The lower esophageal sphincter.
Hershcovici T,Mashimo H,Fass R
Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society
The lower esophageal sphincters (LES) together with the crural diaphragm are the major antireflux barriers protecting the esophagus from reflux of gastric content. However, reflux of gastric contents into the esophagus is a normal phenomenon in healthy individuals occurring primarily during episodes of transient lower esophageal sphincter relaxation (TLESR), defined as LES relaxation in the absence of a swallow. Transient lower esophageal sphincter relaxation is also the dominant mechanism of pathologic reflux in gastroesophageal reflux disorder (GERD) patients. Frequency of TLESR does not differ significantly between healthy individuals and those with GERD, but TLESRs are more likely to be associated with acid reflux in GERD patients. Understanding the mechanisms responsible for elicitation of a TLESR, using recently introduced novel technology is an area of intense interest. Pharmacologic and non-pharmacologic manipulation of receptors involved in the control of TLESR has recently emerged as a potential target for GERD therapy.
Role of the lower esophageal sphincter on esophageal acid exposure - a review of over 2000 patients.
Tsuboi Kazuto,Hoshino Masato,Sundaram Abhishek,Yano Fumiaki,Mittal Sumeet K
Tropical gastroenterology : official journal of the Digestive Diseases Foundation
BACKGROUND AND AIM:Three lower esophageal sphincter (LES) characteristics associated with gastro-esophageal reflux disease (GERD) are, LES pressure = 6 mmHg, abdominal length (AL) <1 cm and overall length (OL) <2 cm. The objective of this study was to validate this relationship and evaluate the extent of impact various LES characteristics have on the degree of distal esophageal acid exposure. METHODS:A retrospective review of a prospectively maintained database identified patients who underwent esophageal manometry and pH studies at Creighton University Medical Center between 1984 and 2008. Patients with esophageal body dysmotility, prior foregut surgery, missing data, no documented symptoms or no pH study, were excluded. Study subjects were categorized as follows: (1) normal LES (N-LES): patients with LES pressure of 6-26 mmHg, AL = 1.0 cm and OL = 2 cm; (2) incompetent LES (Inc-LES): patients with LES pressure <6.0 mmHg orAL <1 cm or OL <2 cm; and (3) hypertensive LES (HTN-LES): patients with LES pressure >26.0 mmHg with AL = 1 cm and OL = 2 cm. The DeMeester score was used to compare differences in acid exposure between different groups. RESULTS:Two thousand and twenty patients satisfied study criteria. Distal esophageal acid exposure as reflected by the DeMeester score in patients with Inc-LES (median=20.05) was significantly higher than in patients with an N-LES (median=9.5), which in turn was significantly higher than in patients with an HTN-LES. Increasing LES pressure and AL provided protection against acid exposure in a graded fashion. Increasing number of inadequate LES characteristics were associated with an increase both in the percentage of patients with abnormal DeMeester score and the degree of acid exposure. CONCLUSION:LES pressure (=6 mmHg) and AL (<1 cm) are associated with increased lower esophageal acid exposure, and need to be addressed for definitive management of GERD.
Excitatory and inhibitory enteric innervation of horse lower esophageal sphincter.
Chiocchetti R,Giancola F,Mazzoni M,Sorteni C,Romagnoli N,Pietra M
Histochemistry and cell biology
The lower esophageal sphincter (LES) is a specialized, thickened muscle region with a high resting tone mediated by myogenic and neurogenic mechanisms. During swallowing or belching, the LES undergoes strong inhibitory innervation. In the horse, the LES seems to be organized as a "one-way" structure, enabling only the oral-anal progression of food. We characterized the esophageal and gastric pericardial inhibitory and excitatory intramural neurons immunoreactive (IR) for the enzymes neuronal nitric oxide synthase (nNOS) and choline acetyltransferase. Large percentages of myenteric plexus (MP) and submucosal (SMP) plexus nNOS-IR neurons were observed in the esophagus (72 ± 9 and 69 ± 8 %, respectively) and stomach (57 ± 17 and 45 ± 3 %, respectively). In the esophagus, cholinergic MP and SMP neurons were 29 ± 14 and 65 ± 24 vs. 36 ± 8 and 38 ± 20 % in the stomach, respectively. The high percentage of nitrergic inhibitory motor neurons observed in the caudal esophagus reinforces the role of the enteric nervous system in the horse LES relaxation. These findings might allow an evaluation of whether selective groups of enteric neurons are involved in horse neurological disorders such as megaesophagus, equine dysautonomia, and white lethal foal syndrome.
Increase of lower esophageal sphincter pressure after osteopathic intervention on the diaphragm in patients with gastroesophageal reflux.
da Silva R C V,de Sá C C,Pascual-Vaca Á O,de Souza Fontes L H,Herbella Fernandes F A M,Dib R A,Blanco C R,Queiroz R A,Navarro-Rodriguez T
Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus
The treatment of gastroesophageal reflux disease may be clinical or surgical. The clinical consists basically of the use of drugs; however, there are new techniques to complement this treatment, osteopathic intervention in the diaphragmatic muscle is one these. The objective of the study is to compare pressure values in the examination of esophageal manometry of the lower esophageal sphincter (LES) before and immediately after osteopathic intervention in the diaphragm muscle. Thirty-eight patients with gastroesophageal reflux disease - 16 submitted to sham technique and 22 submitted osteopathic technique - were randomly selected. The average respiratory pressure (ARP) and the maximum expiratory pressure (MEP) of the LES were measured by manometry before and after osteopathic technique at the point of highest pressure. Statistical analysis was performed using the Student's t-test and Mann-Whitney, and magnitude of the technique proposed was measured using the Cohen's index. Statistically significant difference in the osteopathic technique was found in three out of four in relation to the group of patients who performed the sham technique for the following measures of LES pressure: ARP with P= 0.027. The MEP had no statistical difference (P= 0.146). The values of Cohen d for the same measures were: ARP with d= 0.80 and MEP d= 0.52. Osteopathic manipulative technique produces a positive increment in the LES region soon after its performance.
System design and experimental research of lower esophageal sphincter stimulator for treatment of gastroesophageal reflux disease.
