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• W2106164003 abstract "Background & Aims: Patients with high-amplitude esophageal contractions (nutcracker esophagus [NCE]) show asynchrony of circular muscle (CM) and longitudinal muscle (LM) contraction during peristalsis. The goal of our study was to determine if this asynchrony is related to an increase in the cholinergic receptor activity. Methods: High-frequency intraluminal ultrasound images and pressures of the esophagus were recorded simultaneously in 10 normal subjects and 10 patients with NCE. Recordings were obtained at 2 cm above the lower esophageal sphincter under 2 study conditions in normal subjects (before and after 80 μgm/kg of edrophonium), and under 3 study conditions in the NCE patients (control, 5 μgm and 10 μgm/kg of atropine). Results: In normal subjects, edrophonium induced an increase in the CM and LM contraction amplitude, an increase in the contraction duration, and asynchrony of LM and CM contraction during peristalsis. On the other hand, increased contraction amplitude, duration, and asynchrony of LM and CM contraction observed at the baseline in the NCE patients were reversed by atropine in a dose-dependent fashion. Conclusions: These data prove that the esophageal motor abnormalities in patients with nutcracker esophagus, including asynchrony of CM and LM contraction, are related to a hypercholinergic state. Background & Aims: Patients with high-amplitude esophageal contractions (nutcracker esophagus [NCE]) show asynchrony of circular muscle (CM) and longitudinal muscle (LM) contraction during peristalsis. The goal of our study was to determine if this asynchrony is related to an increase in the cholinergic receptor activity. Methods: High-frequency intraluminal ultrasound images and pressures of the esophagus were recorded simultaneously in 10 normal subjects and 10 patients with NCE. Recordings were obtained at 2 cm above the lower esophageal sphincter under 2 study conditions in normal subjects (before and after 80 μgm/kg of edrophonium), and under 3 study conditions in the NCE patients (control, 5 μgm and 10 μgm/kg of atropine). Results: In normal subjects, edrophonium induced an increase in the CM and LM contraction amplitude, an increase in the contraction duration, and asynchrony of LM and CM contraction during peristalsis. On the other hand, increased contraction amplitude, duration, and asynchrony of LM and CM contraction observed at the baseline in the NCE patients were reversed by atropine in a dose-dependent fashion. Conclusions: These data prove that the esophageal motor abnormalities in patients with nutcracker esophagus, including asynchrony of CM and LM contraction, are related to a hypercholinergic state. Nutcracker esophagus (NCE), a form of primary motor disorder of the esophagus, is characterized by high-amplitude peristaltic contractions in the distal esophagus.1Spechler S.J. Castell D.O. Classification of oesophageal motility abnormalities.Gut. 2001; 49: 145-151Crossref PubMed Scopus (554) Google Scholar, 2Benjamin S.B. Gerhardt D.C. Castell D.O. High amplitude, peristaltic esophageal contractions associated with chest pain and/or dysphagia.Gastroenterology. 1979; 77: 478-483PubMed Scopus (245) Google Scholar In addition to high-contraction amplitude, the duration of the contraction wave is often prolonged in the NCE. The current thinking is that primary motor disorders of the esophagus (ie, achalasia of the esophagus and diffuse esophageal spasm) are related to the loss of inhibitory innervation of the esophagus and lower esophageal sphincter.3Sivarao D.V. Mashimo H.L. Thatte H.S. et al.Lower esophageal sphincter is achalasic in nNOS(−/−) and hypotensive in W/W(v) mutant mice.Gastroenterology. 2001; 121: 34-42Abstract Full Text PDF PubMed Scopus (144) Google Scholar, 4Konturek J.W. Gillessen A. Domschke W. Diffuse esophageal spasm: a malfunction that involves nitric oxide?.Scand J Gastroenterol. 1995; 30: 1041-1045Crossref PubMed Scopus (62) Google Scholar, 5Behar J. Biancani P. Pathogenesis of simultaneous esophageal contractions in patients with motility disorders.Gastroenterology. 1993; 105: 111-118PubMed Google Scholar, 6Hirano I. Tatum R.P. Shi G. et al.Manometric heterogeneity in patients with idiopathic achalasia.Gastroenterology. 