Defining lower esophageal sphincter physiomechanical states among esophageal motility disorders using functional lumen imaging probe panometry

Abstract

Background:

Functional lumen imaging probe (FLIP) panometry assesses esophageal motility in response to controlled volumetric distension. This study aimed to describe the physiomechanical states of the lower esophageal sphincter (LES) in response to serial filling/emptying regimes for esophageal motility disorders.

Methods:

Fourty-five patients with absent contractile response on FLIP and diagnoses of normal motility (n = 6), ineffective esophageal motility (IEM; n = 8), scleroderma (SSc; n = 10), or nonspastic achalasia (n = 21) were included, as were 20 patient controls with normal motility on FLIP and manometry. LES diameter and pressure were measured after stepwise FLIP filling at 60 mL, 70 mL, and emptying to 60 mL with relative changes used to define physiomechanical states.

Key Results:

Passive dilatation after FLIP filling occurred in 63/65 (97%) patients among all diagnoses. After FLIP emptying, passive shortening occurred in 12/14 (86%) normal motility/IEM, 10/10 (100%) SSc, 9/21(43%) achalasia, and 16/20 (80%) controls, with auxotonic relaxation seen in 2/14 (14%) normal motility/IEM, 12/21 (57%) achalasia, and 4/20 (20%) controls. After achalasia treatment (LES myotomy), 21/21 (100%) achalasia had passive shortening after FLIP emptying.

Conclusions & Inferences:

Physiomechanical states of the LES can be determined via response to FLIP filling and emptying regimes. While passive shortening was the general response to FLIP emptying, auxotonic relaxation was observed in achalasia, which was disrupted by LES myotomy. Further investigation is warranted into the clinical impact on diagnosis and treatment of esophageal motility disorders.

1 |. INTRODUCTION

Functional lumen imaging probe (FLIP) panometry provides a unique evaluation of esophageal function, as it assesses the esophageal response to controlled volumetric distension that is sustained during the FLIP study protocol.¹ Using high-resolution impedance planimetry technology to measure luminal dimensions at multiple adjacent cross-sectional areas (CSA), distensive (intrabag) pressure, and the CSA-pressure relationship (distensibility), the FLIP panometry output includes mechanical properties of the esophageal wall, as well as the physiology of distension-mediated esophageal motility (i.e., secondary peristalsis).^1–4 Hence, the mechanical evaluation provided by FLIP panometry has demonstrated utility for evaluating patients with esophageal motility disorders and eosinophilic esophagitis.^3–6

In a recent study of 265 patients that completed FLIP and high-resolution manometry (HRM), we demonstrated that the esophageal response differs between FLIP filling (i.e., the standard stepwise, volume-controlled FLIP study protocol) and after partial emptying of the FLIP.⁷ In particular, there was greater EGJ-distensibility index (DI), that is, CSA/pressure, and greater EGJ diameter after FLIP emptying than with filling, while FLIP pressure was similar or slightly lower. These trends were observed both in patients with impaired and normal lower esophageal sphincter (LES) relaxation (i.e., achalasia and normal motility) on HRM. However, there was also variability in these responses within HRM-defined esophageal motility diagnoses.

While a key conclusion of this study related to the importance of a standardized FLIP study protocol to provide reliable FLIP measures and clinical application, we also recognized the potential to characterize the physiologic and mechanical response of the LES, that is, the physiomechanical state, based on the response with graded FLIP filling or emptying. Defining mechanical states of intestinal muscle was proposed as a technique to help characterize neural activity (i.e., excitation or inhibition), which carries implications for identifying underlying pathophysiology associated with esophageal disease states.⁸ We hypothesized that applying these concepts to define the physiomechanical states of the LES may enhance the evaluation of esophageal motility disorders beyond the static measures of EGJ-distensibility on FLIP or LES pressure on HRM. Hence, this study aimed to describe the physiomechanical state of the LES in response to incremental FLIP filling and emptying for various esophageal motility disorders. Additionally, this study aimed to define the impact of achalasia treatment on the LES physiomechanical state and explore if these features may have an impact on predicting clinical outcomes in achalasia.

