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

项目摘要 由于平均预期寿命的增加，沿着心血管疾病的高发病率， 随着年龄的增长，超过一半的心血管手术是在65岁以上的成年人中进行的。然而，在这方面， 尽管总体安全性良好，但老年人对不良结局的易感性增加。 事实上，暴露于旨在提高生存率的心血管手术可能反而会导致长期 疾病和残疾。更好地理解复原力和脆弱性（即为什么有些人 成功地驾驭健康压力源，而其他人则没有）可能有助于识别影响健康的生理因素。 恢复潜力和长期福祉。这项工作的目标是采取第一步，确定一个 心血管疾病患者易感性的潜在可修改的分子指标。 经导管主动脉瓣置换术（TAVR）是外科主动脉瓣置换术的微创替代方法， 对有症状的严重主动脉瓣狭窄（AS）患者进行瓣膜置换术。尽管超过70%的TAVR 患者的生活质量（QoL）得到改善，生存期延长，死亡率等不良结局， 功能衰退仍然很常见。临床因素，如心血管疾病负担，合并症， 和虚弱预示着更糟糕的结果。此外，初步数据表明， 炎症和免疫活性失调也与更差的结果相关。更好的 了解炎症和免疫活性与TAVR术后结局之间的关系， 指出脆弱性的调节机制，并提出干预目标。 与此相关的是，尽管以前从未在心血管手术中进行过探索， 基因表达模式被称为逆境保守转录反应（CTRA）， 在暴露于健康压力源后会产生不良后果。定义为同时上调 炎症和先天免疫应答下调，健康应激前CTRA表达 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表达是 可修改的，药物和行为干预，成功下调CTRA是 与改善临床结果相关。因此，本项目探讨了增加的假设， 作为炎症和免疫系统功能障碍的标志物，基线CTRA表达将预测 TAVR后的不良长期结局。通过识别与增加的基因表达模式， 脆弱性，结果将为未来探索生理机制的工作提供基础， 有助于减少弹性，并突出治疗操作的潜在目标，以优化 结果。此外，该项目将通过指导收购支持我的专业发展， 研究和领导技能，成为一个成功的独立研究员， 跨学科的方法来了解老年人心血管疾病的健康老龄化。

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.