T1884 High Resolution Manometry Improves Transient Lower Esophageal Relaxations (TLESRs) Detection in Healthy Volunteers

AGA Abstracts

23 healthy subjects (11 women; mean age 23; range 20-26 yr), secondary peristalsis was generated by slow and rapid mid-esophageal injections of air after a baseline recording of esophageal motility. The effects on secondary peristalsis were examined before and after direct esophageal pretreatment with either 15-ml lidocaine (n = 13) or capsaicin-containing red pepper sauce (capsaicin, 0.84 mg)(n = 10). One additional session to generate secondary peristalsis was performed before and after pretreatment with 15-ml saline in all subjects (n = 23). Results: Infusion of capsaicin significantly increased pressure wave amplitude during rapid (P = 0.002) and slow air infusions (P= 0.01). After capsaicin, the threshold volume to generate secondary peristalsis was significantly decreased during rapid (P < 0.05) and slow air infusions (P = 0.02). After lidocaine infusion, the threshold volume to generate secondary peristalsis was significantly increased during rapid (P = 0.001), but not slow air infusions (P = NS). Infusion of lidocaine did not alter any pressure wave amplitude or duration during rapid and slow air infusions (P = NS). Secondary peristalsis was triggered less often in response to rapid air distension after lidocaine infusion (P = 0.001). Infusion of saline did not affect any parameters of secondary peristalsis during rapid or slow air infusion. Conclusions: The acute administration of capsaicin appears to enhance esophageal sensitivity and facilitate secondary contractility in response to esophageal distension, suggesting the involvement of vanilloid receptor 1 in the modulation of esophageal secondary peristalsis in humans. Selectively inhibitory effect of lidocaine on the triggering of secondary peristalsis presents during acute esophageal distension, indicating that sensory part of secondary peristalsis is probably mediated by lidocaine-sensitive mechanoreceptors. However, lidocaine does not alter any motility change in secondary peristalsis as induced by either slow or rapid air infusion.

data developed & analyzed to determine LES lift during swallow-induced LES relaxation, complete & incomplete transient LES relaxations. Results: Satisfactory recordings were obtained for 16 hours (data recorder memory limit) in all subjects. LES relaxation & lift could be easily visualized during the entire recording periods. LES lift was very small (approximately 2mm) in association with swallows. LES lift could not be detected during complete transient LESRs because once LES is completely relaxed LES location/lift can't be determined. On the other hand, LES lift was consistently seen with incomplete TLESRs (n= 80). The amount of LES lift ranged from 6 - 12 mm (mean = 7.6 + 1.4 mm). Conclusion: Our study shows the feasibility of prolonged ambulatory HRM. LES lift during incomplete TLESRs suggests a possible cause & effect relationship between LM contraction and LES relaxation. Using prolonged ambulatory HRM, future studies may investigate the temporal correlation between abnormal LM contraction/spasm & esophageal symptoms.

T1880 Esophageal Emptying and Longitudinal Muscle Contraction in Patients With Achalasia as Defined by High Resolution Manometry, High Frequency Ultrasound (Hfus) and Impedance Su Jin Hong, Valmik Bhargava, Debbie J. den Boer, Ravinder K. Mittal Background: Achalasia esophagus is characterized by loss of peristalsis and incomplete esophagogastric junction (EGJ) relaxation that results in poor esophageal emptying. Aims: To assess mechanism of esophageal emptying in achalasia esophagus using simultaneous high resolution manometry (HRM), high frequency ultrasound imaging (HFUS) and multiintraluminal impedance (MII). Methods: 14 patients with achalasia esophagus were categorized into 3 subtypes based on the esophageal response to swallows, type 1 and type 2 simultaneous pressure waves of < and > 30mmHg respectively, and type 3 - spastic simultaneous esophageal contractions. Results: Predominant HRM achalasia pattern, i.e., type 2 (n= 7) was characterized by a unique motor pattern that consists of upper esophageal sphincter contraction, simultaneous esophageal pressure wave(common cavity)and EGJ contraction following swallows (Figure). HFUS identified longitudinal muscle contraction that was stronger at 2 cm as compared to 10 cm above the EGJ with common cavity pressure waves. MII revealed that esophageal emptying occurred intermittently (48% swallows) during periods of common cavity pressure waves in type 2 achalasia. Type 1 (n=2) and type 3 (n= 4) achalasia patients show no emptying and emptying with majority of swallows respectively. Longitudinal muscle contraction was markedly reduced in type 1 and dis-coordinated in type 3 achalasia. Conclusion: Emptying in achalasia esophagus is the result of swallowinduced longitudinal muscle contraction of distal esophagus that increases esophageal pressure and creates favorable pressure gradient for emptying. Longitudinal muscle contraction patterns are different in 3 achalasia subtypes.