Xin-Chen Sun ,Wan-Jun Tao ,Chuan-Qing Zhu ,Li-Li Zhao ,Min Wang ,Xiao-Ying Lu ,Zhi-Gong Wang ,Zhi-Ning Fan
Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference
Electrical stimulation therapy (EST) of lower esophageal sphincters (LES) is a new technique for the treatment of gastroesophageal reflux disease (GERD). In this paper, an implantable LES stimulator with wireless power transmission is proposed for the treatment of GERD. The LES stimulator is composed of an implantable pulse generator (IPG), an external controller, and a wireless power transmission module. The IPG, whose area is 31×21 mm, is designed to generate voltage-regulated constant-current stimulation pulses. The external controller allows for wireless programming of the IPG via a Bluetooth Low Energy (BLE) module. The wireless power transmission module provides power for the IPG. According to the measurement of output stimulus waveforms, the proposed LES stimulator is capable of delivering electrical stimulations with a current ranging between 0 and 8 mA. To evaluate the safety and efficacy of the proposed LES stimulator, experiments were performed on 12 male New Zealand white rabbits. Esophageal manometry was performed before and after the procedure and the LES pressure (LESP) has been recorded. The mean LESP is increased significantly in the stimulation group than the sham group (stimulation group: 9.25±1.24 mmHg vs 13.99 ±1.28 mmHg, p<;0.05; sham group: 9.00±1.22 mmHg vs 9.23±1.27 mmHg, p=0.267). The results show that the electrical stimulation delivered by the LES stimulator can safely and effectively increase resting LES pressure in acute animal models, suggesting that the implantable LES stimulator is a perspective approach for treating GERD in clinics.
Magnetic lower esophageal sphincter augmentation device removal.
Harnsberger Cristina R,Broderick Ryan C,Fuchs Hans F,Berducci Martin,Beck Catherine,Gallo Alberto,Jacobsen Garth R,Sandler Bryan J,Horgan Santiago
Implantation of a magnetic lower esophageal sphincter augmentation device is now an alternative to fundoplication in the surgical management of gastroesophageal reflux disease (GERD). Although successful management of GERD has been reported following placement of the device, there are instances when device removal is needed. The details of the technique for laparoscopic magnetic lower esophageal sphincter device removal are presented to assist surgeons should device removal become necessary.
Lower esophageal sphincter pressure measurement under standardized inspiratory maneuveurs.
Ribeiro Jeany Borges e Silva,Diógenes Esther Cristina Arruda Oliveira,Bezerra Patrícia Carvalho,Coutinho Tanila Aguiar Andrade,de Almeida Cícera Geórgia Félix,e Souza Miguel Ângelo Nobre
Arquivos brasileiros de cirurgia digestiva : ABCD = Brazilian archives of digestive surgery
BACKGROUND:Through rhythmic variations, the diaphragm influence lower esophageal sphincter (LES) pressure acting as an external sphincter. LES pressure recording is characterized by increased pressure in inspiration due to contraction of the diaphragmatic crura that involves the sphincter. AIM:To describe a method of measuring LES pressure during standardized inspiratory maneuvers with increasing loads. METHODS:The study population comprised of eight healthy female volunteers (average age of 31.5 years). An esophageal high-resolution manometry and impedance system was used for measuring the LES pressure during 3-second inspiratory efforts under 12, 24 and 48 cm H2O loads (Threshold maneuvers). RESULTS:There was a significant difference between the average maximum LES pressure and the average maximum basal LES pressure during the first (76.19±17.92 difference, p=0.0008), second (86.92±19.01 difference, p=0.0004), and third seconds of the maneuver (90.86±17.93 difference, p=0.0002), with 12, 24 and 48 cmH2O loads. CONCLUSION:This maneuver is a standardization of the inspiratory LES pressure and may better differentiate patients with reflux disease from healthy individuals, and may also be useful for monitoring the treatment of these patients through inspiratory muscle training.
Factors influencing lower esophageal sphincter relaxation after deglutition.
Tibbling Lita,Gezelius Per,Franzén Thomas
World journal of gastroenterology
AIM:To study the relationship between upper esophageal sphincter (UES) relaxation, peristaltic pressure and lower esophageal sphincter (LES) relaxation following deglutition in non-dysphagic subjects. METHODS:Ten non-dysphagic adult subjects had a high-resolution manometry probe passed transnasally and positioned to cover the UES, the esophageal body and the LES. Ten water swallows in each subject were analyzed for time lag between UES relaxation and LES relaxation, LES pressure at time of UES relaxation, duration of LES relaxation, the distance between the transition level (TL) and the LES, time in seconds that the peristaltic wave was before (negative value) or after the TL when the LES became relaxed, and the maximal peristaltic pressure in the body of the esophagus. RESULTS:Relaxation of the LES occurred on average 3.5 s after the bolus had passed the UES and in most cases when the peristaltic wave front had reached the TL. The LES remained relaxed until the peristaltic wave faded away above the LES. CONCLUSION:LES relaxation seemed to be caused by the peristaltic wave pushing the bolus from behind against the LES gate.
Effect of electrical stimulation of the lower esophageal sphincter in gastroesophageal reflux disease patients refractory to proton pump inhibitors.