2001; 120: 789-798Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar However, there is no evidence of reduced inhibitory innervation in NCE patients and it is likely that the increased contraction amplitude and duration in these patients is related to excessive cholinergic activity and an increase in the esophageal muscle thickness.7Brito E.M. Camacho-Lobato L. Paoletti V. et al.Effect of different swallow time intervals on the nutcracker esophagus.Am J Gastroenterol. 2003; 98: 40-45Crossref PubMed Scopus (11) Google Scholar In normal subjects, during swallow-induced peristalsis, a close temporal correlation exists between the esophageal circular muscle (CM) and longitudinal muscle (LM) contractions (ie, the 2 muscle layers contract together as measured by the onset, peak, and the end of contraction).8Mittal R.K. Padda B. Bhalla V. et al.Synchrony between circular and longitudinal muscle contractions during peristalsis in normal subjects.Am J Physiol Gastrointest Liver Physiol. 2006; 290: G431-G438Crossref PubMed Scopus (65) Google Scholar It is believed that the fine coordination between the 2 muscle layers reduces wall stress and provides significant biomechanical advantage to the CM contraction.9Pal A. Brasseur J.G. The mechanical advantage of local longitudinal shortening on peristaltic transport.J Biomech Eng. 2002; 124: 94-100Crossref PubMed Scopus (63) Google Scholar, 10Puckett J.L. Bhalla V. Liu J. et al.Oesophageal wall stress and muscle hypertrophy in high amplitude oesophageal contractions.Neurogastroenterol Motil. 2005; 17: 791-799Crossref PubMed Scopus (22) Google Scholar On the other hand, patients with NCE show an asynchrony of contraction of the 2 muscle layers—the peak LM contraction occurs earlier than the peak CM contraction during peristalsis in these patients.11Jung H.Y. Puckett J.L. Bhalla V. et al.Asynchrony between the circular and the longitudinal muscle contraction in patients with nutcracker esophagus.Gastroenterology. 2005; 128: 1179-1186Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar We recently observed that edrophonium, an acetyl-cholinesterase inhibitor, induces discoordination between the contractions of the 2 muscle layers of the esophagus in normal subjects.12Korsapati H. Babaei A. Bhargava V. et al.Asynchrony between the circular and longitudinal muscle contraction during esophageal peristalsis.Am J Physiol Gastrointest Liver Physiol. 2008; 294: G694-G698Crossref PubMed Scopus (19) Google Scholar The purpose of the present study was to determine if the discoordination between the CM and LM contraction observed in NCE is related to an excessive cholinergic activity. Ten normal subjects (4 men) with a mean age of 34 ± 14 years (±SD); and 10 NCE patients (6 men) with a mean age of 49 ± 9 years were studied. Normal subjects had no symptoms suggestive of esophageal disease. Some of the data from these normal controls have been the subject of a recently reported study.12Korsapati H. Babaei A. Bhargava V. et al.Asynchrony between the circular and longitudinal muscle contraction during esophageal peristalsis.Am J Physiol Gastrointest Liver Physiol. 2008; 294: G694-G698Crossref PubMed Scopus (19) Google Scholar Patients with NCE were referred to the University of California San Diego gastrointestinal function laboratory for symptoms of dysphagia/chest pain. Esophageal manometry was performed as a part of their diagnostic work-up. NCE was diagnosed when the mean contraction amplitude of 10 swallow-induced peristaltic contractions at any one recording site in the distal esophagus exceeded 180 mm Hg and the contraction waves were peristaltic. The Human Investigation Committee of University of California San Diego approved the study protocol. Each subject signed an informed consent form before participation in the study protocol. After an overnight fast, recordings were obtained with the subjects in the right recumbent position using a custom-made catheter assembly, as described previously.12Korsapati H. Babaei A. Bhargava V. et al.Asynchrony between the circular and longitudinal muscle contraction during esophageal peristalsis.Am J Physiol Gastrointest Liver Physiol. 