T1883 Upper Esophageal Sphincter Relaxation as a Determinant of Reflux and Symptoms During Transient Lower Esophageal Sphincter Relaxation (TLESR)? Sabine Roman, Anita Fareeduddin, John E. Pandolfino, Monika A. Kwiatek, Peter J. Kahrilas Backgrounds & Aims Reflux events may or may not be symptomatic. Features that have been associated with symptoms during reflux are the nadir pH and proximal extent of the reflux as determined by ambulatory pH-impedance monitoring. TLESR is a major mechanism of reflux and upper esophageal sphincter relaxation (UESR) often occurs in association with TLESR (Pandolfino JE,NGM 2007;19:203). We hypothesized that the proportion of TLESRs associated with symptoms is under-reported and that UESR during TLESR is a determinant of both the occurrence and quality of associated symptoms. Patients and methods Eight GERD patients (7 females, mean age 40 years, range 22-66) underwent stationary high resolution impedance manometry (HRIM) combined with esophageal pH-impedance monitoring for 3 hours after the patient consumed his most refluxogenic meal. The HRIM assembly had 36 pressure sensors at 1 cm spacing and 12 impedance segments at 2 cm spacing (Sierra). Reflux was defined by impedance using the criterion of a retrograde 50% drop in impedance propagating at least 2 impedance segments proximal to the LES. Studies were monitored by an investigator and subjects were queried for symptoms both randomly and when the investigator observed manometric or reflux events. TLESRs and UESRs were scored by an investigator blinded to the occurrence of symptoms. Data were expressed as mean (± SD). Chi-square and Kruskall Wallis statistical tests were used. Results 163 TLESRs were detected (median 11.5 per patient, range 4-83), 133 (82%) of these were associated with symptoms (regurgitation 60, belch 36, heartburn 17, pressure 15, gas 7) and 128 (79%) with reflux (99 acid). Symptoms and UESR occurred more frequently when TLESRs were associated with reflux (85% vs 69%, p=0.046; 87% vs 40%, p<0.01 respectively). UESR occurred with 125 TLESRs (77%); 82% of symptomatic TLESRs and 53% of asymptomatic ones (p<0.01). UESR strongly correlated with reflux to the most proximal impedance segment(p<0.01). Belch and regurgitation were the symptoms most frequently associated with UESR (100% and 87% respectively) whereas heartburn was less frequently associated (47%)(p<0.01). Mean UESR duration was 0.92 s (±0.78) in the symptomatic TLESRs and 0.61 s (±0.35) in the asymptomatic (p=0.06). The longest UESR durations were observed with belch (1.43s(±1.13)) and regurgitation (0.69s(±0.34)). Conclusion Most TLESRs were symptomatic with UESR being a significantly determinant of both symptom occurrence and quality. Longer duration UESR may be indicative of increased gastroesophageal flow of gas and/or liquid as suggested by its correlation with the proximal extent of reflux, belching, and regurgitation.

T1882 T1884

Prolonged Ambulatory High Resolution Manometry: Methodology to Detect Longitudinal Muscle Contraction of the Esophagus Anna M. Karstens, Valmik Bhargava, Thuy Anh T. Le, Ravinder K. Mittal

High Resolution Manometry Improves Transient Lower Esophageal Relaxations (TLESRs) Detection in Healthy Volunteers Sabine Roman, Frank Zerbib, Kafia Belhocine, Stanislas Bruley des Varannes, Francois Mion