Soffer Edy,Rodríguez Leonardo,Rodriguez Patricia,Gómez Beatriz,Neto Manoel G,Crowell Michael D
World journal of gastrointestinal pharmacology and therapeutics
AIM:To evaluate the efficacy of lower esophageal sphincter (LES)-electrical stimulation therapy (EST) in a subgroup of patients that reported only partial response to proton pump inhibitors (PPIs) therapy, compared to a group of patient with complete response. METHODS:Bipolar stitch electrodes were laparoscopically placed in the LES and connected to an implantable pulse generator (EndoStim BV, the Hague, the Netherlands), placed subcutaneously in the anterior abdominal wall. Stimulation at 20 Hz, 215 μsec, 3-8 mAmp in 30 min sessions was delivered starting on day 1 post-implant. Patients were evaluated using gastroesophageal reflux disease (GERD)-HRQL, symptom diaries; esophageal pH and esophageal manometry before and up to 24 mo after therapy and results were compared between partial and complete responders. RESULTS:Twenty-three patients with GERD on LES-EST were enrolled and received continuous per-protocol stimulation through 12 mo and 21 patients completed 24 mo of therapy. Of the 23 patients, 16 (8 male, mean age 52.1 ± 12 years) had incomplete response to PPIs prior to LES-EST, while 7 patients (5 male, mean age 52.7 ± 4.7) had complete response to PPIs. In the sub-group with incomplete response to PPIs, median (IQR) composite GERD-HRQL score improved significantly from 9.5 (9.0-10.0) at baseline on-PPI and 24.0 (20.8-26.3) at baseline off-PPI to 2.5 (0.0-4.0) at 12-mo and 0.0 (0.0-2.5) at 24-mo follow-up (P < 0.05 compared to on-and off-PPI at baseline). Median (IQR) % 24-h esophageal pH < 4.0 at baseline in this sub-group improved significantly from 9.8% (7.8-11.5) at baseline to 3.0% (1.9-6.3) at 12 mo (P < 0.001) and 4.6% (2.0-5.8) at 24 mo follow-up (P < 0.01). At their 24-mo follow-up, 9/11 patients in this sub-group were completely free of PPI use. These results were comparable to the sub-group that reported complete response to PPI therapy at baseline. No unanticipated implantation or stimulation-related adverse events, or any untoward sensation due to stimulation were reported in either group and LES-EST was safely tolerated by both groups. CONCLUSION:LES-EST is safe and effective in controlling symptoms and esophageal acid exposure in GERD patients with incomplete response to PPIs. These results were comparable to those observed PPI responders.
Long-term results of electrical stimulation of the lower esophageal sphincter for treatment of proximal GERD.
Hoppo Toshitaka,Rodríguez Leonardo,Soffer Edy,Crowell Michael D,Jobe Blair A
INTRODUCTION:Electrical stimulation of the lower esophageal sphincter (LES) in gastroesophageal reflux disease (GERD) patients, using EndoStim(®) LES stimulation system (EndoStim BV, the Hague, Netherlands), enhances LES pressure, decrease distal esophageal acid exposure, improves symptoms, and eliminates the need in many patients for daily GERD medications. AIM:To evaluate, in a post hoc analysis, the effect of LES stimulation on proximal esophageal acid exposure in a subgroup of patients with abnormal proximal esophageal acid exposure. METHODS:Nineteen patients (median age 54 years; IQR 47-64; men-10) with GERD partially responsive to proton pump inhibitors (PPI), hiatal hernia ≤ 3 cm, esophagitis ≤ LA grade C underwent laparoscopic implantation of the LES stimulator. LES stimulation at 20 Hz, 215 μs, 5-8 m Amp sessions was delivered in 6-12, 30 min sessions each day. Esophageal pH at baseline and after 12-months of LES stimulation was measured 5 and 23 cm above the manometric upper border of LES. RESULTS:Total, upright and supine values of median (IQR) proximal esophageal pH at baseline were 0.4 (0.1-1.4), 0.6 (0.2-2.3), and 0 (0.0-0.2) %, respectively, and at 12 months on LES-EST were 0 (0-0) % (p = 0.001 total and upright; p = 0.043 supine comparisons). 24-hour distal esophageal acid exposure improved from 10.2 (7.6-11.7) to 3.4 (1.6-7.0) % (p = 0.001). Seven (37%) patients had abnormal (>1.1%) 24-hour proximal acid exposure at baseline; all normalized at 12 months (p = 0.008). In these 7 patients, total, upright, and supine median proximal acid exposure values at baseline were 1.7 (1.3-4.1), 2.9 (1.9-3.7), and 0.3 (0-4.9) %, respectively, and after 12 months of LES-EST were 0 (0-0.0), 0 (0-0.1), and 0 (0-0) % (p = 0.018 total and upright; p = 0.043 supine comparisons). Distal esophageal pH for this group improved from 9.3 (7.8-17.2) at baseline to 3.2 (1.1-3.7) % at 12-months (p = 0.043). There were no GI side effects such as dysphagia, gas-bloat or diarrhea or device or procedure related serious adverse events with LES-EST. There was also a significant improvement in their GERD-HRQL scores. CONCLUSION:LES-EST is associated with normalization of proximal esophageal pH in patients with GERD and may be useful in treating those with proximal GERD. The LES-EST is safe without typical side effects associated with traditional antireflux surgery.
Role of the lower esophageal sphincter on acid exposure revisited with high-resolution manometry.
Hoshino Masato,Sundaram Abhishek,Mittal Sumeet K
Journal of the American College of Surgeons
BACKGROUND:The objective of this study was to investigate the role of lower esophageal sphincter (LES) length and pressure on acid exposure with high-resolution manometry (HRM). STUDY DESIGN:After Institutional Review Board approval, a retrospective review of a prospectively maintained database identified patients who had undergone HRM and 24-hour pH studies. Abdominal LES length (AL) ≤1 cm and overall LES length ≤2 cm were considered inadequate. A new parameter called lower esophageal sphincter pressure integral (LESPI) was analyzed in this study. Distal esophageal acid exposure was analyzed in relation to LES parameters. RESULTS:One hundred eight patients (inadequate AL, n = 54; inadequate overall LES length, n = 54) satisfied study criteria. Patients with inadequate AL had considerably lower LESPI and LES pressure. They also had more severe acid exposure and higher DeMeester score. However, inadequate overall LES length was not associated with abnormal acid exposure. Patients with a positive pH study had considerably lower LESPI than patients with a negative pH study. Inadequate AL and low LESPI (<400 mmHg/s/cm) had a synergistic effect on acid reflux. Multivariate logistic regression analysis identified inadequate AL, low LESPI, and male sex as predictors of a positive pH study. CONCLUSIONS:Using HRM, inadequate AL (≤1cm) and low LESPI (<400 mmHg/s/cm) are associated with gastroesophageal reflux disease and appear to have a synergistic effect on the severity of distal esophageal acid exposure. LESPI, which is a function of both sphincter length and pressure, appears to be the most sensitive HRM parameter for distal esophageal acid exposure.