2 |. METHODS

2.1 |. Subjects

Adult patients (ages 18–89 years) who presented to the Esophageal Center of Northwestern for evaluation of dysphagia between 2019 and 2022 and referred for motility testing with HRM and FLIP were prospectively enrolled into an NIH funded study (P01 DK117824). Patients with previous foregut surgery or esophageal mechanical obstruction (esophageal stricture, eosinophilic esophagitis, severe reflux esophagitis (Los Angeles classification C or D), or hiatal hernia >3 cm) were excluded, as these can cause secondary esophageal motor abnormalities. Patients were also excluded if they had technically limited HRM or FLIP studies or if the emptying 60 mL fill volume was not included in the FLIP protocol (the emptying 60 mL fill volume was incorporated into our standard clinical FLIP protocol during year 2 (of 4) of enrollment for P01 DK117824). Most patients also completed symptom questionnaires (patient reported outcomes) and timed barium esophagram (TBE), as part of their clinical evaluations.

Since the study aimed to define LES physiomechanical states among distinct esophageal motility states, specific patient subgroups were selected from the total cohort for dedicated analysis; Figure 1. The primary analysis focused on patients with an absent contractile response (ACR) on FLIP (to minimize peristalsis-associated pressure and diameter changes from the LES) and were further selected based on HRM-CCv4.0 diagnoses. A group of “Patient Controls” with antegrade secondary peristalsis were also included for comparison. Patient subgroups included (a) normal or ineffective esophageal motility (IEM) on HRM (“Normal/IEM”), (b) systemic sclerosis (“SSc”; rheumatologic diagnosis and absent contractility or IEM on HRM), or (c) nonspastic (type I or type II) achalasia (“Achalasia”). Achalasia patients were included only if they also completed FLIP at follow-up after achalasia treatment with pneumatic dilation, PerOral Endoscopic Myotomy (POEM), or laparoscopic Heller myotomy. The comparison group of 20 “patient controls” were randomly selected among the symptomatic patient cohort with normal esophageal motility on HRM and normal motility (i.e., antegrade contractions and normal EGJ opening) on FLIP panometry, that is patients with functional dysphagia.⁹

FIGURE 1.

Flow chart demonstrating inclusion and exclusion criteria. ACR, absent contractile response; CCv4.0, Chicago Classification version 4.0; FLIP, functional lumen imaging probe; HRM, high-resolution manometry; IEM, ineffective esophageal motility.

Written informed consent was obtained from all patients. The study protocol was approved by the Northwestern University Institutional Review Board.

2.2 |. FLIP protocol and analysis

The FLIP study was performed during sedated endoscopy using a 16-cm FLIP catheter (EndoFlip EF-322 N; Medtronic) and analyzed as previously described.^5,10,11 Endoscopy was performed in the left-lateral decubitus position generally using midazolam and fentanyl for sedation. Other medications, for example, propofol, were used with monitored anesthesia in some cases at the discretion of the endoscopist. Although these medications used for endoscopic sedation can alter esophageal motility, the patterns of motility during the FLIP protocol are reproducible and shown to predict motility patterns on HRM performed without these medications.^10–12 After withdrawal of the endoscope and calibration to atmospheric pressure, the FLIP was placed transorally and positioned in the esophagus with 1–3 impedance sensors beyond the EGJ. This positioning was maintained throughout the FLIP study. Beginning with 40 mL, stepwise 10-ml FLIP distensions were performed increasing to a target volume of 70 mL (i.e., 50, 60, 70 mL) and then the FLIP was partially emptied to 60 mL. Each stepwise distension volume was maintained for 30–60 s.

FLIP data were exported to and analyzed with a customized program (available open source at http://www.wklytics.com/nmgi) to generate FLIP panometry plots for analysis.³ FLIP analysis was performed blinded to clinical characteristics, including HRM and TBE findings. Analysis of the EGJ specifically focused on the filling 60 mL, 70 mL, and emptying 60 mL FLIP fill volumes. Measures of EGJ diameter and associated FLIP pressure were made at three time-points of greatest EGJ opening diameters during expiration for each fill volume with the median values of these measures applied for analysis; Figure 2. The measures were made at least 5 s after active filling or emptying to avoid direct filling/emptying related effects.

FIGURE 2.

