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Keywords:

  • common cavity;
  • distal reflux;
  • high-resolution manometry;
  • impedance;
  • proximal reflux;
  • transient lower esophageal sphincter relaxation

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author Contributions
  9. Conflict of interests
  10. References

Background  Factors that determine the spread of gastro-esophageal reflux (GER) along the length of the esophagus are not known. We investigated if cardiovascular (CV) compressions on the esophagus may determine the spread of refluxate into the proximal esophagus.

Methods  High-resolution manometry (HRM) and multi-channel intra-luminal impedance recording (MIIR) were performed simultaneously in 10 normal subjects in the recumbent and upright positions. Pulsatile pressure increases on the esophagus (marker of CV compression) were identified on the HRM. Spread of refluxate into the esophagus was determined by the MIIR.

Key Results  Cardiovascular compression zones were observed in the esophagus in 9 out of 10 subjects in recumbent position. Forty percent of GER episodes were limited to the distal esophagus in the recumbent position and CV compression pressure was greater than distal esophageal pressure at the time of GER in all such cases. On the other hand, distal esophageal pressure was greater than CV compression pressure when the refluxate extended into the proximal esophagus. In the upright position, CV compression was less frequent than recumbent position and only 12% of GER episodes were limited to the distal esophagus.

Conclusions & Inferences  Cardiovascular compression of the esophagus is frequently observed in normal healthy subject and restricts the spread of refluxate into the proximal esophagus.


Abbreviations:
CC

common cavity

CV

cardiovascular

GER

gastro-esophageal reflux

TLESR

transient lower esophageal relaxation

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author Contributions
  9. Conflict of interests
  10. References

It is clear that reflux esophagitis is caused by increased duration of mucosal contact with noxious reflux contents, especially acid. The genesis of heartburn symptom and its relationship to gastro-esophageal reflux (GER) episodes, on the other hand, is not clear. For example, it is not known why only a small fraction of all acid reflux episodes are associated with heartburn symptom. Weusten et al. found that acid reflux with higher proximal extent were more likely to be associated with heartburn1,2; similar findings have been reported with weakly acidic reflux.3,4 Furthermore, it appears that in non-erosive reflux disease, proximal esophagus is more sensitive to reflux contents than distal esophagus.3,5 Along similar lines, in patients with reflux laryngitis, more reflux episodes extend to proximal esophagus at night as compared to patients without laryngitis.6–8 Therefore, the study of factors that determine proximal spread of refluxed contents is highly relevant. Physical properties of the reflux contents, i.e., viscosity,9 volume, presence of gas,10 posture/gravity,10 gastroesophageal pressure gradient,11 compliance of gastroesophageal junction12 and distal esophageal tone13,14 have been implicated as possible factors that may determine spread of reflux along the esophagus.

Cardiovascular compression (CV) of the esophagus is commonly observed during clinical esophageal manometry studies. Stagias et al. reported that approximately 20% of manometry records demonstrate CV high pressure zone along the length of esophagus.15 Dysphagia in association with CV compression of the esophagus has been described by several authors but is uncommon.16,17 In our studies of esophagus with high-resolution manometry (HRM) and multi-channel intra-luminal impedance recording (MIIR), we observed that GER episodes restricted to distal esophagus were trapped below the CV compression sites. Therefore, the goal of our study was to determine the relationship between CV compression and spread of GER in the esophagus in a systematic fashion.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author Contributions
  9. Conflict of interests
  10. References

Study population, protocol and a portion of the data in the current article have been used in a prior publication18 where we investigated the effect of posture and reflux contents on the upper esophageal sphincter response. However, the data presented in the current article investigate a different issue, i.e., compartmentalization of esophagus by the CV compression and spread of reflux in the esophagus.

Study protocol

Ten healthy subjects (34 ± 10 years, four males) participated in the study. The ‘Human Investigation Committee of University of California San Diego’ approved the study protocol and each subject signed an informed written consent before enrollment into the study. Subjects had no history of gastrointestinal, cardiovascular and respiratory disorders, and they were not taking any acid suppressive, antihypertensive, bronchodilator and cardiac medications. Following 6 h fast and local lidocaine application to the nose and throat, a 4.2 mm diameter, solid-state HRM catheter equipped with 36 circumferential pressure sensors, spaced 1 cm apart (Sierra Scientific, Los Angeles, CA, USA) was placed into the esophagus and stomach in such a fashion that at least three distal sensors were positioned in the stomach. A 1.5 mm diameter Comfortec MII-pH probe (Sandhill Scientific, Highlands Ranch, CO, USA) was placed via the same nostril as the HRM catheter and positioned such that the impedance electrodes were located at 2, 4, 6, 8, 10, 14, 16 and 18 cm above the LES to record esophageal impedance at 3, 5, 7, 9, 15, 17 cm and pH at 5 cm above the upper border of the LES.