2008; 294: G694-G698Crossref PubMed Scopus (19) Google Scholar Briefly, an 8-lumen manometry catheter (Dent sleeve; Mui Scientific, Toronto, Ontario, Canada) with 4 circumferentially placed side holes located 2 mm from the distal end, and an intravascular ultrasound (US) catheter was used to record pressure and US images simultaneously. The remaining 4 side holes were located at 5, 10, 15, and 20 cm above the 4 radially oriented side holes. A 30-MHz, 3.2-F, Micro-Rail US catheter (Cardiovascular Imaging Systems, Sunnyvale, CA) was placed through the core lumen of the manometry catheter in such a fashion that the US transducer was located just distal to the tip of the manometry catheter. The US transducer was encased in a water-filled polyethylene bag of the same diameter as the manometry catheter. This catheter arrangement allows us to record pressure and US images from the same region of the esophagus (within 2–3 mm) and at the same time capture a full 360° tomographic US image of the esophagus. The catheter assembly was introduced through the nose into the stomach after topical anesthesia of the nasal cavity and oropharynx using 1% lidocaine gel and 1% benzocaine spray. A station pull-through technique was used to determine the location of the lower esophageal sphincter. Recordings were acquired at 2 cm above the lower esophageal sphincter. In normal subjects, five 5-mL water swallows were recorded during the control period and within 5 minutes after intravenous administration of 80 μg/kg edrophonium. In the NCE patients, five 5-mL water swallows were recorded during each of the following periods: (1) the control period, (2) 5 minutes after intravenous administration of 5 μg/kg of atropine, and (3) 5 minutes after administration of 10 μg/kg of atropine. The second atropine injection was given approximately 30 minutes after the first atropine injection. All swallows were recorded 5 minutes after atropine administration, induced 30 seconds apart, and subjects refrained from swallowing in-between. Pressures were recorded on a computer interfaced to Polygraph ID or Polygram 98 (Medtronic Synectics, Shoreview, MN). US images were recorded on an S-VHS tape recorder using HP Sonos 100 platform (Hewlett-Packard, Watertown, MA). Pressure and US recordings were synchronized using a digital timer (Thalner Electronics, Ann Arbor, MI) that encodes analog time on the video images and an event marker on the polygraph with a 10-ms resolution. Esophageal muscle cross-sectional area (CSA) measured from the B-mode (tomographic) US images is an accurate marker of LM contraction.12Korsapati H. Babaei A. Bhargava V. et al.Asynchrony between the circular and longitudinal muscle contraction during esophageal peristalsis.Am J Physiol Gastrointest Liver Physiol. 2008; 294: G694-G698Crossref PubMed Scopus (19) Google Scholar, 13Nicosia M.A. Brasseur J.G. Liu J.B. et al.Local longitudinal muscle shortening of the human esophagus from high-frequency ultrasonography.Am J Physiol Gastrointest Liver Physiol. 2001; 281: G1022-G1033PubMed Google Scholar However, measurements of the muscle CSA on a frame-by-frame basis over prolonged periods is extremely time consuming and therefore impractical. Furthermore, because of partial drop-out in the US images at times, the CSA quantitation may not be possible. Several studies have shown an excellent correlation between the muscle CSA and muscle thickness during longitudinal muscle activity, especially during the part of esophageal contraction when there are no changes in the esophageal lumen. The latter is the case during the entire period of contraction or the manometrically recorded pressure wave.13Nicosia M.A. Brasseur J.G. Liu J.B. et al.Local longitudinal muscle shortening of the human esophagus from high-frequency ultrasonography.Am J Physiol Gastrointest Liver Physiol. 2001; 281: G1022-G1033PubMed Google Scholar, 14Miller L.S. Liu J.B. Colizzo F.P. et al.Correlation of high-frequency esophageal ultrasonography and manometry in the study of esophageal motility.Gastroenterology. 1995; 109: 832-837Abstract Full Text PDF PubMed Scopus (70) Google Scholar A recent study from our laboratory showed the validity of muscle thickness measurement as an adequate surrogate marker of the longitudinal muscle contraction.15Babaei A. Abrahao L.J. Mittal R. et al.Is muscle thickness a good surrogate for muscle cross sectional area as a parameter of longitudinal muscle contraction?.Gastroenterology. 