Inflammatory and immune system gene expression as a marker of vulnerability in older adult patients undergoing a cardiovascular procedure

项目总结 由于平均预期寿命的增加，以及#年心血管疾病的高发病率 老龄化，超过一半的心血管手术是在65岁以上的成年人身上进行的。然而， 尽管总体上安全状况良好，但老年人对不良后果的易感性增加。 事实上，暴露在旨在提高存活率的心血管手术中可能反而会加速长期的 疾病和残疾。更好地理解复原力和脆弱性(即为什么有些人 成功地驾驭健康应激源，而其他人却没有)可以帮助识别影响 复苏潜力和长期福祉。这项工作的目标是采取第一步确定一个 心血管疾病患者脆弱性的潜在可修改分子指示器。 经导管主动脉瓣置换术(TAVR)是外科主动脉的一种微创替代方法 有症状的重度主动脉瓣狭窄(AS)者行瓣膜置换术。尽管超过70%的TAVR 患者获得了更高的生活质量(QOL)和更长的生存时间，结果较差，如死亡率和 功能衰退仍然很常见。临床因素如心血管疾病的负担，合并症， 而脆弱则预示着更糟糕的结果。此外，初步数据表明，增加的标志物 炎症和免疫活性失调也与更糟糕的结果有关。更好的 了解炎症和免疫活动与TAVR术后预后之间的关系可能 指出调节脆弱性的机制，并建议干预目标。 与此相关的是，尽管以前从未探讨过与心血管程序有关的问题，但具体的 被称为保守逆境转录反应(CTRA)的基因表达模式与 暴露在健康应激源下后有不良后果。由同时上调的 健康应激前先天免疫反应、CTRA表达的炎症和下调 暴露可预测不良事件，如不良生活质量和死亡率。重要的是，CTRA的表达是 成功下调CTRA的可修改的药理学和行为干预措施包括 与改善临床结果相关。因此，这个项目探索了一种假设，即 作为炎症和免疫系统功能障碍的标志物，基线时CTRA的表达将预测 TAVR术后不良的远期结局。通过识别与增加有关的基因表达模式 脆弱性，这一结果将为未来探索 有助于降低恢复力，并强调治疗操作的潜在目标以优化 结果。此外，该项目将通过在导师的指导下收购 成为一名成功的独立研究员所必需的研究和领导技能 用跨学科的方法了解患有心血管疾病的老年人的健康老龄化。

PROJECT SUMMARY Due to increasing average life expectancy, along with the high incidence of cardiovascular disease in aging, more than half of all cardiovascular procedures are performed in adults over 65 years of age. However, despite overall favorable safety profiles, older adults have an increased susceptibility to adverse outcomes. Indeed, exposure to cardiovascular procedures intended to promote survival may instead precipitate long-term disease and disability. A better understanding of resilience and vulnerability (i.e. why some individuals successfully navigate health stressors while others do not) may help identify physiologic factors that affect recovery potential and long-term wellbeing. The goal of this work is to take the first steps in identifying a potentially modifiable molecular indicator of vulnerability in patients with cardiovascular disease. Transcatheter aortic valve replacement (TAVR) is a minimally invasive alternative to surgical aortic valve replacement for those with symptomatic severe aortic stenosis (AS). Although over 70% of TAVR patients achieve improved quality of life (QoL) and prolonged survival, poor outcomes such as mortality and functional decline remain common. Clinical factors like the burden of cardiovascular disease, comorbidities, and frailty predict worse outcomes. Furthermore, preliminary data suggests that increased markers of inflammation and dysregulated immune activity are associated with worse outcomes, as well. A better understanding of the relationship between inflammatory and immune activity and outcomes after TAVR may point to mechanisms mediating vulnerability and suggest targets for intervention. Relevant to this, although never before explored in relation to cardiovascular procedures, a specific gene expression pattern known as the conserved transcriptional response to adversity (CTRA) is associated with adverse outcomes after exposure to a health stressor. Defined by the simultaneous upregulation of inflammation and downregulation of innate immune responses, CTRA expression prior to health-stress exposure predicts adverse events such as poor QoL and mortality. Importantly, CTRA expression is modifiable, and pharmacologic and behavioral interventions that successfully downregulate CTRA are associated with improved clinical outcomes. Therefore, this project explores the hypothesis that increased CTRA expression at baseline, as a marker of inflammatory and immune system dysfunction, will predict adverse long-term outcomes after TAVR. By identifying gene expression patterns that relate to increased vulnerability, the results will provide a foundation for future work exploring physiologic mechanisms that contribute to diminished resilience, and highlight potential targets for therapeutic manipulation to optimize outcomes. Furthermore, this project will support my professional development through mentored acquisition of research and leadership skills necessary to become a successful independent researcher with a transdisciplinary approach to understanding healthful aging in older adults with cardiovascular disease.