Michael Y. Tye

Evaluation of Esophageal Motility Utilizing the Functional Lumen Imaging Probe

Objectives:Esophagogastric junction (EGJ) distensibility and distension-mediated peristalsis can be assessed with the functional lumen imaging probe (FLIP) during a sedated upper endoscopy. We aimed to describe esophageal motility assessment using FLIP topography in patients presenting with dysphagia.Methods:In all, 145 patients (aged 18–85 years, 54% female) with dysphagia that completed upper endoscopy with a 16-cm FLIP assembly and high-resolution manometry (HRM) were included. HRM was analyzed according to the Chicago Classification of esophageal motility disorders; major esophageal motility disorders were considered “abnormal”. FLIP studies were analyzed using a customized program to calculate the EGJ-distensibility index (DI) and generate FLIP topography plots to identify esophageal contractility patterns. FLIP topography was considered “abnormal” if EGJ-DI was <2.8 mm2/mm Hg or contractility pattern demonstrated absent contractility or repetitive, retrograde contractions.Results:HRM was abnormal in 111 (77%) patients: 70 achalasia (19 type I, 39 type II, and 12 type III), 38 EGJ outflow obstruction, and three jackhammer esophagus. FLIP topography was abnormal in 106 (95%) of these patients, including all 70 achalasia patients. HRM was “normal” in 34 (23%) patients: five ineffective esophageal motility and 29 normal motility. In all, 17 (50%) had abnormal FLIP topography including 13 (37%) with abnormal EGJ-DI.Conclusions:FLIP topography provides a well-tolerated method for esophageal motility assessment (especially to identify achalasia) at the time of upper endoscopy. FLIP topography findings that are discordant with HRM may indicate otherwise undetected abnormalities of esophageal function, thus FLIP provides an alternative and complementary method to HRM for evaluation of non-obstructive dysphagia.

Cardiomyocytes induce macrophage receptor shedding to suppress phagocytosis

BACKGROUND Mobilization of the innate immune response to clear and metabolize necrotic and apoptotic cardiomyocytes is a prerequisite to heart repair after cardiac injury. Suboptimal kinetics of dying myocyte clearance leads to secondary necrosis, and in the case of the heart, increased potential for collateral loss of neighboring non-regenerative myocytes. Despite the importance of myocyte phagocytic clearance during heart repair, surprisingly little is known about its underlying cell and molecular biology. OBJECTIVE To determine if phagocytic receptor MERTK is expressed in human hearts and to elucidate key sequential steps and phagocytosis efficiency of dying adult cardiomyocytes, by macrophages. RESULTS In infarcted human hearts, expression profiles of the phagocytic receptor MER-tyrosine kinase (MERTK) mimicked that found in experimental ischemic mouse hearts. Electron micrographs of myocardium identified MERTK signal along macrophage phagocytic cups and Mertk-/- macrophages contained reduced digested myocyte debris after myocardial infarction. Ex vivo co-culture of primary macrophages and adult cardiomyocyte apoptotic bodies revealed reduced engulfment relative to resident cardiac fibroblasts. Inefficient clearance was not due to the larger size of myocyte apoptotic bodies, nor were other key steps preceding the formation of phagocytic synapses significantly affected; this included macrophage chemotaxis and direct binding of phagocytes to myocytes. Instead, suppressed phagocytosis was directly associated with myocyte-induced inactivation of MERTK, which was partially rescued by genetic deletion of a MERTK proteolytic susceptibility site. CONCLUSION Utilizing an ex vivo co-cultivation approach to model key cellular and molecular events found in vivo during infarction, cardiomyocyte phagocytosis was found to be inefficient, in part due to myocyte-induced shedding of macrophage MERTK. These findings warrant future studies to identify other cofactors of macrophage-cardiomyocyte cross-talk that contribute to cardiac pathophysiology.