2008; 134: 1121AGoogle Scholar For these reasons, we measured muscle thickness, rather than muscle CSA, as the marker of LM contraction in our study. For measurement of muscle thickness, B-mode US images were digitized with a frame grabber (Pinnacle Express, Mountain View, CA) interfaced to a personal computer using Adobe Premiere 6.0 (Adobe Systems, Mountain View, CA). After identifying each event on manometry, corresponding US images were acquired and converted to 32-equispaced M-mode images (every 11.25°) passing through the center of the ultrasound catheter. The M-mode images corresponding to an image plane passing orthogonally through the esophageal wall, which did not show significant echo drop-out over the study period, were selected for image analysis. The M-mode US image was time aligned with the pressure data using proprietary software programs. From the M-mode image, 2 edges, the inner edge of the CM and the outer edge of the LM, were manually detected and traced using Sigma Scan Pro (Jandel Scientific, San Rafael, CA). The distance between these 2 borders was computed in millimeters as the muscle thickness. From these plots, the duration of contraction, amplitude, and time difference between the peak pressure (maximal CM contraction) and peak muscle thickness (maximal LM contraction) were calculated. Resting muscle thickness, during a 10-second period when there were no esophageal contractions, and peak muscle thickness, at the peak of manometric pressure wave, were measured. Respiratory variations in the muscle thickness during the no-contraction period are usually within 10% of the baseline thickness.16Korsapati B.A.H. Bhargava V. Zheng W. et al.A unique pattern of longitudinal muscle contraction during transient lower esophageal sphincter relaxation.Gastroenterology. 2008; 134: 1322-1331Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar Therefore, an increase in the muscle thickness greater than 20% of the baseline thickness value was considered related to esophageal contraction. Baseline pressure was defined as the end-expiratory pressure before the onset of contraction. The onset of manometric contraction was defined at the point of the rapid upstroke on pressure wave (rate of pressure increase >40 mm Hg/s). This point usually follows the bolus pressure wave, which is the initial slow and small increase in pressure, usually 10 mm Hg above the baseline esophageal pressure. The end of pressure wave was defined as the point at which the pressure returned to the baseline value. The time lag between the peak LM and the peak CM contractions was determined for each contraction and was considered positive when LM contraction preceded CM contraction. Data are shown as mean ± SEM. All comparisons were performed by first calculating the mean value of all swallows for each parameter in a given subject, for each of the interventions, except when indicated otherwise. The Student t test was used for parametric data comparison. To determine which muscle layer contracts first, the percentage of contractions with CM first and with LM first was calculated for each subject under each condition (ie, control and after the administration of edrophonium and 2 levels of atropine). These paired percentages were compared across conditions using the nonparametric Wilcoxon matched-pairs signed-rank test. In 10 normal subjects, 50 contractions during the control period and another 50 contractions after the administration of edrophonium were analyzed. On the other hand, in the 10 NCE patients, 50 contractions during the control period, 50 after the administration of 5 μg/kg of atropine, and another 50 after administration of 10 μg/kg of atropine were scored. As expected, edrophonium caused an increase in the contraction amplitude and an increase in the contraction duration in the normal subjects. The contraction amplitude and contraction duration in the NCE patients were significantly higher than the normal subjects at baseline; atropine caused a reduction in both. Furthermore, the effects of atropine were dose-dependent; 10 μg/kg resulted in lower contraction amplitude and contraction duration as compared with 5 μg/kg (Figure 1, Figure 2).Figure 2B-mode images showing baseline thickness