Pathophysiology of Anorectal Disorders

描述（由申请人提供）：排便障碍（DD）通常引起慢性便秘，通过临床特征辅以异常肛门直肠试验进行诊断，应通过生物反馈治疗进行盆底再训练，而不是通过泻药进行治疗。DD归因于排便时骨盆底收缩“适应不良”。这种模式忽略了内脏紊乱的贡献（例如，肛门静息压增加或肛门高血压）。生物反馈疗法尚未广泛应用，目前尚无药物治疗DD的方法。肛门直肠试验并不广泛使用，并且关键诊断试验的准确性，即在模拟排空期间的负直肠肛门梯度（直肠<肛门压力）是值得怀疑的，因为许多无症状的受试者也具有负梯度。 我们已经确定了3种不同的表型（即“高位肛门”，“低位直肠”和“杂交”），这是由直肠压力和肛门松弛的大小在排空过程中定义的。因此，“高位肛门”模式的定义是正常的直肠压力（推进力），但受损的肛门放松在疏散。高位肛门表型的特征还在于高肛门静息压（肛门高血压）。基于初步研究，我们的假设是：（1）肛门高压与DD患者肛门扩张性降低、肛门内括约肌僵硬度增加和排便障碍有关。在60例健康受试者和60例DD患者中，分别通过肛门球囊扩张和磁共振弹性成像（MRE）评价肛门扩张性和刚度，并通过动态盆腔MRI评估直肠排空。(2)α1-肾上腺素能紧张有助于DD患者的肛门高压。我们将评估α1-肾上腺素能拮抗剂对36名健康受试者和36名DD患者肛门压力的影响，以及对36名DD患者症状的影响，（3）与左侧卧位相比，坐位时直肠压力更高，直肠肛门压力测量更准确地识别DD（3a），便携式测压仪可以准确测量直肠肛门压力（3b）。我们将比较60名健康受试者和60名DD患者在坐位和左侧卧位通过高分辨率和便携式测压法测量的压力;将通过动态MRI评价盆底运动和直肠排空。一个多学科的合作团队将采用创新的方法，以高度完善的方式解决这些假设。每项研究都旨在改善人类患者的护理。

DESCRIPTION (provided by applicant): Defecatory disorders (DD), which commonly cause chronic constipation, are diagnosed by clinical features supplemented by abnormal anorectal tests, and should be managed by pelvic floor retraining by biofeedback therapy rather than by laxatives. DD are attributed to "maladaptive" pelvic floor contraction during defecation. This paradigm overlooks the contribution of visceral disturbances (e.g., increased anal resting pressure or anal hypertension). Biofeedback therapy is not widely available and there are no pharmacological approaches to manage DD currently. Anorectal tests are not widely available, and the accuracy of a key diagnostic test, i.e. a negative rectoanal gradient (rectal < anal pressure), during simulated evacuation is questionable because many asymptomatic subjects also have a negative gradient. We have identified 3 distinct phenotypes (i.e. "high anal", "low rectal" and "hybrid") which are defined by the magnitude of rectal pressure and anal relaxation during evacuation. Thus, the "high anal" pattern is defined by normal rectal pressure (propulsive force) but impaired anal relaxation during evacuation. The high anal phenotype is also characterized by high anal resting pressure (anal hypertension). Based on preliminary studies, our hypotheses are that: (1) Anal hypertension is associated with reduced anal distensibility, increased internal anal sphincter stiffness, and impaired evacuation in DD. Anal distensibility and stiffness will be evaluated by anal balloon distention and magnetic resonance elastography (MRE) respectively and rectal evacuation will be assessed by dynamic pelvic MRI in 60 healthy subjects and 60 patients with DD. (2) α1- adrenergic tone contributes to anal hypertension in DD. We will evaluate the effects of an α1-adrenergic antagonist on anal pressures in 36 healthy subjects and 36 patients with DD, and on symptoms in 36 patients with DD, and (3) Rectal pressure is higher and rectoanal pressure measurements are more accurate for identifying DD in the seated than the left lateral position (3a) and rectoanal pressures can be accurately measured by portable manometry (3b). We will compare pressures measured by high resolution and portable manometry in the seated and left lateral positions in 60 healthy subjects and 60 patients with DD; pelvic floor motion and rectal evacuation will be evaluated by dynamic MRI. A multi-disciplinary collaborative team will apply innovative approaches to address these hypotheses in a highly refined manner. Each study is designed to improve patient care in humans.