our prior work and preliminary studies provide strong support for our hypothesis and demonstrate that our experienced multidisciplinary team is uniquely qualified to complete the proposed study. We have identified metabolomic signatures that relate strongly to measures of cardiac function and structure and predict mortality after AVR, and also proteomic signatures relating to cardiac function that differentiate severe AS and associate with mortality. Within this proposal, we adopt a longitudinal systems biology approach that leverages the latest in proteomic and metabolomic (multi-omic) sciences to: discover, test, and cross-validate multi-omic signatures of cardiac function and structure in patients with severe AS (Aim 1); characterize longitudinal multi-omic signatures and associations with changes in cardiac structure and function after AVR (Aim 2); and evaluate the accuracy with which multi-omic signatures predict response to AVR (Aim 3). Our approach will enable us to identify multi-omic signatures of irreversible cardiac remodeling and injury in patients with severe AS. These data will support the development of new precision medicine-based strategies for identifying patients who would benefit from earlier clinical intervention in an effort to reduce mortality and maximize health after AVR.