in control (ctrl) and after edrophonium (edr) administration in normal subjects and in NCE patients during control, after 5 μg/kg of atropine (atr5), and 10 μg/kg of atropine (atr10).View Large Image Figure ViewerDownload Hi-res image Download (PPT) Baseline muscle thickness (before swallow-induced distension), peak muscle thickness (at the peak of contraction), and durations of increase in the muscle thickness with contraction were significantly higher in the NCE as compared with normal subjects. In normal subjects, edrophonium resulted in an increase in all of the earlier-described parameters. On the other hand, in the NCE patients atropine resulted in a reduction in the baseline muscle thickness from a value of 2.56 ± 0.31 mm to 1.96 ± 0.20 mm (P < .05) after 5 μg/kg of atropine, and a further reduction to 1.73 ± 0.10 mm (P < .05) after 10 μg/kg of atropine. Atropine also caused a dose-dependent reduction in the peak muscle thickness as well as a decrease in the duration of muscle thickness increase during the swallow-induced contraction in the NCE patients (Figure 3). The US images showed that each swallow resulted in a bolus-induced distention of the esophagus, followed by collapse of the esophageal lumen and an increase in the muscle thickness. A close temporal correlation exists between the peak pressure and the peak muscle thickness during the control period in normal subjects. The mean time lag between the peak LM and the peak CM contraction was 0.03 seconds (range, −0.08 to 0.18 s) (Figures 4A and 5). The LM contraction peaks before the CM contraction peaks during a majority of the instances. After edrophonium administration, there is a disassociation between the peak pressure and the peak muscle thickness during contraction, with a mean time difference of 1.1 seconds (range, 0.2–3.4 s) (P < .001).Figure 5Graph illustrates the frequency with which muscle layer (LM or CM) peaks first during the control (ctrl) period and after administrations of edrophonium (edr) in normal subjects. Similar data are shown in NCE patients after 5 μg/kg (atr5) and 10 μg/kg (atro10) of atropine. ▫, CM first; ▪, LM first.View Large Image Figure ViewerDownload Hi-res image Download (PPT) In NCE patients there is asynchrony (disassociation) of the CM and LM contractions; the peak muscle thickness occurs earlier than the peak pressure (Figure 4B) in the control period. The mean time difference between the peak LM and CM contraction was 2.1 ± 0.5 seconds (range, 0.58–4.1 s). An atropine dose of 5 μg/kg caused a decrease in the LM and CM disassociation to 0.1 ± 0.09 seconds (range, −0.4 to 0.6 s) (P < .001). An atropine dose of 10 μg/kg resulted in reversal of the pattern of contraction of CM and LM layers with a disassociation time of −1.23 ± 0.22 seconds (range, 0.2 to −1.4 s) (P < .001) (Figure 5). Based on our previous studies, as well as the current study, the time lag between the peaks of LM and CM contractions in the control period is less than 0.2 seconds. Henceforth, we chose 0.2 seconds as a cut-off value and considered the CM and LM contractions to be simultaneous if the time lag was less than 0.2 seconds. Of the 50 contractions analyzed in the normal subjects during the control period, 42 (84%) were simultaneous; in 2 contractions the CM peaked first and in the remaining 6 the LM contraction peaked first (Figure 6). In normal subjects, after edrophonium administration, the LM peaked earlier (P < .005) than the CM peaked in 48 of 50 contractions and in the remaining 2 they were simultaneous. In NCE patients, of the 50 contractions analyzed in the control period the LM contraction peaked first in all instances. After 5 μg/kg of atropine, during 22 (44%) contractions the LM and CM contractions were simultaneous, during 13 (26%) the CM peaked earlier than the LM, and in the remaining 15 (30%) (P < .05) the LM contraction peaked first. After administration of 10 μg/kg of atropine, during 13 (26%) contractions the LM and CM contractions were simultaneous, during 31 (62%) the CM peaked earlier than the LM, and in the remaining 6 (12%) the LM contraction peaked first (P < .005). In summary, our data showed that edrophonium causes an increase in the amplitude and duration of CM and LM contractions in normal subjects. On the other hand, in patients