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: 10200796
• 负责人: JOHN E PANDOLFINO
• 金额: $ 36.99万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10200796
• 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 吞咽困难是非常常见的，并导致生活质量的大幅下降 与营养不良有关的发病率和死亡率增加，以及与反流有关的并发症， 抱负不幸的是，我们对吞咽困难和胃食管反流病的病理生理学的理解一直是 主要集中在循环肌肉活动和忽视的生物力学特性， 促进正常排空的食管壁。我们最初的工作探讨了团内注射与 压力（IBP）和食管胃连接处（EGJ）顺应性作为流出阻力的度量。这项工作 强调了IBP和EGJ开放之间的直接关系，是开发 食管运动障碍的新分类方案，“芝加哥分类”。尽管这一改进 尽管对大剂量输运动力学的理解集中在大剂量输运动力学上，但仍然存在以大剂量输运动力学为中心的重大未解决问题。 缺乏症状的真实相关性或不良结果的预测模型。鉴于这些限制，我们 我们已经将我们的注意力转向更直接的评估，即壁的扩张性和血管壁的反应如何， 食道体体积膨胀将改变正常的食团传输。我们假设， 食管壁的特性将可能通过干扰正常的低压状态而改变食团输送 是无症状食团通过食管所必需的。 为了验证我们的假设，即壁力学是食管疾病的主要决定因素，我们 必须开发新方法和新技术来直接测量机械壁状态。使用 阻抗技术结合测压，我们现在能够评估IBP和直径变化 时空连续体（4D-IM）。这种方法将使我们能够研究团传输的机制 除了通过测压法量化的等长环形肌肉收缩之外， 食道通过等张松弛和被动扩张来适应传播的食团， 食管通过被动反冲和张力增强收缩推进食团的能力。此外，我们还有 还改良了FLIP技术，以评估食管壁对容积扩张的反应， FLIP-全景测量分析。食管壁对食团滞留或反流的反应是最常见的反应之一。 食管在预防误吸、反流损伤或相关症状并发症方面的重要功能 药物滞留我们最近报道，对容积扩张的正常反应与 重复性顺行收缩（RAC），这种反应在特定疾病状态下发生改变。我们 总体目标将是研究明确定义的患者人群在针对壁的干预前后 扩张性，以确定扩张性和对体积扩张的反应是否异常， 结果的重要预测因素。这项工作将建立在以前成功的芝加哥分类的基础上 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点。