Two-year results of intermittent electrical stimulation of the lower esophageal sphincter treatment of gastroesophageal reflux disease.
Rodríguez Leonardo,Rodriguez Patricia,Gómez Beatriz,Ayala Juan C,Oxenberg Danny,Perez-Castilla Alberto,Netto Manoel G,Soffer Edy,Boscardin W John,Crowell Michael D
BACKGROUND:Lower esophageal sphincter (LES) electrical stimulation therapy (EST) has been shown to improve outcome in gastroesophageal reflux disease (GERD) patients at 1 year. The aim of this open-label extension trial (NCT01578642) was to study the 2-year safety and efficacy of LES-EST in GERD patients. METHODS:GERD patients responsive partially to proton pump inhibitors (PPI) with off-PPI GERD health-related quality of life (HRQL) of ≥20, 24-hour esophageal pH ≤4.0 for >5% of the time, hiatal hernia ≤3 cm, and esophagitis LA grade C or lower participated in this trial. Bipolar stitch electrodes and a pulse generator (EndoStim BV, The Hague, The Netherlands) were implanted laparoscopically. LES-EST at 20 Hz, 215 μs, 3-8 mAmp was delivered over 30-minute sessions, 6-12 sessions per day, starting on day 1 after implantation. Patients were evaluated using GERD-HRQL, symptom diaries, Short Form-12, and esophageal pH testing at regular intervals. Stimulation sessions were optimized based on residual symptoms and esophageal pH at follow-up. RESULTS:Twenty-five patients (mean age [SD] = 52  years; 14 men) were implanted successfully; 23 patients participated in the 2-year extension trial, and 21 completed their 2-year evaluation. At 2 years, there was improvement in their median GERD-HRQL on LES-EST compared with both their on-PPI (9 vs 0; P = .001) and off-PPI (23.5 vs. 0; P < .001) baseline scores. Median 24-hour distal esophageal acid exposure improved from 10% at baseline to 4% (per-protocol analysis; P < .001) at 2 years with 71% demonstrating either normalization or a ≥50% decrease in their distal esophageal acid exposure. All except 5 patients (16/21) reported complete cessation of PPI use; only 2 patients were using a PPI regularly (≥50% of days). There was significant improvement in sleep quality and daily symptoms of heartburn and regurgitation on LES-EST. At baseline, 92% of the subjects (22/24) reported that they were "unsatisfied" with their condition off-PPI and 71% (17/24) on-PPI compared with 0% (0/21) "unsatisfied" at the 24-month visits on LES-EST. There were no device- or therapy-related serious adverse events and no untoward sensation or dysphagia reported with LES-EST. CONCLUSION:LES-EST is safe and effective for treating patients with GERD over a period of 2 years. LES-EST resulted in a significant and sustained improvement in GERD symptoms, and esophageal acid exposure and eliminated PPI use in majority of patients (16 of 21). Further, LES-EST was not associated with any gastrointestinal side effects or adverse events.
The gastric accommodation response to meal intake determines the occurrence of transient lower esophageal sphincter relaxations and reflux events in patients with gastro-esophageal reflux disease.
Pauwels A,Altan E,Tack J
Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society
BACKGROUND:Gastro-esophageal reflux (GER), the retrograde flow of gastric contents into the esophagus is a physiologic phenomenon, which can evoke symptoms and/or lesions in the esophagus (=gastro-esophageal reflux disease or GERD). Proton pump inhibitors (PPIs) reduce gastric acidity; however, as they are unable to control transient lower esophageal sphincter relaxations (TLESRs), the main mechanism for reflux in GERD, they do not abolish reflux. TLESRs occur predominantly in the postprandial period, and they are believed to be triggered by gastric distention. Gastric accommodation (GA) is the physiologic response to gastric distention and serves to prevent a rise in gastric wall tension during food intake. We aimed to study the relationship between GA and TLESRs, as they both are triggered by gastric distention. METHODS:We studied 12 GERD patients (average age 37 years [range 18-62], 7m/5f) and nine healthy volunteers (average age 27 years [range 22-36], 2m/7f) using high resolution manometry-impedance measurement before and after a mixed meal challenge. We determined the number of TLESRs (with or without reflux) and measured pre- and postprandial IGP. The change in IGP between the pre- and postprandial period (ΔIGP) is used as surrogate for GA. We also measured LES pressure before and after the meal and calculated the change (ΔLESp). KEY RESULTS:There were no statistical differences between pre- and postprandial IGP in GERD and healthy volunteers and similarly, there was no significant difference between pre- and postprandial LES pressures in GERD patients and healthy volunteers. The number of TLESRs (with or without reflux) was similar in GERD and healthy volunteers. More importantly, we did observe a negative correlation between ΔIGP and the number of TLESRs, irrespective of whether they were associated with reflux or not, in the GERD patients (without reflux r = -0.67, p = 0.017; with reflux r = -0.81, p = 0.0014). The same observations were found in healthy volunteers, where ΔIGP and the number of TLESRs are significantly inversely correlated (without reflux r = -0.87, p = 0.0045; with reflux r = -0.75, p = 0.021). We could not establish a correlation between ΔLESp and the number of TLESRs, neither in GERD patients nor in healthy volunteers. CONCLUSIONS & INFERENCES:This is the first study showing a clear negative correlation between ΔIGP and the number of TLESRs, irrespective of whether they were associated with reflux or not, both in GERD patients and in healthy subjects. These results suggest that TLESRs and GA are closely linked, probably through activation of mechanoreceptors involved in triggering of TLESRs.
Circular and longitudinal muscles shortening indicates sliding patterns during peristalsis and transient lower esophageal sphincter relaxation.