Defining physiomechanical states of LES function using FLIP Panometry. FLIP Panometry from patients with achalasia (type I) at baseline (i.e., untreated) (A), achalasia after treatment with POEM (B), and scleroderma (C) are displayed. The plots include color-coded FLIP diameter topography (top), EGJ diameter (middle), and FLIP pressure (bottom) over time (x-axis), with the corresponding FLIP fill volumes (filling 60 mL, 70 mL, emptying 60 mL) listed at the top. The vertical dashed lines indicate the three measures of EGJ diameter and pressure per fill volume (each taken during expiration by identifying the crural contraction on the FLIP topography plot). The listed measures of EGJ diameter (mm) and pressure (mmHg) reflected the median of these three values at the 60 mL (filling), 70 mL, and 60 mL (emptying) FLIP volumes, with the relative changes associated with FLIP filling (60 mL–70 mL) or FLIP emptying (70 mL–60 mL) applied to define the physiomechanical states of LES function. Figure used with permission of the Esophageal Center of Northwestern.

Finally, the relative changes in EGJ diameter and pressure after FLIP filling (from 60 mL to 70 mL), and after FLIP emptying (from 70 mL to 60 mL) were applied to define LES physiomechanical states, based on previous work by Costa et al; Figures 2 and 3.⁸ The commonly observed LES physiomechanical states included passive dilatation (increase in diameter and pressure), passive shortening (decrease in diameter and pressure), auxotonic relaxation (increase in diameter with decrease in pressure), or auxotonic contraction (decrease in diameter with increase in pressure); Figure 3.

FIGURE 3.

Summary of observed LES physiomechanical states. Physiomechanical states were defined by the change in FLIP pressure and change in EGJ diameter observed after FLIP filling (60 mL–70 mL) or after FLIP emptying (70 mL to 60 mL).

2.3 |. HRM protocol and analysis

HRM studies were completed after a 6-h fast using a 4.2-mm outer diameter solid-state assembly with 36 circumferential pressure sensors at 1-cm intervals (Medtronic, Shoreview, MN). The HRM assembly was placed transnasally and positioned to record from the hypopharynx to the stomach with approximately 3 intragastric pH sensors. After a 2-min baseline recording, the HRM protocol was performed with ten, 5-mL liquid swallows in a supine position and then five, 5-mL liquid swallows.¹³ Studies were analyzed according to the CCv4.0 and blinded to clinical characteristics, for example, FLIP and TBE findings; Table S1.¹³

2.4 |. Clinical Outcomes in Achalasia

Most patients completed self-reported symptom scores, including the Eckardt Score and/or timed barium esophagram (TBE) around the time of testing with FLIP and HRM at baseline and during follow-up after achalasia treatment with pneumatic dilation, POEM, or laparoscopic Heller myotomy.¹⁴ Symptom scores or TBE were not completed by all patients (e.g., some patients chose not to complete the symptom questionnaires).

The Eckardt Score includes four 4-point Likert scale questions (scored 0–3) that assess the frequency of dysphagia, chest pain, and regurgitation and the degree of weight loss, with items summed to yield a score of 0–12. Treatment success was defined as Eckardt Score ≤3 when obtained at follow-up after achalasia treatment.

During TBE, patients were in the upright position and consumed 200 mL of low-density barium sulfate with images obtained at 1 and 5 min.¹⁵ The height of the barium column was measured vertically from the EGJ.

2.5 |. Statistical analysis

Results were reported as mean (standard deviation; SD) or median (interquartile range; IQR) depending on the data distribution. Baseline data was compared using the Kruskal–Wallis test across all groups with posthoc testing using Mann–Whitney (and applying a Bonferroni correction for multiple comparison tests). In achalasia, baseline and follow-up data was compared using the Wilcoxon Signed Ranks test. Unless otherwise signified, a p value <0.05 was applied to indicate statistical significance.

3 |. RESULTS

3.1 |. Subjects

Sixty-five patients with mean (SD) age 50 (17) years, 65% female, were included; Table 1. HRM classifications among patient subgroups included normal motility in six patients or IEM in eight patients, SSc in 10 patients (HRM with absent contractility in 9 and IEM in 1), and achalasia type I in seven patients and type II in 14 patients. Achalasia treatment was with pneumatic dilation in 1, POEM in 17, and Heller in 3 with follow-up completed at a mean (SD) of 8 (4) months after treatment. By selection, there were also 20 symptomatic “patient controls” with normal motility on HRM and FLIP; Table 1.