with NCE, who show high baseline and peak muscle thickness during high-amplitude contraction, atropine causes a reduction in all of the CM and LM contraction parameters in a dose-dependent fashion. During swallow-induced peristalsis, the peak of CM and LM contractions occurs synchronously in normal subjects and edrophonium causes a disassociation between the 2 peaks, with the peak of LM contraction occurring earlier than that of the CM. Finally, patients with NCE show disassociation between the peak LM and CM contractions in the baseline state. Atropine decreases the disassociation between CM and LM contractions in NCE patients in a dose-dependent fashion. Several investigators have studied the coordination between CM and LM of the esophagus during peristalsis and found that the LM contraction starts earlier and lasts longer than the CM contraction, but the peak of contractions of the 2 muscle layers occur at the same time.13Nicosia M.A. Brasseur J.G. Liu J.B. et al.Local longitudinal muscle shortening of the human esophagus from high-frequency ultrasonography.Am J Physiol Gastrointest Liver Physiol. 2001; 281: G1022-G1033PubMed Google Scholar, 17Sugarbaker D.J. Rattan S. Goyal R.K. Swallowing induces sequential activation of esophageal longitudinal smooth muscle.Am J Physiol. 1984; 247: G515-G519PubMed Google Scholar, 18Pouderoux P. Lin S. Kahrilas P.J. Timing, propagation, coordination, and effect of esophageal shortening during peristalsis.Gastroenterology. 1997; 112: 1147-1154Abstract Full Text PDF PubMed Scopus (105) Google Scholar A recent study from our laboratory, however, found that the 2 muscle layers are coordinated precisely with regards to the onset, peak, and end of contractions in normal subjects.8Mittal R.K. Padda B. Bhalla V. et al.Synchrony between circular and longitudinal muscle contractions during peristalsis in normal subjects.Am J Physiol Gastrointest Liver Physiol. 2006; 290: G431-G438Crossref PubMed Scopus (65) Google Scholar The difference between our study and the other studies is related to the techniques used to measure the LM and CM contractions, and in the definition of the onset of CM contraction. If one defines the onset of CM contraction at the time of onset of lumen collapse of the esophagus after esophageal distension, as opposed to the onset of pressure wave recorded by manometry, the onset of CM and LM contractions is indeed simultaneous. Our data suggest that manometry actually misses a part of the CM contraction, both at the beginning and at the end of the pressure wave, which we believe is the reason for an apparent earlier onset and longer duration of the LM contraction as compared with the CM contraction. With regards to the peak of contraction, there is general consensus that the CM and LM contractions peak at the same time. It is interesting that during peristalsis the LM and CM contractions in the guinea pig colon also are synchronous.19Spencer N.J. Smith T.K. Simultaneous intracellular recordings from longitudinal and circular muscle during the peristaltic reflex in guinea-pig distal colon.J Physiol. 2001; 533: 787-799Crossref PubMed Scopus (81) Google Scholar, 20Spencer N.J. Bayguinov P. Hennig G.W. et al.Activation of neural circuitry and Ca2+ waves in longitudinal and circular muscle during CMMCs and the consequences of rectal aganglionosis in mice.Am J Physiol Gastrointest Liver Physiol. 2007; 292: G546-G555Crossref PubMed Scopus (40) Google Scholar NCE, a form of primary motor disorder of the esophagus, is characterized by high-amplitude, peristaltic contractions (as recorded by intraluminal pressure recording) of the esophagus. These patients frequently present with symptoms of intermittent chest pain (noncardiac chest pain) and intermittent mild dysphagia. Ultrasound imaging of the esophagus documents that NCE patients have thicker esophageal muscles, both circular and longitudinal layers, as compared with normal subjects. This increased muscle thickness is present both at baseline as well as at the peak of peristaltic contractions.21Pehlivanov N. Liu J. Kassab G.S. et al.Relationship between esophageal muscle thickness and intraluminal pressure: an ultrasonographic study.Am J Physiol Gastrointest Liver Physiol. 