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

摘要：大约5-10%的老年人患有主动脉瓣狭窄（AS），预计到2050年将翻一番;由于没有可用的药物治疗来减缓进展，治疗仅限于主动脉瓣置换术（AVR）。虽然AVR历来被保留用于症状性重度AS，但心脏重塑和不可逆损伤发生在症状发作之前和AS为“重度”之前，并导致AVR后1年内高达40%的患者死亡和持续性心力衰竭（HF）症状/再住院，这表明心脏不可逆变化发作之前的AVR可能改善AVR后结局。幸运的是，随机策略试验正在进行中，以测试在症状和严重AS之前早期微创经导管AVR（TAVR）的益处。然而，早期TAVR并不是万能药;除了固有的手术风险，当人工瓣膜退化时，这也会导致更多的重复手术（有风险/成本）。超声心动图和标准生物标志物（例如，左心室肥大[LVH]，BNP）对于检测适应不良重构敏感性/特异性有限，且缺乏相关的生物学见解。在准备这项申请时，我们鉴定了心脏中组织/整体心脏表型的循环蛋白质组特征，（例如LVH、纤维化、心脏磁共振[CMR]/回波的收缩/舒张功能）（轻度至重度），定义了与HF/死亡风险增加相关的生物学合理和新型蛋白质的子集，在更广泛的无AS的高危人群中进行验证。我们的中心假设是，AS（轻度-中度;无症状重度）病程早期的心肌重塑/功能障碍将伴随着循环蛋白质组的改变，这些改变指向导致HF的已知/新途径，并为临床监测和药理学靶向提供早期分子晴雨表。我们将利用最先进的心脏成像以及高通量蛋白质组学对来自四个AS队列的纵向样本进行分析，包括轻度至重度无症状AS、对照、TAVR前后采样以及两项随机试验：（1）开发/验证循环蛋白质组特征，反映与AS监测相关的不良心肌重塑/功能障碍和AVR的个性化时机;和（2）识别已知/新的潜在心脏重塑（AVR前）和心脏恢复（AVR后）的途径，用于下游药物靶向，以降低HF的剩余风险。我们的具体目标是：（1）确定心肌重塑/功能障碍的蛋白质组学特征是否在传统临床干预阈值之前早期出现在AS中;（2）确定严重AS中AVR后LVH消退的蛋白质组学特征;（3）确定心脏健康的蛋白质组学特征是否与AVR后结局相关，是否能够识别从即时AVR中获益的无症状患者。如果成功，本申请将确定一组与AS早期心脏重塑表型相关的循环蛋白（已知/新型），用于临床监测、精确治疗、机制研究和药理学靶向。

ABSTRACT: Approximately 5-10% of older adults have aortic stenosis (AS) with anticipated doubling by 2050; with no available medical therapy to slow progression, treatment is limited to aortic valve replacement (AVR). While AVR has historically been reserved for symptomatic severe AS, cardiac remodeling and irreversible injury occur before the onset of symptoms and before AS is "severe" and contribute to death and persistent heart failure (HF) symptoms/rehospitalization in up to 40% of patients 1 year after AVR, suggesting that AVR before onset of irreversible changes to the heart is likely to improve post-AVR outcomes. Fortunately, randomized strategy trials are underway to test the benefit of earlier less invasive transcatheter AVR (TAVR) before symptoms and severe AS. However, earlier TAVR isn't a panacea; beyond inherent procedural risks, this will also lead to more repeat procedures (with risks/costs) when prosthetic valves degenerate. Echocardiography and standard biomarkers (e.g., left ventricular hypertrophy [LVH], BNP) have limited sensitivity/specificity for detecting maladaptive remodeling and lack relevant biological insight. In preparation for this application, we identified circulating proteomic signatures of tissue/global cardiac phenotypes in the heart (e.g. LVH, fibrosis, systolic/diastolic function with cardiac magnetic resonance [CMR]/echo) in a group of 115 individuals across a spectrum of AS (mild to severe), defining subsets of biologically plausible and novel proteins associated with an increased risk of HF/mortality, with validation in a broader at-risk population without AS. Our central hypothesis is that myocardial remodeling/dysfunction early in the course of AS (mild-moderate; asymptomatic severe) will be accompanied by alterations in the circulating proteome pointing to known/novel pathways contributing to HF and providing an early molecular barometer for clinical surveillance and pharmacologic targeting. We will utilize state-of-the-art cardiac imaging alongside high-throughput proteomics on longitudinal samples from four cohorts of AS, including mild to severe asymptomatic AS, controls, pre- and post-TAVR sampling, and two randomized trials to: (1) develop/validate circulating proteomic signatures that reflect adverse myocardial remodeling/dysfunction relevant to AS surveillance and personalized timing of AVR; and (2) identify known/novel pathways underlying cardiac remodeling (before AVR) and cardiac recovery (after AVR) for downstream pharmacological targeting to reduce residual risk from HF. Our specific aims are: (1) identify whether proteomic signatures of myocardial remodeling/dysfunction are present early in AS before traditional clinical thresholds for intervention; (2) identify proteomic signatures of LVH regression after AVR in severe AS; and (3) determine whether proteomic signatures of cardiac health are associated with post-AVR outcomes and able to identify asymptomatic patients who benefit from prompt AVR. If successful, the current application will identify a set of circulating proteins (known/novel) linked to early cardiac remodeling phenotypes in AS for clinical surveillance, precision therapy, mechanistic study, and pharmacologic targeting.