TABLE 1.

Cohort characteristics.

Characteristic	Normal motility/IEM	Scleroderma (SSc)	Achalasia	Patient-controlsa
N	14	10	21	20
Age, mean (SD), years	63 (9)	52 (15)	47 (18)	42 (17)
Sex, female, n (%)	9 (64)	8 (80)	9 (43)	16 (80)
Endoscopic findings, n (%)
Erosive esophagitis: Los Angeles Classification A/B	0/3 (21)	0/2 (20)	0/0	1 (5)/0
Small hiatal hernia	6 (43)	8 (80)	2 (10)	10 (50)
HRM characteristics
Chicago Classification v4.0, n (%)b
Normal	6 (43)	0	0	20 (100)
Ineffective esophageal motility	8 (57)	1 (10)	0	0
Absent contractility	0	9 (90)	0	0
Type I achalasia	0	0	7 (33)	0
Type II achalasia	0	0	14 (67)	0
Integrated relaxation pressure (IRP), supine, mmHg, median (IQR)	11 (8–14)	10 (5–12)	28 (21–36)	10 (6–14)
Basal EGJ pressure (at end-expiration), mmHg, median IQR	14 (6–17)	10 (6–15)	23 (16–34)	14 (11–19)
FLIP characteristics
EGJ-distensibility index (filling 60 mL), mm2 mmHg−1, median (IQR)	2.7 (1.7–3.0)	5.3 (4.1–8.4)	1.0 (0.8–1.4)	4.9 (3.3–6.9)
Maximum EGJ diameter, mm, median (IQR)	10.3 (10–11.2)	15.6 (13.1–16.7)	6.5 (5.8–7.2)	17.0 (14.0–19.4)
FLIP EGJ opening classification, n (%)
Normal	8 (57)	8 (80)	0	20 (100)b
Borderline	5 (36)	2 (20)	5 (24)	0
Reduced	1 (7)	0	16 (76)	0
FLIP contractile response, n (%)b
Normal	0	0	0	17 (85)
Borderline	0	0	0	3 (15)
Impaired-disordered	0	0	0	0
Absent	14 (100)	10 (100)	21 (100)	0

^aSymptomatic patients with normal motility on high-resolution manometry (HRM) and on FLIP Panometry.^3,13

^bVariables utilized for patient selection (inclusion criteria).

Abbreviation: EGJ, esophagogastric junction.

3.2 |. FLIP panometry findings

Normal EGJ opening (i.e., EGJ-DI ≥2.0 mm²/mmHg and maximum EGJ diameter ≥ 16 mm during the FLIP filling protocol) was observed in the majority of patients with normal/IEM (57%), SSc (80%), and patient controls (85%), while reduced EGJ opening (i.e., EGJ-DI <2.0 mm² mmHg⁻¹ and maximum EGJ diameter < 16 mm) was observed in the majority (76%) of achalasia (baseline, pretreatment); Table 1. There was one patient with reduced EGJ opening in the normal/IEM group (zero with reduced EGJ opening in SSc) and zero patients with normal EGJ opening with achalasia (baseline). The remainder had borderline EGJ opening. At follow-up after achalasia treatment, 71% of patients had normal EGJ opening and 29% had borderline EGJ opening; zero had reduced EGJ opening.

3.3 |. Changes in FLIP pressure and EGJ diameter after FLIP filling and emptying

EGJ diameter was greater in normal/IEM, SSc, and patients controls than in achalasia at filling 60 mL (adjusted p-values <0.001–0.037), 70 mL (adjusted p-values <0.001–0.005), and emptying 60 mL (adjusted p-values <0.001–0.021); Figure S1. FLIP pressure also differed and was greater in patient controls than in normal/IEM, SSc, or achalasia at filling 60 mL (adjusted p-values <0.001–0.019) and emptying 60 mL (adjusted p-values <0.001–0.023), but did not differ at the 70 mL fill volume (p = 0.103), nor between normal/IEM, SSc, and achalasia at filling or emptying 60 mL; Figure S1.