Patel Nirali,Jiang Yanfen,Mittal Ravinder K,Kim Tae Ho,Ledgerwood Melissa,Bhargava Valmik
American journal of physiology. Gastrointestinal and liver physiology
Esophageal axial shortening is caused by longitudinal muscle (LM) contraction, but circular muscle (CM) may also contribute to axial shortening because of its spiral morphology. The goal of our study was to show patterns of contraction of CM and LM layers during peristalsis and transient lower esophageal sphincter (LES) relaxation (TLESR). In rats, esophageal and LES morphology was assessed by histology and immunohistochemistry, and function with the use of piezo-electric crystals and manometry. Electrical stimulation of the vagus nerve was used to induce esophageal contractions. In 18 healthy subjects, manometry and high frequency intraluminal ultrasound imaging during swallow-induced esophageal contractions and TLESR were evaluated. CM and LM thicknesses were measured (40 swallows and 30 TLESRs) as markers of axial shortening, before and at peak contraction, as well as during TLESRs. Animal studies revealed muscular connections between the LM and CM layers of the LES but not in the esophagus. During vagal stimulated esophageal contraction there was relative movement between the LM and CM. Human studies show that LM-to-CM (LM/CM) thickness ratio at baseline was 1. At the peak of swallow-induced contraction LM/CM ratio decreased significantly (<1), whereas the reverse was the case during TLESR (>2). The pattern of contraction of CM and LM suggests sliding of the two muscles. Furthermore, the sliding patterns are in the opposite direction during peristalsis and TLESR.
Endoscopic magnet placement into subadventitial tunnels for augmenting the lower esophageal sphincter using submucosal endoscopy: ex vivo and in vivo study in a porcine model (with video).
Dobashi Akira,Wu Shu-Wei,Deters Jodie L,Miller Charles A,Knipschield Mary A,Cameron Graham P,Lu Lichun,Rajan Elizabeth,Gostout Christopher J
BACKGROUND AND AIMS:Endolumenal therapies serve as a treatment option for GERD. This study aimed to determine if magnets could be placed endoscopically using the adventitial layer to create a subadventitial space near the esophagogastric junction to augment the lower esophageal sphincter using submucosal endoscopy. METHODS:This study consisted of 2 phases, ex vivo and in vivo, with domestic pig esophagus. A long submucosal tunnel was made at the mid to lower esophagus. The muscularis propria was incised by a needle-knife within the submucosal tunnel. A subadventitial tunnel was made by biliary balloon catheter blunt dissection, and a magnet was deployed in the subadventitial space. The same maneuver was done within the opposing esophageal wall, with magnet placement in the opposing subadventitial space. RESULTS:Submucosal tunnels and subadventitial tunnels were successful without perforation ex vivo in all attempts and in 9 of 10 cases, respectively. Magnets were deployed in the subadventitial space in 7 cases. Magnets connected and separated with atraumatic endoscope passage into the stomach and reconnected when the endoscope was withdrawn under fluoroscopy in 5 of 7 cases (71.4%). In vivo submucosal tunnels and subadventitial tunnels were successful in all 5 cases, and magnet augmentation was functionally active in 4 cases (80%). CONCLUSION:Subadventitial tunnels were feasible and could represent a new working space for endoscopic treatment. Endoscopic placement of magnets within the subadventitial space may be an attractive alternative endolumenal therapy for GERD.
Lower Esophageal Sphincter Augmentation for Gastroesophageal Reflux Disease: The Safety of a Modern Implant.
Smith C Daniel,Ganz Robert A,Lipham John C,Bell Reginald C,Rattner David W
Journal of laparoendoscopic & advanced surgical techniques. Part A
INTRODUCTION:Use of the magnetic sphincter augmentation device (MSAD) for gastroesophageal reflux disease (GERD) is increasing. As this innovative treatment for GERD gains widespread use and adoption, an assessment of its safety since U.S. market introduction is presented. METHODS:Events were collected from the Manufacturer and User Facility Device Experience (MAUDE) database, which reports events submitted to the Food and Drug Administration (FDA) of suspected device-associated deaths, serious injuries, and malfunctions. The reporting period was from March 22, 2012 (FDA approval) through May 31, 2016, and included only events occurring in the United States. Additional information was provided by the manufacturer, allowing calculation of implant rates and durations. RESULTS:An estimated 3283 patients underwent magnetic sphincter augmentation (165 surgeons at 191 institutions). The median implant duration was 1.4 years, with 1016 patients implanted for at least 2 years. No deaths, life-threatening events, or device malfunctions were reported. The overall rate of device removal was 2.7% (89/3283). The most common reasons for device removal were dysphagia (52/89) and persistent reflux symptoms (19/89). Removal for erosion and migration was 0.15% (5/3283) and 0% (0/3283), respectively. There were no perforations. Of the device removals, 57.3% (51/89) occurred <1 year after implant, 30.3% (27/89) between 1 and 2 years, and 12.4% (11/89) >2 years after implant. The rate of device removal and erosion with an implant duration >2 years were 1.1% (11/1016) and 0.1% (1/1016), respectively. All device removals and erosions were managed nonemergently, with no complications or long-term consequences. CONCLUSIONS:During a 4-year period in more than 3000 patients, no unanticipated MSAD complications have emerged, and there is no data to suggest a trend of increased events over time. The presentation and management of device-related issues have been less complicated than revisions for laparoscopic fundoplication or other interventions for GERD. MSAD is considered safe for the widespread treatment of GERD.
Effect of electrical stimulation therapy of the lower esophageal sphincter in GERD patients with ineffective esophageal motility.
Paireder Matthias,Kristo Ivan,Asari Reza,Jomrich Gerd,Steindl Johannes,Rieder Erwin,Schoppmann Sebastian F
BACKGROUND:Electrical stimulation therapy (EST) of the lower esophageal sphincter (LES) is a novel technique in antireflux surgery. Due to the minimal alteration at the LES during surgery, LES-EST is meant to be ideal for patients with gastroesophageal reflux disease (GERD) and ineffective esophageal motility (IEM). The aim of this prospective trial (NCT03476265) is to evaluate health-related quality of life and esophageal acid exposure after LES-EST in patients with GERD and IEM. METHODS:This is a prospective non-randomized open-label study. Patients with GERD and IEM undergoing LES-EST were included. Follow-up (FUP) at 12 months after surgery included health-related quality of life (HRQL) assessment with standardized questionnaires (GERD-HRQL) and esophageal functional testing. RESULTS:According to the study protocol, 17 patients fulfilled eligibility criteria. HRQL score for heartburn and regurgitation improved from 21 (interquartile range (IQR) 15-27) to 7.5 (1.25-19), p = 0.001 and from 17 (11-23.5) to 4 (0-12), p = 0.003, respectively. There was neither significant improvement of esophageal acid exposure nor reduction of number of reflux events in pH impedance measurement. Distal contractile integral improved from 64 (11.5-301) to 115 (IQR 10-363) mmHg s cm, p = 0.249. None of the patients showed any sign of dysphagia after LES-EST. One patient needed re-do surgery and re-implantation of the LES-EST due to breaking of the lead after one year. CONCLUSION:Although patient satisfaction improved significantly after surgery, this study fails to demonstrate normalization or significant improvement of acid exposure in the distal esophagus after LES-EST.
