The mechanics of symptom generation in dysphagia

描述(申请人提供)：吞咽困难非常普遍，导致生活质量大幅下降，与营养不良有关的发病率和死亡率增加，以及与反流和吸入有关的并发症。不幸的是，我们对症状产生的病理生理学解释的理解很差。在我们的第一个资金周期中，我们探索了团注内压(IBP)和食管胃交界处(EGJ)顺应性之间的关系，作为衡量流出阻力的指标。这项工作强调了IBP和EGJ开放之间的直接关系，并为开发一种新的食道运动障碍分类方案“芝加哥分类”奠定了基础。尽管对团注转运动力学的了解有所改善，但仍有一些重大的悬而未决的问题集中在缺乏与症状的真正相关性上。我们之前的工作确实表明，IBP的测量比之前认识到的要复杂得多。IBP似乎有不同的成分，这些成分受到标准测压评估看不到的食管壁额外的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平面测量，我们现在能够在吞咽功能的4个特定阶段[1-食道调节、2-食管区隔化、3-食道剥离和4-壶腹排空]的框架内评估IBP。我们假设吞咽不同阶段IBP的异常将受到不同疾病状态的影响，这些变化将表现为食道排空障碍和症状增加。为了更好地了解IBP和食管体之间的复杂关系，将重点放在确定IBP吞咽四个阶段的连续体上的新技术将是极其重要的。我们创造了新的方法和分析范例，结合测压和阻抗，可以准确地确定吞咽每个阶段的压力梯度，并增加了确定通过EGJ的流量和与食管体功能受损相关的团注滞留的体积的好处。此外，我们还改进了阻抗平面测量技术来研究食管壁对容量扩张的反应，以研究对IBP的机械反应和刺激食道收缩的阈值。这些工具和技术已经在西北大学开发，并提供了必要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。我们的最终目标是超越目前的运动模式标准，发展对食道疾病发病机制的理解，并将生物力学原理纳入这些疾病的管理和治疗范例中。这项工作将建立在芝加哥分类法之前的成功基础上，通过定义新的重要的疾病活动生物标志物和临床相关的吞咽困难表型。

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.