Role of altered response to volumetric distension in esophageal disease

食管疾病中体积扩张反应改变的作用

• 批准号: 10439752
• 负责人: JOHN E PANDOLFINO
• 金额: $ 37.29万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10439752
• 关键词: Achalasia; Acids; Affect; Architecture; Biological Markers; Biology; Biomechanics; Bolus Infusion; Caliber; Chicago; Classification; Classification Scheme; Cognitive; Data; Deglutition; Deglutition Disorders; Development; Disease; Engineering; Enteral; Eosinophilic Esophagitis; Epithelial; Esophageal Diseases; Esophagogastric Junction; Esophagus; Fibrosis; Foundations; Functional disorder; Gastroesophageal reflux disease; Generations; Goals; Impairment; Injury; Intervention; Isometric Exercise; Isotonic Exercise; Length; Link; Malnutrition; Manometry; Measures; Mechanics; Mediating; Minor; Molecular; Morbidity - disease rate; Muscle; Muscle Contraction; Neurons; Obstruction; Outcome Measure; Patients; Pattern; Phenotype; Physiological; Physiology; Program Research Project Grants; Property; Psychometrics; Publications; Quality of life; Reflux; Relaxation; Reporting; Research Subjects; Resistance; Role; Scleroderma; Severity of illness; Symptoms; System; Techniques; Testing; Therapeutic Intervention; Time; Tissues; Work; adverse outcome; cholinergic; common symptom; design; electric impedance; experimental study; functional outcomes; imaging probe; improved; innovation; mathematical model; mechanical properties; mortality; motor disorder; new technology; new therapeutic target; novel strategies; outcome prediction; patient population; predictive modeling; pressure; prevent; response; success; tool

PROJECT SUMMARY Swallowing difficulties are extremely common and result in a substantial reduction in the quality of life and increased morbidity and mortality related to malnutrition and complications related to regurgitation and aspiration. Unfortunately, our understanding regarding the pathophysiology of dysphagia and GERD has been hampered by focusing predominantly on circular muscle activity and ignoring the biomechanical properties of the esophageal wall that promote normal emptying. Our initial work explored the relationship between intrabolus pressure (IBP) and esophagogastric junction (EGJ) compliance as a metric for outflow resistance. This work highlighted the direct relationship between IBP and EGJ opening and was the foundation for the development of a new classification scheme for esophageal motor disorders, “the Chicago Classification.” Despite this improved understanding focused on bolus transit dynamics, there are still significant unresolved issues centered on the lack of a true correlate for symptoms or a predictive model for adverse outcomes. Given these limitations, we have evolved our focus toward a more directed assessment of how wall distensibility and the response of the esophageal body to volumetric distention will alter normal bolus transit. We hypothesize that the mechanical properties of the esophageal wall will likely alter bolus transport by disturbing the normal low pressure state that is required for asymptomatic bolus transit through the esophagus. In order to test our hypothesis that wall mechanics are a major determinant of esophageal diseases, we have had to develop new approaches and new technology to directly measure mechanical wall state. Using impedance techniques combined with manometry, we are now capable of assessing IBP and diameter changes across a space-time continuum (4D-IM). This approach will allow us to study the mechanics of bolus transport beyond the isometric circular muscle contraction quantified by manometry and allow us to assess the ability of the esophagus to accommodate the propagating bolus via isotonic relaxation and passive distention and the ability of the esophagus to propel the bolus via passive recoil and auxotonic contraction. Additionally, we have also modified FLIP techniques to assess the response of the esophageal wall to volumetric distention using FLIP-panometry analysis. The response of the esophageal wall to bolus retention or reflux is one of the most important functions of the esophagus in preventing complications of aspiration, reflux injury, or symptoms related to bolus retention. We recently reported that the normal response to volumetric distention is associated with repetitive antegrade contractions (RACs) and that this response was altered in specific disease states. Our overarching goal will be to study well-defined patient populations before and after interventions targeting wall distensibility to determine whether abnormalities in distensibility and response to volumetric distention are important predictors of outcome. This work will build upon the previous success of the Chicago Classification by defining new biomechanical biomarkers of disease activity and new targets for therapeutic intervention.

项目摘要 吞咽困难极为普遍，导致生活质量大大降低 并增加了与营养不良以及与反流和并发症有关的发病率和死亡率 抽吸。不幸的是，我们对吞咽困难和GERD的病理生理学的理解已经 通过主要集中在循环肌肉活动上并忽略的生物力学特性而受到阻碍 促进正常排空的食管壁。我们的最初工作探讨了核内的关系 压力（IBP）和食管胃结（EGJ）依从性作为出口电阻的度量。这项工作 强调了IBP和EGJ开放之间的直接关系，是发展的基础 一种针对食道运动障碍的新分类方案，“芝加哥分类”。尽管有改善 理解集中于推注交通动力学，仍然存在着重大的未解决的问题。 缺乏症状的真正相关性或广告结果的预测模型。考虑到这些局限性，我们 已经将我们的重点发展为对墙壁可扩张性和如何反应的更直接评估 食管体到体积延伸将改变正常的推注转透。我们假设机械 食管壁的性质可能会通过干扰正常低压状态的良好推注转运 通过食道无症状的大注体转运所需。 为了检验我们的假设，即壁画是食管疾病的主要决定剂，我们 必须开发新的方法和新技术来直接测量机械墙状态。使用 阻抗技术结合了测量法，我们现在能够评估IBP和直径变化 跨时空连续体（4D-IM）。这种方法将使我们能够研究推注的机制 除了通过测量法量化的等距循环肌肉收缩，并允许我们评估 食道通过等渗松弛和被动距离来容纳繁殖的大推注， 食道通过被动后坐力和辅助收缩推动推注的能力。另外，我们还有 还修改了翻转技术，以评估食道壁对使用体积扩张的响应 翻转横幅分析。食管壁对推注保留或反射术的反应是最多的 食道在防止抽吸并发症，反射X损伤或症状相关的重要功能 保留推注。我们最近报道说，对体积扩张的正常响应与 重复的流行收缩（RAC），并且在特定疾病状态下这种反应发生了改变。我们的 总体目标是在针对墙的干预措施之前和之后研究定义明确的患者人群 确定不信任性异常和对体积扩张的反应是否是可扩张的性能是 结果的重要预测指标。这项工作将基于芝加哥分类的先前成功 通过定义疾病活动的新生物力学生物标志物和治疗干预的新靶标。