Introduction: Longitudinal muscle (LM) comprises approximately half of the muscle mass of the esophagus, yet its role in health & disease is not clear, because LM contraction is tedious to study. Lower esophageal sphincter (LES) lift seen on high resolution manometry (HRM) is a possible surrogate marker of the LM contraction Aim: The goal of our study was to determine, 1; the feasibility of prolonged ambulatory HRM and 2; to detect LES lift during transient LES relaxation as a surrogate of LM contraction. Methods: We studied 8 healthy normal volunteers using a custom designed HRM catheter equipped with 16 solidstate pressure transducers, located 1 cm apart. Catheter was placed such that the 2 most distal pressure sensors were in the stomach & remainder straddled the distal esophagus & LES. Recording were performed in the ambulatory setting of subject's home environment using a 16 channel recorder. Data were recorded at 8Hz. Color contour plots of pressure

AGA Abstracts

Backgrounds & Aims TLESRs represent the main motor event associated with the occurrence of gastro-esophageal reflux episodes. However, as LES is moving, detecting TLESRs is difficult and deserves the use of manometric probes fitted out with a sleeve. Very close multiple pressure transducers as in probes used in HRM might facilitate the detection of TLESRs. The aim of this study was to compare manometric sleeve and HRM in detecting TLESRs. Subjects and methods Fifteen healthy volunteers (7 males, mean age 28 years, range 2155) were included. All subjects underwent HRM combined with Dentsleeve and HRM alone in a random order. Examinations were separated by 2 to 7 days. Esophageal LES pressure was monitored 1-hour fasting and 2 hours after a liquid meal (400 ml, 600 kCal, 30%

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occurs as a consequence of hydrostatic emptying in the sitting position reclassifying Type II patients as Type I. Although there was good overall agreement in diagnosis between postures, supine studies were more sensistive in the detection of achalasia. Agreement in Achalasia Subtypes Categorization

AGA Abstracts

lipids). TLESRs were detected according to the criteria described by Holloway (Am J Physiol 1995). Dentsleeve tracings and HRM spatio-temporal plots obtained during combined recordings were reviewed independently first, and then simultaneously. The concordance rate between the 2 examinations was assessed using kappa coefficient (95% confidence interval). To study inter observer agreement with kappa coefficient, 2 investigators reviewed independently Dentsleeve examinations and HRM recordings performed alone. Results Combined recordings were available in 14 subjects. Three hundred and forty six independent TLESRs were detected (190 with Dentsleeve vs 256 with HRM, p=0.054, paired t test for the number of TLESRs per subject). One hundred TLESRs (29%; median per subject 27%, range 6-100) were detected by both techniques giving a kappa concordance rate of 0.42 (0.35-0.49). After simultaneous review of both tracings, 238 (69%; median per subject 70%, range 35100) were detected by both examinations. For the 5 subjects with a concordance rate of less than 70 %, we observed 4 intra-gastric sleeve migrations after the meal (corresponding to esophageal shortening on HRM), and 1 abnormal pressure signal at the level of the sleeve. Inter observer agreement was evaluated in 15 patients. Investigator 1 detected significantly more events than investigator 2 with Dentsleeve (222 vs 127 events, p<0.01) but not with HRM (239 events detected by each investigator, p > 0.05). The inter observer agreement was fair with Dentsleeve (kappa = 0.37 (0.28-0.45)) whereas it was substantial with HRM (kappa = 0.83 (0.79-0.87)). Conclusion HRM is more sensitive than Dentsleeve to detect TLESRs during prolonged LES pressure monitoring. In addition a better inter-observer agreement was obtained with HRM. Altogether, these results suggest that HRM should become the gold standard for detecting TLESRs.