EGJ diameter increased after FLIP filling for all groups, with a greater increase observed with normal/IEM than in patient controls (p = 0.003) or in achalasia (trend; p = 0.012); Figure 4. After FLIP emptying, there were differences in EGJ diameter changes between groups (p < 0.001) with a greater decrease in EGJ diameter with normal/IEM (adj p = 0.002) or SSc (adj p = 0.012) than in achalasia. Compared with baseline, posttreatment achalasia had a greater degree of EGJ diameter change after both FLIP filling (i.e., greater increase; p = 0.005) and FLIP emptying (i.e., greater decrease; p < 0.001); Figure 4. EGJ diameter changes did not differ between posttreatment achalasia versus normal/IEM or SSc after FLIP filling (adj p-values 0.982 and 0.999) or emptying (adj p-values 0.147 and 0.999).

FIGURE 4.

Comparison of absolute change in FLIP metrics of EGJ diameter (A) and pressure (B) between patient subgroups after FLIP filling and FLIP emptying. FLIP filling was 60 mL to 70 mL and FLIP emptying was 70 mL to 60 mL. Box plots depict median, first and third quartiles, with whiskers representing 1.5 times interquartile range and outlier points.

FLIP pressure increased after FLIP filling for all groups, with a greater increase observed with normal/IEM than in patient controls (p = 0.003) or in achalasia (trend; p = 0.012); Figure 4. After FLIP emptying, there were differences in pressure change between groups (p < 0.001) with a greater decrease in pressure in achalasia than in normal/IEM (trend; adj p = 0.056), SSc (adj p = 0.012), and patient controls (adj p < 0.001). Pressure changes did not differ between the other groups. Compared with baseline, posttreatment achalasia had a greater degree of pressure change both after FLIP filling (i.e., trend toward greater increase; p = 0.073) and FLIP emptying (i.e., greater decrease; p = 0.020); Figure 4. Pressure changes did not differ between posttreatment achalasia versus normal/IEM or SSc after FLIP filling or emptying (adj p-values 0.999).

3.4 |. LES physiomechanical states defined by FLIP panometry

In response to FLIP filling (60 mL–70 mL), passive dilatation was observed in 44/45 (98%) patients with ACR on FLIP, as well as 19/20 (95%) patient controls; Figure 5. Auxotonic contraction was observed in 1/21(5%) achalasia (type II) and 1/20 (5%) patient controls. At follow-up after achalasia treatment, all 21 patients demonstrated passive dilatation after FLIP filling.

FIGURE 5.

Lower esophageal sphincter (LES) physiomechanical state defined during FLIP Panometry. The lines reflect the relative change in pressure and change in EGJ diameter after FLIP filling (from 60 mL to 70 mL; solid lines) and after FLIP emptying (from 70 mL to 60 mL; dashed lines), which were applied to define LES physiomechanical states, among the study subgroups: (A) Achalasia (baseline, untreated)^a, (B) Treated achalasia (at follow-up)^a, (C) Scleroderma (SSc)^a, (D) Normal motility (HRM)^a, (E) Ineffective esophageal motility (IEM)^a, (F) Patient controls. ^aWith absent contractile response (ACR) on FLIP Panometry. Figure used with permission of the Esophageal Center of Northwestern.

After FLIP emptying (70–60 mL), passive shortening was observed in 12/14 (86%) normal motility/IEM, 10/10 (100%) SSc, and 9/21 (43%) achalasia (3/7 (43%) type I and 6/14 (43%) type II); Figure 5. Passive shortening after FLIP emptying was also observed in 16/20 (80%) patient controls. Auxotonic relaxation was observed after FLIP emptying in 12/21 (57%) achalasia (4/7 (57%) type I and 8/14 (57%) type II achalasia). Auxotonic relaxation was also observed after FLIP emptying in two patients with normal motility/IEM, which included the one patient with reduced EGJ opening and one patient with borderline EGJ opening. Both had normal motility on HRM. Auxotonic relaxation was observed in 4/20 (20%) patient controls. At follow-up after achalasia treatment, all 21 patients demonstrated passive dilatation (Figure 5) in response to FLIP filling and passive shortening after FLIP emptying (i.e., similar to the response in SSc); Figure 2.