Manometric Changes to the Lower Esophageal Sphincter After Magnetic Sphincter Augmentation in Patients With Chronic Gastroesophageal Reflux Disease.
Warren Heather F,Louie Brian E,Farivar Alexander S,Wilshire Candice,Aye Ralph W
Annals of surgery
OBJECTIVE:To evaluate the manometric changes, function, and impact of magnetic sphincter augmentation (MSA) on the lower esophageal sphincter (LES). BACKGROUND:Implantation of a MSA around the gastroesophageal junction has been shown to be a safe and effective therapy for gastroesophageal reflux disease, but its effect on the LES has not been elucidated. METHODS:Retrospective case control study (n = 121) evaluating manometric changes after MSA. Inclusion criteria consisted of a confirmed diagnosis of gastroesophageal reflux disease by an abnormal esophageal pH study (body mass index <35 kg/m, hiatal hernia <3 cm, and absence of endoscopic Barrett disease). Manometric changes, pH testing, and proton pump inhibitor use were assessed preoperatively and 6 and 12 months after MSA. RESULTS:MSA was associated with an overall increase in the median LES resting pressure (18 pre-MSA vs 23 mm Hg post-MSA; P = 0.0003), residual pressure (4 vs 9 mm Hg; P < 0.0001), and distal esophageal contraction amplitude (80 vs 90 mm Hg; P = 0.02). The percent peristalsis remained unaltered (94% vs 87%; P = 0.71).Overall, patients with a manometrically defective LES were restored 67% of the time to a normal sphincter with MSA. Those with a structurally defective or severely defective LES improved to a normal LES in 77% and 56% of patients, respectively. Only 18% of patients with a normal preoperative manometric LES deteriorated to a lower category. CONCLUSION:MSA results in significant manometric improvement of the LES without apparent deleterious effects on the esophageal body. A manometrically defective LES can be restored to normal sphincter, whereas a normal LES remains stable.
Esophageal motility disorders: new perspectives from high-resolution manometry and histopathology.
Sato Hiroki,Takahashi Kazuya,Mizuno Ken-Ichi,Hashimoto Satoru,Yokoyama Junji,Hasegawa Go,Terai Shuji
Journal of gastroenterology
High-resolution manometry (HRM) and peroral endoscopic myotomy (POEM) have contributed significantly to the field of esophageal motility disorders in recent years. The development of HRM has categorized various esophageal motility disorders with a focus on a diverse range of manometric anomalies. Additionally, the Chicago classification criteria is widely used for manometric diagnosis. Moreover, POEM was introduced as a minimally invasive radical therapy for achalasia and shows promise for other spastic esophageal motility disorders as well. POEM has also enabled a transluminal endoscopic approach for determining the histology of the esophageal muscle layer, which is expected to assist in elucidating the etiology of disorders associated with esophageal motility. The purpose of this review is to update the diagnosis, pathology, and treatment of esophageal motility disorders, with a focus on the recent advances in this field.
Contraction Reserve With Ineffective Esophageal Motility on Esophageal High-Resolution Manometry is Associated With Lower Acid Exposure Times Compared With Absent Contraction Reserve.
Quader Farhan,Rogers Benjamin,Sievers Tyson,Mumtaz Shaham,Lee Mindy,Lu Thomas,Gyawali C Prakash
The American journal of gastroenterology
INTRODUCTION:Ineffective esophageal motility (IEM) is a minor motor disorder with potential reflux implications. Contraction reserve, manifested as augmentation of esophageal body contraction after multiple rapid swallows (MRS), may affect esophageal acid exposure time (AET) in IEM. METHODS:Esophageal high-resolution manometry (HRM) and ambulatory reflux monitoring studies were reviewed over 2 years to identify patients with normal HRM, IEM (≥50% ineffective swallows), and absent contractility (100% failed swallows). Single swallows and MRS were analyzed using HRM software tools (distal contractile integral, DCI) to determine contraction reserve (mean MRS DCI to mean single swallow DCI ratio >1). Univariate analysis and multivariable regression analyses were performed to determine motor predictors of abnormal AET in the context of contraction reserve. RESULTS:Of 191 eligible patients, 57.1% had normal HRM, 37.2% had IEM, and 5.8% had absent contractility. Contraction reserve had no affect on AET in normal HRM. Nonsevere IEM (5-7 ineffective swallows) demonstrated significantly lower proportions with abnormal AET in the presence of contraction reserve (30.4%) compared with severe IEM (8-10 ineffective swallows) (75.0%, P = 0.03). Abnormal AET proportions in nonsevere IEM with contraction reserve (32.7%) resembled normal HRM (33.0%, P = 0.96), whereas that in severe IEM with (46.2%) or without contraction reserve (50.0%) resembled absent contractility (54.5%, P ≥ 0.6). Multivariable analysis demonstrated contraction reserve to be an independent predictor of lower upright AET in nonsevere (odds ratio 0.44, 95% confidence interval 0.23-0.88) but not severe IEM. DISCUSSION:Contraction reserve affects esophageal reflux burden in nonsevere IEM. Segregating IEM into severe and nonsevere cohorts has clinical value.
High resolution manometry and new classification of esophageal motility disorders.