High-Resolution Impedance Manometry Metrics of the Esophagogastric Junction for the Assessment of Treatment Response in Achalasia

OBJECTIVES:We aimed to evaluate the value of novel high-resolution impedance manometry (HRIM) metrics, bolus flow time (BFT), and esophagogastric junction (EGJ) contractile integral (CI), as well as EGJ pressure (EGJP) and the integrated relaxation pressure (IRP), as indicators of treatment response in achalasia.METHODS:We prospectively evaluated 75 patients (ages 19–81, 32 female) with achalasia during follow-up after pneumatic dilation or myotomy with Eckardt score (ES), timed-barium esophagram (TBE), and HRIM. Receiver-operating characteristic (ROC) curves for good symptomatic outcome (ES≤3) and good radiographic outcome (TBE column height at 5 min<5 cm) were generated for each potential predictor of treatment response (EGJP, IRP, BFT, and EGJ-CI).RESULTS:Follow-up occurred at a median (range) 12 (3–291) months following treatment. A total of 49 patients had good symptomatic outcome and 46 had good radiographic outcome. The area-under-the-curves (AUCs) on the ROC curve for symptomatic outcome were 0.55 (EGJP), 0.62 (IRP), 0.77 (BFT) and 0.56 (EGJ-CI). The AUCs for radiographic outcome were 0.64 (EGJP), 0.48 (IRP), 0.73 (BFT), and 0.65 (EGJ-CI). Optimal cut-points were determined as 11 mm Hg (EGJP), 12 mm Hg (IRP), 0 s (BFT), and 30 mm Hg•cm (EGJ-CI) that provided sensitivities/specificities of 57%/46% (EGJP), 65%/58% (IRP), 78%/77% (BFT), and 53%/62% (EGJ-CI) to predict symptomatic outcome and 57%/66% (EGJP), 57%/41% (IRP), 76%/69% (BFT), and 57%/66% (EGJ-CI) to predict radiographic outcome.CONCLUSIONS:BFT, a novel HRIM metric, provided an improved functional assessment over manometric measures of EGJP, IRP, and EGJ-CI at follow-up after achalasia treatment and may help direct clinical management.

Postprandial High-Resolution Impedance Manometry Identifies Mechanisms of Nonresponse to Proton Pump Inhibitors

BACKGROUND & AIMS: Recognition of rumination and supragastric belching is often delayed as symptoms may be mistakenly attributed to gastroesophageal reflux disease. However, distinct from gastroesophageal reflux disease, rumination and supragastric belching are more responsive to behavioral interventions than to acid‐suppressive and antireflux therapies. Postprandial high‐resolution impedance manometry (PP‐HRIM) is an efficient method to identify rumination and belches. We investigated the distribution of postprandial profiles determined by PP‐HRIM, and identified patient features associated with postprandial profiles among patients with nonresponse to proton pump inhibitors (PPIs). METHODS: We performed a retrospective analysis of PP‐HRIM studies performed on 94 adults (mean age, 50.6 y; 62% female) evaluated for PPI nonresponsiveness at an esophageal referral center, from January 2010 through May 2016. Following a standard esophageal manometry protocol, patients ingested a solid refluxogenic test meal (identified by patients as one that induces symptoms) with postprandial monitoring up to 90 minutes (median, 50 min). Patients were assigned to 1 of 4 postprandial profiles: normal; reflux only (>6 transient lower esophageal sphincter relaxations (TLESRs)/h); supragastric belch (>2 supragastric belches/h), with or without TLESR; or rumination (≥1 rumination episode/h) with or without TLESR and supragastric belching. The primary outcome was postprandial profile. RESULTS: Of the study participants, 24% had a normal postprandial profile, 14% had a reflux‐only profile, 42% had a supragastric belch profile, and 20% had a rumination profile. In multinomial regression analysis, the rumination group most frequently presented with regurgitation, the supragastric belch and rumination groups were younger in age, and the reflux‐only group had a lower esophagogastric junction contractile integral. The number of weakly acidic reflux events measured by impedance‐pH monitoring in patients receiving PPI therapy was significantly associated with frequency of rumination episodes and supragastric belches. CONCLUSIONS: In a retrospective analysis of 94 nonresponders to PPI therapy evaluated by PP‐HRIM, we detected an abnormal postprandial pattern in 76% of cases: 42% of these were characterized as supragastric belching, 20% as rumination, and 14% as reflux only. Age, esophagogastric junction contractility, impedance‐pH profiles, and symptom presentation differed significantly among groups. PP‐HRIM can be used in the clinic to evaluate mechanisms of PPI nonresponse.