3.5 |. Associations of achalasia treatment outcomes on baseline LES physiomechanical state

Among achalasia patients who completed TBE at baseline (15 of 21 patients), patients with passive shortening after emptying on baseline FLIP (n = 8) had greater barium column height at 5 min (p = 0.021) and a trend toward greater barium column height at 1 min (p = 0.054) compared to achalasia with auxotonic relaxation on baseline FLIP (n = 7); Figure 6. Baseline Eckardt Score (n = 14 completed) did not differ between passive shortening (n = 6) and auxotonic relaxation (n = 8); p = 0.345.

FIGURE 6.

Clinical outcomes in achalasia relative to baseline (pretreatment) LES mechanical state. Timed barium esophagram (TBE) column heights and Eckardt symptom scores are displayed from (A) baseline (pretreatment) and (B) follow-up after treatment relative to the baseline LES mechanical state determined by FLIP Panometry.

At follow-up after treatment, among achalasia patients who completed TBE at follow-up (15 of 21 patients), barium column height did not differ between baseline FLIP LES physiomechanical states (passive shortening [n = 6] vs. auxotonic relaxation [n = 9]) at 5 min (p = 0.776) nor 1 min (p = 0.864) on TBE. There also was not a difference in post-treatment Eckardt Score between baseline passive shortening (n = 9) and auxotonic relaxation (n = 9); p = 0.667.

4 |. DISCUSSION

The major findings of this study were that the LES physiomechanical state could be defined among esophageal motility disorders using graded FLIP panometry filling and emptying regimes. Specific clinical esophageal motility subgroups were studied to facilitate a mechanistic evaluation of these LES physiomechanical states, which demonstrated that passive dilatation was the LES response to filling in the vast majority of cases across all esophageal motility diagnoses. However, there was more variability in response to emptying, particularly among achalasia. While passive shortening was ubiquitously observed with FLIP emptying in scleroderma and the majority of patients with normal motility or IEM (both with ACR on FLIP and in patient controls), achalasia had mixed LES physiomechanical states, including passive shortening (43%) or auxotonic relaxation (57%), which was similar between type I or type II achalasia. Further, achalasia treatment (LES myotomy) appeared to disrupt the auxotonic relaxation response, though a difference in treatment response based on clinical outcomes was not clearly observed.

Assessing mechanical states has been described as a novel application to evaluate neuromuscular function of gastrointestinal motility to help advance insights into mechanisms of bolus transit and disease states.⁸ Elegant studies led by the Australian group have applied impedance-manometry with or without concurrent video fluoroscopy to measures changes in luminal diameter and intraluminal pressure, which are applied to define mechanical state of smooth muscle function.^8,16–18 In the esophagus, mechanical state analysis was applied to upper LES function and esophageal peristalsis in healthy volunteers, where alterations in mechanical states were shown to be related to bolus perception in otherwise asymptomatic subjects.^16–18 This, to our knowledge, is the first study to apply mechanical state analysis to LES function or to specific esophageal motility disorders including achalasia. Given the potential for active LES relaxation or contraction involved, we termed these physiomechanical states.

This study also introduces a novel application of FLIP panometry testing by assessing the LES response to both volume filling and volume emptying. FLIP is well suited for mechanical state analysis, as it directly measures luminal cross-sectional area (diameter) using impedance planimetry technology and intrabag pressure in response to controlled, volumetric distension. The FLIP pressure may be influenced by other factors than LES tone (e.g., esophageal wall stiffness or peristalsis), however, the pressure within the FLIP is relatively uniform along its length and thus with this approach reflects the distensive pressure applied to the LES and its relationship with opening diameter. Further, while the analytic approaches with impedance-manometry (which extrapolates luminal diameter from intraluminal impedance) and FLIP panometry provide similar output (intraluminal diameter and pressure), they differ related to the stimuli assessed with the two technologies, that is, swallowed bolus with HRM (and thus primary peristalsis and deglutitive LES relaxation) versus volume distension on FLIP (with potential for secondary peristalsis and mechanical opening of the LES). Further, the distension with FLIP is unique from previous studies of esophageal distension, which typically use focal esophageal distension with air or water infusion or small balloon, in that the 16-cm length FLIP simultaneously distends the LES and distal esophageal body.^19–21