Ivashkin V T,Maev I V,Trukhmanov A S,Storonova O A,Kucheryavyi Yu A,Barkalova E V,Ovsepyan M A,Andreev D N,Paraskevova A B,Rumyantseva D E
AIM:To present application of Chicago classification criteria of esophageal motility disorders defined in high resolution manometry in clinical practice. MATERIALS AND METHODS:High-resolution manometry is the most exact hi-tech diagnostic method for esophageal motor function disorders according to Chicago classification v3.0. Uniqueness of the method consists in capacity to define integrated quantitative and qualitative metrics of esophageal contractile function and to establish their specific disorders e.g.: change of intrabolus pressure at disorders of esophagogastric junction (EGj) outflow, hypercontractile esophagus, fragmented contractions and weak or failed peristalsis, distal esophageal spasm. Assessment of the type of achalasia subtypes has significant impact on the patients' treatment choice. According to anatomical location of the lower esophageal sphincter and crural diaphragm several morphological types of gastro-esophageal junction are defined that determine severity of gastroesophageal reflux disease. Multiple rapid swallow responses during esophageal high-resolution manometry reflect esophageal body peristaltic reserve and is a predictor of postoperative complications. Differential diagnosis of belching type became possible at combined application of high-resolution manometry and impedance measurement. RESULTS: CONCLUSION:High-resolution manometry is a fundamental diagnostic test of esophageal motor function disorders. Clinical application of this method significantly expands diagnostic potential and allows to carry out personalized treatment that increases treatment quality.
Physiology of the upper segment, body, and lower segment of the esophagus.
Miller Larry,Clavé Pere,Farré Ricard,Lecea Begoña,Ruggieri Michael R,Ouyang Ann,Regan Julie,McMahon Barry P
Annals of the New York Academy of Sciences
The following discussion on the physiology of the esophagus includes commentaries on the function of the muscularis mucosa and submucosa as a mechanical antireflux barrier in the esophagus; the different mechanisms of neurological control in the esophageal striated and smooth muscle; new insights from animal models into the neurotransmitters mediating lower esophageal sphincter (LES) relaxation, peristalsis in the esophageal body (EB), and motility of esophageal smooth muscle; differentiation between in vitro properties of the lower esophageal circular muscle, clasp muscle, and sling fibers; alterations in the relationship between pharyngeal contraction and relaxation of the upper esophageal sphincter (UES) in patients with dysphagia; the mechanical relationships between anterior hyoid movement, the extent of upper esophageal opening, and aspiration; the application of fluoroscopy and manometry with biomechanics to define the stages of UES opening; and nonpharmacological approaches to alter the gastroesophageal junction (GEJ).
Distension-related responses in circular and longitudinal muscle of the human esophagus: an ultrasonographic study.
Yamamoto Y,Liu J,Smith T K,Mittal R K
The American journal of physiology
Both circular muscles (CM) and longitudinal muscles (LM) of the esophagus participate in peristalsis. Various measurement techniques have yielded conflicting information as to the temporal correlation between contraction in the two muscle layers. High-frequency intraluminal ultrasound (HFIUS) is a novel technique to detect contraction of LM and CM of the esophagus. We investigated the temporal correlation between the CM and LM contraction during ascending excitatory and descending inhibitory reflexes using HFIUS. A manometric catheter equipped with two balloons and a 12.5-MHz ultrasound transducer catheter was used to study 10 normal healthy subjects. The changes in muscle thickness and pressure, proximal and distal to esophageal distension, were recorded at 5 and 10 cm above the lower esophageal sphincter (LES). The esophageal distension induced an increase in pressure and an increase in muscle thickness of both CM and LM layers proximal to the distension site. The onset of increase in muscle thickness and peak muscle thickness in two layers occurred at the same time. There was a close temporal correlation between the changes in pressure and changes in muscle thickness. Atropine inhibited the distension-related pressure and muscle thickness increase in both layers. Distal to the esophageal distension, there was no change in pressure but a decrease in the thickness of the two muscle layers. The decrease in muscle thickness of the two layers occurred at the same time. The responses of the two muscle layers to distension were similar at 5- and 10-cm sites above the LES. HFIUS is a relatively noninvasive technique to study the LM layer response during peristalsis in vivo. Our data indicate that the two muscle layers may contract and relax together during distension-related peristaltic reflexes in the esophagus.
Longitudinal muscle of the esophagus: its role in esophageal health and disease.
Mittal Ravinder K
Current opinion in gastroenterology
PURPOSE OF REVIEW:The muscularis propria of the esophagus is organized into circular and longitudinal muscle layers. The function of the longitudinal muscle and its role in bolus propulsion are not clear. The goal of this review is to summarize what is known of the role of the longitudinal muscle in health, as well as in sensory and motor disorders of the esophagus. RECENT FINDINGS:Simultaneous manometry and ultrasound imaging reveal that, during peristalsis, the two muscle layers of the esophagus contract in perfect synchrony. On the contrary, during transient lower esophageal sphincter (LES) relaxation, longitudinal muscle contracts independent of the circular muscle. Recent studies have provided novel insights into the role of the longitudinal muscle in LES relaxation and descending relaxation of the esophagus. In certain diseases (e.g. some motility disorders of the esophagus), there is discoordination between the two muscle layers, which likely plays an important role in the genesis of dysphagia and delayed esophageal emptying. There is close temporal correlation between prolonged contractions of the longitudinal muscles of the esophagus and esophageal 'angina-like' pain. Novel techniques to record longitudinal muscle contraction are reviewed. SUMMARY:Longitudinal muscles of the esophagus play a key role in the physiology and pathophysiology of esophageal sensory and motor function. Neuro-pharmacologic controls of circular and longitudinal muscle are different, which provides an opportunity for the development of novel pharmacological therapies in the treatment of esophageal sensory and motor disorders.
Stem cell treatments for oropharyngeal dysphagia: Rationale, benefits, and challenges.