Psychosocial Distress and Quality of Life Impairment Are Associated With Symptom Severity in PPI Non-Responders With Normal Impedance-pH Profiles

Objectives:Up to 50% of patients with reflux symptoms do not manifest a satisfactory symptom response to proton pump inhibitor (PPI) therapy. Our primary aim in this study was to identify factors associated with symptom perception among PPI non-responder phenotypes.Methods:This prospective observational cohort study was performed from September 2014 to January 2017 at a single academic medical center and included PPI non-responders who underwent 24-h impedance-pH monitoring and completed a questionnaire set measuring patient-reported symptom severity, quality of life (QOL), and psychosocial distress. Participants were separated into cohorts based on impedance-pH results: on PPI: −acid exposure time (AET)/−symptom–reflux association (SRA), +AET, and −AET/+SRA; off PPI: functional (−AET/−SRA), gastroesophageal reflux disease (GERD) (+AET), and reflux hypersensitivity (RHS) (−AET/+SRA). The primary outcome was abnormal GERD symptom severity defined by GerdQ≥8.Results:One hundred and ninety-two participants were included. Impedance-pH on PPI was performed on 125: 72 (58%) −AET/−SRA, 42 (34%) +AET, and 11 (9%) −AET/+SRA. Among the −AET/−SRA group, younger age, higher dysphagia scores, QOL impairment, and higher brief symptom index were associated with GerdQ≥8. Among the +AET group, higher number of reflux-associated symptoms and lower distal contractile integral was associated with GerdQ≥8. Impedance-pH off PPI was performed on 67 participants: 39 (58%) functional, 16 (24%) GERD, and 12 (18%) RHS. Among the functional group, higher QOL impairment and dysphagia scores were seen with GerdQ≥8.Conclusions:Perceptions of reflux symptoms are associated with psychosocial distress, reduced QOL, and sensation of dysphagia among PPI non-responders with normal impedance-pH. Among PPI refractory GERD patients, patient-reported symptom severity is associated with physiological differences, as opposed to psychosocial factors.

Improved Assessment of Bolus Clearance in Patients With Achalasia Using High-Resolution Impedance Manometry

Background & Aims: Esophageal retention is typically evaluated by timed‐barium esophagram in patients treated for achalasia. Esophageal bolus clearance can also be evaluated using high‐resolution impedance manometry. We evaluated the associations of conventional and novel high‐resolution impedance manometry metrics, esophagram, and patient‐reported outcomes (PROs) in achalasia. Methods: We performed a prospective study of 70 patients with achalasia (age, 20–81 y; 30 women) treated by pneumatic dilation or myotomy who underwent follow‐up evaluations from April 2013 through December 2015 (median, 12 mo after treatment; range, 3–183 mo). Patients were assessed using timed‐barium esophagrams, high‐resolution impedance manometry, and PROs, determined from Eckardt scores (the primary outcome) and the brief esophageal dysphagia questionnaire. Barium column height was measured from esophagrams taken 5 minutes after ingestion of barium (200 mL). Impedance‐manometry was analyzed for bolus transit (dichotomized) and with a customized MATLAB program (The MathWorks, Inc, Natick, MA) to calculate the esophageal impedance integral (EII) ratio. Results: Optimal cut points to identify a good PRO (defined as Eckardt score of ≤3) were esophagram barium column height of 3 cm (identified patients with a good PRO with 63% sensitivity and 75% specificity) and an EII ratio of 0.41 (identified patients with a good PRO with 83% sensitivity and 75% specificity). Complete bolus transit identified patients with a good PRO with 28% sensitivity and 75% specificity. Of the 25 patients who met these cut points for both esophagram barium column height and EII ratio, 23 (92%) had a good PRO. Of the 17 patients who met neither cut point, 14 (82%) had a poor PRO (Eckardt score above 3). Conclusions: In a prospective study of 70 patients with achalasia, we found EII ratio identified patients with good PROs with higher levels of sensitivity (same specificity) than timed‐barium esophagram or impedance‐manometry bolus transit assessments. The EII ratio should be added to achalasia outcome evaluations that involve high‐resolution impedance manometry as an independent measure and to complement timed‐barium esophagram.

The relationship between esophageal acid exposure and the esophageal response to volumetric distention

Increased esophagogastric junction (EGJ) distensibility is thought to contribute to gastroesophageal reflux disease (GERD). Using the functional lumen imaging probe (FLIP), we aimed to assess the esophageal response to distension among patients undergoing esophageal pH monitoring.

High‐resolution manometry assessment of the lower esophageal sphincter after‐contraction: Normative values and clinical correlation

The Chicago Classification v3.0 proposed extending the distal contractile integral (DCI) measurement domain to include the lower esophageal sphincter (LES) to enhance the detection of esophageal hypercontractility. However, normative and clinical data for this approach are unreported. We aimed to describe the application of an extended DCI measurement in asymptomatic controls and patients.