2001; 280: G1093-G1098PubMed Google Scholar, 22Melzer E. Ron Y. Tiomni E. et al.Assessment of the esophageal wall by endoscopic ultrasonography in patients with nutcracker esophagus.Gastrointest Endosc. 1997; 46: 223-225Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, 23Mittal R.K. Kassab G. Puckett J.L. et al.Hypertrophy of the muscularis propria of the lower esophageal sphincter and the body of the esophagus in patients with primary motility disorders of the esophagus.Am J Gastroenterol. 2003; 98: 1705-1712Crossref PubMed Scopus (58) Google Scholar The precise reason for thicker muscles in NCE is not known but muscle hypertrophy and an increase in the baseline tone of the LM are the 2 possibilities. We found that in normal subjects edrophonium increased the baseline muscle thickness, proving that an increase in the cholinergic tone can cause an increase in the baseline muscle thickness. In an earlier study we found that atropine reduced the baseline muscle thickness from 1.47 ± 0.16 mm to 1.33 ± 0.1 mm in normal subjects.12Korsapati H. Babaei A. Bhargava V. et al.Asynchrony between the circular and longitudinal muscle contraction during esophageal peristalsis.Am J Physiol Gastrointest Liver Physiol. 2008; 294: G694-G698Crossref PubMed Scopus (19) Google Scholar In the present study we found that in NCE patients, who have a greater muscle thickness at baseline (2.5 mm), an atropine dose of 10 μg/kg reduced it to 1.75 mm. The reduction in the muscle thickness with atropine is greater in NCE patients as compared with normal subjects, which suggests a higher cholinergic activity in the baseline state in NCE patients. On the other hand, a higher muscle thickness after atropine injection in NCE, as compared with normal, subjects may represent esophageal muscle hypertrophy. Therefore, we propose that an increase in esophageal muscle thickness in NCE is related to both (1) an increase in longitudinal muscle tone and (2) muscle hypertrophy. We speculate that esophageal muscle hypertrophy in NCE is in response to chronic outflow obstruction related to a defect in the relaxation or opening function of the lower esophageal sphincter.24Mittal R.K. Liu J. Puckett J.L. et al.Sensory and motor function of the esophagus: lessons from ultrasound imaging.Gastroenterology. 2005; 128: 487-497Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar In an earlier study, we observed that patients with NCE show an asynchrony of LM and CM layer contractions during peristalsis.11Jung H.Y. Puckett J.L. Bhalla V. et al.Asynchrony between the circular and the longitudinal muscle contraction in patients with nutcracker esophagus.Gastroenterology. 2005; 128: 1179-1186Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar Even though the onset of contraction of the CM and LM layers in NCE is same, the peak of LM contraction occurs earlier than the peak of CM contraction. We observed that edrophonium, an acetyl-cholinesterase inhibitor, which increases the availability of acetylcholine at the neuromuscular junction, induces discoordination between the contractions of 2 muscle layers of the esophagus in normal subjects.12Korsapati H. Babaei A. Bhargava V. et al.Asynchrony between the circular and longitudinal muscle contraction during esophageal peristalsis.Am J Physiol Gastrointest Liver Physiol. 2008; 294: G694-G698Crossref PubMed Scopus (19) Google Scholar The discoordination induced by edrophonium in normal subjects is somewhat similar to what is observed in NCE patients in the baseline state (ie, the LM contraction peaks earlier than the CM contraction peak). The major finding of the present study is that atropine reverses the asynchrony of contraction of the CM and LM layers in NCE patients. The effects of atropine on the LM and CM asynchrony are dose dependent and in fact a higher dose caused the CM to contract before the LM during a significant number of instances, similar to what we observed in normal subjects. We propose that excessive cholinergic activity can explain several findings in NCE patients (ie, an increase in the contraction amplitude, an increase in the contraction duration of the pressure waves, and asynchrony of contractions of the CM and LM layers). One may argue that a hypercholinergic state cannot explain contraction amplitudes of greater than 200 mm Hg seen in NCE patients because edrophonium rarely