Tran Eric K,Juarez Kevin O,Long Jennifer L
World journal of stem cells
Dysphagia, defined as difficulty swallowing, is a common symptom negatively impacting millions of adults annually. Estimated prevalence ranges from 14 to 33 percent in those over age 65 to over 70 percent in a nursing home setting. The elderly, those with neurodegenerative diseases, head and neck cancer patients, and those with autoimmune conditions such as Sjögren's syndrome are disproportionately affected. Oropharyngeal dysphagia refers specifically to difficulty in initiating a swallow due to dysfunction at or above the upper esophageal sphincter, and represents a large proportion of dysphagia cases. Current treatments are limited and are often ineffective. Stem cell therapy is a new and novel advancement that may fill a much-needed role in our treatment regimen. Here, we review the current literature regarding stem cell treatments for oropharyngeal dysphagia. Topics discussed include tissue regeneration advancements as a whole and translation of these principles into research surrounding tongue dysfunction, xerostomia, cricopharyngeal dysfunction, and finally an overview of the challenges and future directions for investigation. Although this field of study remains in its early stages, initial promising results show potential for the use of stem cell-based therapies to treat oropharyngeal dysphagia and warrant further research.
The efficacy of mesenchymal stem cell transplantation in caustic esophagus injury: an experimental study.
Kantarcioglu Murat,Caliskan Bahadir,Demirci Hakan,Karacalioglu Ozgur,Kekilli Murat,Polat Zulfikar,Gunal Armagan,Akinci Melih,Uysal Cagri,Eksert Sami,Gurel Hasan,Celebi Gurkan,Avcu Ferit,Ural Ali Ugur,Bagci Sait
Stem cells international
Introduction. Ingestion of corrosive substances may lead to stricture formation in esophagus as a late complication. Full thickness injury seems to exterminate tissue stem cells of esophagus. Mesenchymal stem cells (MSCs) can differentiate into specific cell lineages and have the capacity of homing in sites of injury. Aim and Methods. We aimed to investigate the efficacy of MSC transplantation, on prevention of esophageal damage and stricture formation after caustic esophagus injury in rats. 54 rats were allocated into four groups; 4 rats were sacrificed for MSC production. Group 1, untreated controls (n: 10). Group 2, membrane labeled MSCs-treated rats (n: 20). Group 3, biodistribution of fluorodeoxyglucose labeled MSCs via positron emission tomography (PET) imaging (n: 10). Group 4, sham operated (n: 10). Standard caustic esophageal burns were created and MSCs were transplanted 24 hours after. All rats were sacrificed at the 21st days. Results. PET scan images revealed the homing behavior of MSCs to the injury site. The histopathology damage score was not significantly different from controls. However, we demonstrated Dil labeled epithelial and muscle cells which were originating from transplanted MSCs. Conclusion. MSC transplantation after caustic esophageal injury may be a helpful treatment modality; however, probably repeated infusions are needed.
Fusion of human bone hemopoietic stem cell with esophageal carcinoma cells didn't generate esophageal cancer stem cell.
Fan H,Lu S
Prior studies showed that cell fusion between bone marrow-derived cell (BMDC) and somatic cell might be the origin of cancer stem cell. Our previous study suggested that cell fusion of human bone marrow-derived mesenchymal stem cell (MSC) with esophageal cancer cell did not generate cancer stem cells. But up to now, the origin of cancer stem cell is still ambiguous. In this study, we carried out the cell fusion experiment between hemopoietic stem cells (HSCs) and human esophageal cancer cells, and found that cell fusion slowed the growth speed of esophageal cancer cells and decreased the clone formation ability and tumorigenicity in NOD/SCID mice. In addition, cell fusion did not increase the ratio of side population (SP) cells and the resistance to chemotherapeutic drugs. Collectively, our data indicated that cell fusion between HSCs and esophageal cancer cells has a therapeutic effect rather than generate cells with characteristics of esophageal cancer stem cells.
Stromal cells participate in the murine esophageal mucosal injury response.
Shaker Anisa,Binkley Jana,Darwech Isra,Swietlicki Elzbieta,McDonald Keely,Newberry Rodney,Rubin Deborah C
American journal of physiology. Gastrointestinal and liver physiology
We identified α-smooth muscle actin (α-SMA)- and vimentin-expressing spindle-shaped esophageal mesenchymal cells in the adult and neonate murine esophageal lamina propria. We hypothesized that these esophageal mesenchymal cells express and secrete signaling and inflammatory mediators in response to injury. We established primary cultures of esophageal mesenchymal cells using mechanical and enzymatic digestion. We demonstrate that these primary cultures are nonhematopoietic, nonendothelial, stromal cells with myofibroblast-like features. These cells increase secretion of IL-6 in response to treatment with acidified media and IL-1β. They also increase bone morphogenetic protein (Bmp)-4 secretion in response to sonic hedgehog. The location of these cells and their biological functions demonstrate their potential role in regulating esophageal epithelial responses to injury and repair.
Local injection of bone marrow progenitor cells for the treatment of anal sphincter injury: in-vitro expanded versus minimally-manipulated cells.
Mazzanti Benedetta,Lorenzi Bruno,Borghini Annalisa,Boieri Margherita,Ballerini Lara,Saccardi Riccardo,Weber Elisabetta,Pessina Federica
Stem cell research & therapy
BACKGROUND:Anal incontinence is a disabling condition that adversely affects the quality of life of a large number of patients, mainly with anal sphincter lesions. In a previous experimental work, in-vitro expanded bone marrow (BM)-derived mesenchymal stem cells (MSC) were demonstrated to enhance sphincter healing after injury and primary repair in a rat preclinical model. In the present article we investigated whether unexpanded BM mononuclear cells (MNC) may also be effective. METHODS:Thirty-two rats, divided into groups, underwent sphincterotomy and repair (SR) with primary suture of anal sphincters plus intrasphincteric injection of saline (CTR), or of in-vitro expanded MSC, or of minimally manipulated MNC; moreover, the fourth group underwent sham operation. At day 30, histologic, morphometric, in-vitro contractility, and functional analysis were performed. RESULTS:Treatment with both MSC and MNC improved muscle regeneration and increased contractile function of anal sphincters after SR compared with CTR (p < 0.05). No significant difference was observed between the two BM stem cell types used. GFP-positive cells (MSC and MNC) remained in the proximity of the lesion site up to 30 days post injection. CONCLUSIONS:In the present study we demonstrated in a preclinical model that minimally manipulated BM-MNC were as effective as in-vitro expanded MSC for the recovery of anal sphincter injury followed by primary sphincter repair. These results may serve as a basis for improving clinical applications of stem cell therapy in human anal incontinence treatment.