T1887 High Resolution Esophageal Topography is Superior to Conventional Sleeve Manometry for the Detection of TLESRs Associated With Reflux Wout Rohof, David P. Hirsch, Guy E. Boeckxstaens AIM: Transient lower esophageal sphincter relaxations (TLESRs) are the main mechanism underlying gastro-esophageal reflux and are detected during manometric studies using well defined criteria. Until recently, water perfused sleeve manometry was considered the gold standard to detect TLESRs. Recently, high-resolution esophageal pressure topography (HREPT) has been introduced and is now considered the new standard to study esophageal and lower esophageal sphincter (LES) function. To what extent this technique using the isocontour or Clouse plot mode is superior to depict TLESRs remains to be studied. In the present study we performed a head-to-head comparison between HREPT and conventional manometry for the detection of TLESRs. METHODS: A setup with two parallel synchronized MMS-solar systems was used. A solid state HREPT catheter, a water perfused sleeve catheter and a multi intraluminal impedance pH (MII-pH) catheter were positioned in ten healthy volunteers (M6F4, age 19-56). Subjects were studied 0.5hr before and 3hrs after ingestion of a standardized meal. Tracings were blinded and analyzed by the three authors according to the modified TLESR criteria presented at the DDW2008. Sleeve manometry criteria were applied to HREPT, with an exception for the relaxation rate, which cannot be determined in HREPT. A TLESR was scored when there was agreement between at least two out of the three investigators. RESULTS: In the HREPT mode 157 TLESRs were scored, versus 143 with the sleeve manometry (P=0.08). 123 TLESRs were scored by both techniques. Of all TLESRs (177), 131 were associated with reflux (74%). HREPT detected significantly more TLESRs with reflux (126 vs 113, P=0,011, McNemar test) resulting in a sensitivity of 96% compared to 86% respectively. Analysis of the discordant TLESRs with reflux showed that TLESRs were missed by sleeve manometry due to low basal LES pressure (N=4), unstable pharyngeal signal (N=4) and residual sleeve pressure > 2mmHg (N=10). This high residual sleeve pressure is explained by the axial movement of the gastric sleeve after esophageal shortening, when the LES is fully relaxed (N=10). Inter-observer variability for HREPT is comparable to sleeve manometry (Κ=0,59 (P=0,066) vs Κ=0,69 (P=0,053)). CONCLUSION: HREPT is superior to conventional sleeve manometry for the detection of TLESRs associated with reflux.

T1885 TRPV1 Induced CA2+-Dependent Production of Platelet Activating Factor (PAF) in Human Esophageal Epithelial Cells Jie Ma, Karen M. Harnett, Jose Behar, Piero Biancani, Weibiao Cao The transient receptor potential channel, vanilloid subfamily member-1 (TRPV1), is a cation channel expressed by several cell types including human esophageal epithelial cells (HET1A). TRPV1 receptors are activated by acids, heat and by the selective agonist capsaicin. Thus TRPV1 receptors in esophageal epithelium may be activated by acid reflux. TRPV1 receptors were identified in HET-1A cells by RT-PCR, and by Western blot. In Fura-2AM loaded cells capsaicin caused a 4-fold cytosolic calcium increase, supporting a role of TRPV1 as a cation channel in these cells. Capsaicin caused a 12-fold increase in PAF, an important inflammatory mediator that acts as a chemoattractant and activator of immune cells. The increase was reduced by the p38 MAP kinase (p38) inhibitor SB203580, by the cytosolic phospholipase A2 (cPLA2) inhibitor AACOCF3 and by the lyso-PAF acetyltransferase inhibitor sanguinarin, indicating that capsaicin-induced PAF production may be mediated by activation of cPLA2, p38 and lyso-PAF acetyltransferase. To establish a sequential signaling pathway, we examined the phosphorylation of p38 and cPLA2 by Western blot. Capsaicininduced p38 phosphorylation was not affected by AACOCF3. Conversely, capsaicin-induced cPLA2 phosphorylation was blocked by SB203580, indicating that capsaicin-induced PAF production depends on sequential activation of p38 and cPLA2. To investigate how p38 phosphorylation may result from TRPV1 mediated calcium influx we examined a possible role of calmodulin kinase. P38 phosphorylation was stimulated by the calcium ionophore A23187 and by capsaicin and the response to both agonists was reduced by a calmodulin inhibitor and by calmodulin kinase II (CAMKII) inhibitors, indicating that calcium induced activation of calmodulin and CAMKII results in P38 phosphorylation. AcetylCoA transferase activity increased in response to capsaicin and was inhibited by SB203580 indicating that P38 phosphorylation in turn causes activation of acetylCoA transferase to produce PAF. Thus in epithelial cells production of PAF in response to TRPV1 is mediated by calcium elevation, activation of CAMKII, phosphorylation of p38, and p38-induced activation of cPLA2 and lyso-PAF acetyltransferase, to produce PAF. As PAF is a potent phospholipid mediator of many leukocyte functions, its activation in esophageal epithelial cells may play an important role in the pathophysiology of inflammatory disorders in the esophagus. Supported by NIDDK RO1 57030

