The mechanics of symptom generation in dysphagia

描述（由申请人提供）：吞咽困难非常常见，导致生活质量大幅下降，与营养不良相关的发病率和死亡率增加，以及与反流和误吸相关的并发症。不幸的是，我们对症状产生的病理生理学解释的理解很差。在我们的第一个资助周期中，我们探索了团内压（IBP）和食管胃交界处（EGJ）顺应性之间的关系，作为流出阻力的指标。这项工作强调了有创血压和EGJ开放之间的直接关系，并为食管运动障碍的新分类方案“芝加哥分类”的发展奠定了基础。“尽管对团注传输动力学的理解有所提高，但仍然存在一些重大的未解决问题，这些问题集中在缺乏与症状的真正相关性上。我们以前的工作确实表明，IBP的测量比以前认识到的要复杂得多。IBP似乎具有不同的组分，这些组分受到标准测压评估不可见的食管壁的其他生理和机械特性的调节。使用阻抗技术结合测压和高分辨率面积测量，我们现在能够在吞咽功能的4个特定阶段的框架内评估IBP [1-食管调节，2-食管分隔，3-食管剥离和4-壶腹排空]。我们假设，在不同阶段的吞咽的IBP异常将受到不同的疾病状态，这些变化将表现为受损的食管排空和症状增加。 为了更好地理解IBP和食管体之间的复杂关系，关注于沿吞咽的4个阶段的连续体沿着定义IBP的新技术将是极其重要的。我们已经创建了新的方法和分析范例，利用组合测压与阻抗，可以准确地定义在吞咽的每个阶段的压力梯度，具有额外的好处，定义通过EGJ的流量和与受损的食管体功能相关的丸剂滞留量。此外，我们还改进了阻抗测面技术，以研究食管壁对容积扩张的反应，研究对IBP的机械反应和刺激食管收缩力的阈值。这些工具和技术已经在西北大学开发，并提供了所需的细节来测试我们的假设，重点是异常食管壁力学在产生症状和并发症中的作用。我们的最终目标是发展的食管疾病的发病机制的理解超出了目前的标准的动力模式，并将生物力学原理纳入这些疾病的管理和治疗模式。这项工作将建立在以前的成功芝加哥分类，通过定义新的重要的生物标志物的疾病活动和临床相关的吞咽困难的表型。

DESCRIPTION (provided by applicant): 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 pathophysiologic explanation for symptom generation is poor. During our first funding cycle, we 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 regarding bolus transit dynamics, there were still significant unresolved issues focused on the lack of a true correlate for symptoms. Our previous work did suggest that the measure of IBP was much more complex than previously appreciated. It appeared that IBP had distinct components that were modulated by additional physiological and mechanical properties of the esophageal wall invisible to the standard manometric assessment. Using impedance techniques combined with manometry and high-resolution planimetry, we are now capable of assessing IBP within the framework of 4 specific phases of swallow function [1-esophageal accommodation, 2-esophageal compartmentalization, 3-esophageal stripping and 4- ampullary emptying]. We hypothesize that abnormalities in IBP at different stages of the swallow will be influenced by different disease states and that these changes will manifest as impaired esophageal emptying and increased symptoms. In order to better understand the complex relationship between IBP and the esophageal body, new techniques that focus on defining IBP along the continuum of the 4 phases of swallowing would be extremely important. We have created new methodology and analysis paradigms utilizing combined manometry with impedance that can accurately define the pressure gradients during each phase of swallowing with the added benefit of defining flow through the EGJ and the volume of bolus retention associated with impaired esophageal body function. Additionally, we have also refined impedance planimetry techniques to study the response of the esophageal wall to volumetric distention to study the mechanical response to IBP and the threshold for stimulating esophageal contractility. These tools and techniques have been developed at Northwestern and provide the needed detail to test our hypotheses focused on the role of abnormal esophageal wall mechanics in generating symptoms and complications. Our ultimate goal is to evolve the understanding of the pathogenesis of esophageal diseases beyond the current standards of motility patterns and to incorporate biomechanical principles into the management and treatment paradigms of these disorders. This work will build upon the previous success of the Chicago Classification by defining new important biomarkers of disease activity and clinically relevant phenotypes of dysphagia.