The esophageal response to distension is complex and varies based on the pattern of the distension. The typical response to focal distension of the proximal esophagus is distal relaxation of the esophageal body and LES, with peristalsis triggered when distension is released.²⁰ With FLIP, there appears to be LES relaxation with associated EGJ opening when antegrade contractions (secondary peristalsis) are triggered, though these mechanisms, and those when secondary peristalsis are not triggered, remain uncertain. For this study, we opted to focus on patients with an absent contractile response on FLIP to reduce the influence of contractility on LES diameter and pressure, while also identifying a comparison group of patient controls with normal motility on FLIP, and observed relatively similar physiomechanical states at the LES between patients with normal HRM with or without secondary peristalsis on FLIP. While infrequent, there were several cases among these symptomatic patients (who may have been diagnosed as functional dysphagia) that exhibited auxotonic relaxation with emptying (a finding otherwise most commonly observed in untreated achalasia). This response could have pathophysiologic relevance, and thus, future study remains needed to clarify its potential significance.

Notably, although the majority of untreated achalasia had reduced EGJ opening using the FLIP EGJ opening classification, there was variability to the response to FLIP emptying among the achalasia patients, with auxotonic “relaxation” or passive shortening observed.²² The auxotonic relaxation response was ablated by LES myotomy, though an impact on treatment outcomes was not readily observed (noting potential limitation related to the sample size). Esophageal relaxation may be due to active relaxation driven by inhibitory neural signaling or via the reduction of excitatory signaling. We hypothesize that the observed auxotonic relaxation is more so related to the reduction of excitatory signaling, possibly related to release of the distension stimuli, such as reduced stretch triggering, or due to exhaustion of ion flow (e.g., Ca⁺⁺). Further, this difference among achalasia could reflect a relative degree of ganglion loss (i.e., reflect disease stage or severity) and related excitatory/inhibitory imbalance, even though there was not an apparent difference between type I and type II achalasia.²³ Future mechanistic studies, potentially utilizing pharmacologic challenges and/or histologic review of LES muscle specimens, remain warranted to better understand the observed physiologic responses related to the esophageal response to distension.

While this study provides a novel evaluation of LES function in esophageal motility disorders, there are several limitations. We specifically selected key physiologic and clinical scenarios of esophageal motility for the purposes of this study, potentially limiting the generalizability to broader patient populations, which can be pursued in future analyses to expand this approach to other clinical cohorts. Further, we applied any change in pressure or diameter to define physiomechanical states (similar to the approach described with impedance-manometry), however, it is possible that differing thresholds for relevant diameter or pressure changes could be refined with future studies that could improve these approaches.^8,16,17 Additionally, while the LES physiomechanical state approach with FLIP panometry offers a novel approach with the potential to offer insights into the physiology of esophageal health and disease, small sample sizes and missing data limited inferences regarding the clinical impact in the present study. Hence, although the present study did not detect significant correlation with symptoms or treatment outcomes in achalasia, future studies will focus on applying this approach to achalasia treatment failures or inconclusive FLIP or HRM studies to further examine its clinical utility.

In conclusion, this study described a novel approach applying mechanical state analysis to assess LES function using FLIP panometry among esophageal motility disorders. While future studies are warranted to better define the underlying pathophysiologic mechanisms and clinical impact, this introduction of the approach provides an exciting background to spur future investigation. Overall, defining the physiomechanical state of esophageal neuromuscular function provides an opportunity for advancing beyond static measures of LES function, such as LES pressure with esophageal manometry or EGJ-distensibility index on FLIP, that may offer novel and important insights into esophageal disorders.

Key points.

Functional lumen imaging probe (FLIP) panometry assesses the esophageal physiologic and mechanical responses to volumetric distension. The purpose of this study was to utilize FLIP filling and emptying regimes to define physiomechanical states of the lower esophageal sphincter (LES) among esophageal motility disorders.

Most patients, regardless of esophageal motility disorder, had passive dilatation of the LES in response to FLIP filling. After FLIP emptying, passive shortening was observed in most normal motility, ineffective esophageal motility, and scleroderma while auxotonic relaxation occurred in many achalasia patients. After treatment for achalasia with LES myotomy, patients demonstrated passive shortening after FLIP emptying.

A novel approach to define the physiomechanical states of the LES with FLIP panometry may offer unique insights into the pathophysiology of esophageal motility disorders.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.