T1888 Reproducibility of Esophageal High-Resolution Manometry Auke Bogte, Albert J. Bredenoord, Jac Oors, Peter D. Siersema, André Smout Background: Esophageal high-resolution manometry (HRM) measurement is a novel method for esophageal functional testing that has prompted the development of new parameters for quantitative analysis of the recordings. The reproducibility of the findings made with esophageal HRM has not yet been tested. Aim: To investigate the reproducibility of HRM of the esophagus. Methods: Twenty healthy volunteers underwent HRM on two separate days. LES, UES and gastric pressure, contraction amplitudes, integrated relaxation pressure during 4 seconds (IRP4), distal contractile integral (DCI), intrabolus pressure (IBP), contractile front velocity (CFV), and transition zone (TZ) length were measured. For each variable, the mean percentage of covariation (%COV) of the 20 observations of the first measurement and the 20 observations of the second measurement was calculated as 100 x SD / mean. An overall mean %COV was derived as a measure of inter-individual variation. The overall mean %COV calculated from the values in the same subject on the two measurements was calculated as a measure of intra-individual variation. As a second measure for reproducibility, Kendall's coefficients of concordance (W values) were calculated. Results: For most parameters, the intra-individual %COV was at least 25% smaller than the inter-individual %COV, indicating lower variability within subjects than between subjects. W-values were above 0.5 for all parameters. Statistically significant concordance values and lowest intra-individual %COVs were found for UES pressure (W=0.90, p=0.02), transition zone length (W=0.92, p=0.01), LES pressure (W=0.84, p=0.03) and gastric pressure (W=0.81, p=0.04). In addition, contraction amplitude 5 cm above the LES was also reproducible (W=0.86, p=0.03). Concordance values for DCI, IBP, IRP4, and CFV did not reach levels of statistical significance. Conclusion: In esophageal HRM, parameters that represent anatomic landmarks, such as the TZ length, gastric pressure and UES and LES pressures, show better reproducibility than contraction wave parameters. The limited reproducibility of the latter should be taken into account when borderline findings are made during HRM.

T1886 The Effect of Body Posture on Esophageal Pressure Topography Subtypes in Achalasia Sean T. McCarthy, Eric Leslie, Peter J. Kahrilas, Monika A. Kwiatek, Daniel Luger, John E. Pandolfino Background: Achalasia has been categorized into three subtypes based on esophageal body pressure patterns observed using High-Resolution Esophageal Pressure Topography (HREPT). This study aimed to determine if body posture during the HREPT study alters the subtype categorization. Methods: HREPT studies of 65 consecutive achalasia patients were done with both supine and upright swallows and analyzed using ManoView software. All patients had abnormal esophagogastric junction relaxation with an elevated 4 second integrated relaxation pressure (IRP) in the supine position (>15 mmHg). Patients were categorized as type I (absent peristalsis with minimal esophageal pressurization), II (compression with panesophageal pressurization) or III (spastic) based on previous definitions [Gastroenterology. 2008 Nov;135(5):1526-33]. The effect of posture on diagnosis and subtype classification was analyzed to determine agreement and discordance between the supine and sitting positions. 12 mmHg was used as the upper limit of normal for the IRP in the sitting position. Results: The achalasia subtype distribution in the supine position was: Type I, 7.6% (n=5) Type II, 73.8% (n=48) and Type III, 18.4% (n=12). The agreement in diagnosis for achalasia subtype between the supine and upright position was 71% (46/65) (Table). The majority of the discordance (20%) occurred as a consequence of 13 subtype II patients converting to a Type I pattern in the sitting position. Two Type II patients exhibited spastic contractions in the sitting position and 2 Type III patients failed to exhibit spasm in the sitting position. In addition, 2 patients had a normal IRP in the sitting position (<12 mmHg) causing them to not meet criteria for achalasia and instead be classified as absent peristalsis. Both of these patients were subsequently treated as achalasia and responded to pneumatic dilation. Conclusions: HREPT diagnostic criteria for achalasia and achalasia subtype are affected by body posture. Most of the discrepancy between diagnoses in the supine and sitting position

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AGA Abstracts