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狭窄(AS)，预计到2050年将增加一倍；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(AVR)。虽然AVR历史上被保留用于症状性重度AS，但心脏重构和不可逆转的损伤在症状出现之前和AS严重程度之前发生，并导致高达40%的患者在AVR一年后死亡和持续性心力衰竭(HF)症状/再住院，这表明在心脏发生不可逆转变化之前的AVR可能会改善AVR后的预后。幸运的是，随机策略试验正在进行中，以测试在出现症状和严重AS之前早期进行侵入性较小的经导管AVR(TAVR)的益处。然而，早期的TAVR不是灵丹妙药；除了固有的程序风险外，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(如左心室肥厚、BNP)在检测不良适应性重构方面的敏感性/特异性有限，缺乏相关的生物学洞察力。在为这一应用做准备时，我们在115名AS患者(从轻度到重度)中确定了心脏组织/整体心脏表型的循环蛋白质组特征(例如，LVH、纤维化、心脏磁共振收缩/舒张期功能[CMR]/ECHO)，确定了与心力衰竭/死亡率增加相关的生物学上可信的和新的蛋白质亚集，并在更广泛的无AS的高危人群中进行了验证。我们的中心假设是，AS(轻-中度；无症状重度)早期的心肌重构/功能障碍将伴随循环蛋白质组的改变，指向导致HF的已知/新途径，并为临床监测和药物靶向提供早期分子晴雨表。我们将利用最先进的心脏成像和高通量蛋白质组学技术，对四个AS队列的纵向样本进行高通量蛋白质组分析，包括轻度到重度无症状AS、对照组、TAVR前和TAVR后的样本，以及两项随机试验，以：(1)开发/验证循环蛋白质组特征，以反映与AS的监测和AVR的个性化时机相关的不良心肌重构/功能障碍；以及(2)识别潜在的心脏重构(AVR前)和心脏恢复(AVR后)的已知/新途径，用于下游药物靶向治疗，以降低心力衰竭的残余风险。我们的具体目标是：(1)确定是否存在心肌重构/功能障碍的蛋白质组特征，如在传统的临床干预阈值之前；(2)确定重度AS患者AVR后LVH消退的蛋白质组特征；以及(3)确定心脏健康的蛋白质组特征是否与AVR后的结果相关，并能够识别无症状患者谁受益于及时的AVR。如果成功，目前的应用将识别一组与早期心脏重构表型相关的循环蛋白(已知/新的)，用于临床监测、精确治疗、机制研究和药物靶向。

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.