caused such contraction amplitude in normal subjects. We believe that the muscle hypertrophy as well as possible decrease in the nitrinergic innervation of the esophagus also may play significant roles in the pathogenesis of high-amplitude contractions of NCE. A possible limitation of our study was that the analysis was not blinded. However, it is extremely difficult to incorporate bias in the data analysis because of the following reasons: (1) during the image analysis the pressure data were unknown to the operator; and (2) during analysis of ultrasound data, both CM and LM edges were drawn manually to estimate wall thickness. Synchrony between LM and CM could be defined only after temporally aligning the muscle thickness and pressure data using a real-time clock signal. What is the physiologic relevance of synchrony and asynchrony of contractions of the 2 muscle layers in the normal and diseased state, respectively? It is proposed that the LM contraction brings together the rings of CM and hence increases the effectiveness of CM contraction.17Sugarbaker D.J. Rattan S. Goyal R.K. Swallowing induces sequential activation of esophageal longitudinal smooth muscle.Am J Physiol. 1984; 247: G515-G519PubMed Google Scholar Furthermore, increase in the muscle thickness caused by LM contraction decreases the stress on the esophageal wall, in accordance with Laplace's law.9Pal A. Brasseur J.G. The mechanical advantage of local longitudinal shortening on peristaltic transport.J Biomech Eng. 2002; 124: 94-100Crossref PubMed Scopus (63) Google Scholar, 10Puckett J.L. Bhalla V. Liu J. et al.Oesophageal wall stress and muscle hypertrophy in high amplitude oesophageal contractions.Neurogastroenterol Motil. 2005; 17: 791-799Crossref PubMed Scopus (22) Google Scholar Asynchrony of contraction of the 2 muscle layers increases the stress on the esophageal wall because the site of pressure increase and the site of muscle thickening in the esophagus are not at the same location (Figure 7). We propose that an increase in wall stress may play a role in the formation of esophageal diverticulum and it is interesting that the latter is seen in association with NCE.25Dodds W.J. Stef J.J. Hogan W.J. et al.Radial distribution of esophageal peristaltic pressure in normal subjects and patients with esophageal diverticulum.Gastroenterology. 1975; 69: 584-590PubMed Google Scholar, 26Nehra D. Lord R.V. DeMeester T.R. et al.Physiologic basis for the treatment of epiphrenic diverticulum.Ann Surg. 2002; 235: 346-354Crossref PubMed Scopus (128) Google Scholar We did not examine for the presence of esophageal diverticulum in our NCE patients, but future studies may investigate if asynchrony of LM and CM contraction is indeed responsible for the esophageal diverticula seen in these patients as well as in patients with diffuse esophageal spasm and achalasia of the esophagus. Finally, our findings may have implications in explaining symptoms of NCE patients; however, we did not study the relationship between asynchrony of contraction of the 2 muscle layers and esophageal chest pain. This Month in GastroenterologyGastroenterologyVol. 135Issue 3PreviewThe “nutcracker esophagus” is an esophageal motility disorder characterized by the occurrence of high-amplitude peristaltic contractions in the distal esophagus with a normally relaxing lower esophageal sphincter. Most commonly occurring in patients with chest pain of noncardiac origin, the pathogenesis of nutcracker esophagus is unknown, but excessive cholinergic activity and muscle hypertrophy have been implicated. Conventional esophageal manometry is limited to the assessment of circular muscle contractions, but the use of intraluminal ultrasound allows detection of longitudinal muscle contractions as a thickening in cross-sectional area. Full-Text PDF" @default.
• W2106164003 created "2016-06-24" @default.
• W2106164003 creator A5000525091 @default.
• W2106164003 creator A5046055402 @default.
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• W2106164003 date "2008-09-01" @default.
• W2106164003 modified "2023-10-11" @default.
• W2106164003 title "Reversal of Asynchrony Between Circular and Longitudinal Muscle Contraction in Nutcracker Esophagus by Atropine" @default.
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