Following catheters placement, subjects ate a standard 1000 kcal meal and were asked to lie in the right recumbent position for 1 h. Subjects then changed their position to upright and recordings were obtained for an additional hour. All pressure measurements were recorded on the Sierra Scientific System at 35 Hz frequency. All impedance-pH measurements were recorded on a Sandhill Scientific System (Denver, CO, USA) at 30 Hz frequency. Manometry and pH-impedance data were synchronized using hand-inserted bookmarks to temporally align the physiological signals. We determine that the difference with hand-inserted markers on the two machines is at the most 0.03 s (one hundred trials) and with sampling rate of 30 and 35 Hz in two recorders the maximum difference can be 0.030 + 0.033 + 0.029 = 0.092. Hence, the time resolution for the identification of pressure and impedance events based on the frequency of data collection and synchronization was less than 0.1 s.18

Pressure data analysis

All pressures were measured in reference to the atmospheric pressure. Transient lower esophageal relaxations were identified using previously published criteria19 adapted for the HRM. The LES and UES pressures were measured with the electronic sleeve function of the Manoview software program (Sierra Scientific). We hypothesized that for the GER to cross the CV compression zone the esophageal pressure during GER, below the CV compression zone, must exceed the CV compression pressure. Therefore, we measured the esophageal and CV compression pressures during all GER episodes. Distal and proximal esophageal pressures were measured as an average value of the two adjacent pressure sensors, 5–7 cm above the LES and 3–5 cm below the UES respectively.20 If the above sensors were affected by the CV compression, adjacent sensors, not affected by the CV compression, were selected for esophageal pressure measurement. Cardiovascular compression on the esophagus (Fig. 1) was identified when cyclic pressure oscillations occurred with a frequency 50–100/min15 and were visually synchronous with the pulse oxymeter waveform seen on a separate live monitor. Spatial location (upper and lower border) of the pulsatile markings in reference to the upper border of LES and their vertical extent were determined.

image

Figure 1.  Esophageal and cardiovascular (CV) pressure topography: (A, B) Represent recumbent and upright postures of the same subject, respectively; note middle and distal CV compression sites in the esophagus that divide the esophagus into two segments. Proximal esophagus: esophageal segment above the middle CV compression site. Distal esophagus: esophageal segment below the distal CV compression site. (C) Demonstrates less common proximal vascular compression site in another subject in upright position. Proximal esophagus is located below proximal CV compression site if present. (D) Pressure waveforms of middle and distal CV compression zones. Note that respiratory and circulatory complete cycles are identifiable in this tracing based on their frequency. Peak pressure of distal and middle CV compression zone is not entirely synchronized.

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The threshold for identification of the pulsatile compression was 4 mmHg higher than the adjacent baseline esophageal pressure. We scored following parameters prior to each TLESR: (i) CV compression pressure, (ii) distal and proximal esophageal pressure, and (iii) LES pressure over five respiratory cycles during the stable tidal volume respirations when no pharyngeal, gastric, esophageal, UES or LES events were seen. Pressures are presented as average, peak and nadir values. Proximal and distal esophageal pressures during TLESR were measured over at least one respiratory cycle prior to the onset and after the impedance recorded GER (if present). Cardiovascular compression pressure measurements were compared with the distal esophageal pressures after reflux episode and correlated with the proximal extent of GER.

MII and pH data analysis

MII and pH recordings during TLESRs were examined for evidence of GER by the pH or the impedance criteria, using Bio-View analysis software (Sandhill Scientific). Computerized automated analysis software determined the time of GER entry into the esophagus from the MIIR. Onset of liquid reflux was identified as retrograde drop of impedance to 50% of the baseline value on at least two consecutive sensors and air reflux was identified as a sharp rise (>3 kΩ s−1) in the impedance of two consecutive sensors to at least 200% of the baseline value.21 Change in impedance at 3 and 5 cm (distal), and 15 and 17 cm (proximal) above the LES were recorded for liquid and air GER. Mixed GER episodes (air and liquid) were identified when the drop and the rise in impedance values were observed in the same GER event. A GER episode throughout this article implies an impedance-detected episode.

Statistical methods

Data are presented as mean ± SD unless specified otherwise. Comparisons were made using Student’s two-tailed t-test. Paired t-test was used when appropriate.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author Contributions
  9. Conflict of interests
  10. References

We recorded and analyzed 109 TLESRs events (58 in the upright and 51 in the recumbent position) in 10 subjects, median of 11 (range 8–14) per subject, majority of the TLESRs were associated with GER.

Cardiovascular compression markings vary among subjects and partly depend on the subject’s posture (Fig. 1A, B). However, even in the same subject and apparently in the same posture they are quite variable, more pronounced at some times than other. However, minor changes in the posture cannot be excluded as the cause of these pressure changes. Cardiovascular compression on the esophagus was observed at three locations: proximal, middle, and distal esophagus. The most proximal CV compression site was located just below the UES and it was observed in only 3 of 10 subjects (Fig. 1C). The proximal CV site was not further evaluated because it was not prevalent and did not affect the spread of GER in the esophagus. Middle and distal CV compression sites divide esophagus into three compartments: proximal, middle, and distal esophagus. However, middle esophageal segment is usually very small and at times indistinguishable from both CV compression zones above and below it. Therefore, we focused our observation on middle and distal CV compression zones and distal and proximal esophageal segments.

Generally, nadir and peak pressures at the CV compression sites follow diastolic and systolic phase of the cardiac cycle with a frequency of 50–100 min−1 (Fig. 1D). The CV compression pressures also fluctuate with respiration such that the nadir and the peak pressures correspond with end-inspiration and expiration respectively (Fig. 1D). Peak CV compression pressure in the distal and the middle esophageal segments are not completely synchronous (Fig. 1D). Pressure and spatial profiles of the CV compression zones at the baseline, in recumbent and upright posture are shown in Table 1.

Table 1.   Spatial and pressure profiles (mmHg) of middle and distal cardiovascular compression (CV) sites compared to gastric, proximal and distal esophageal pressure during 58 and 51 transient lower esophageal relaxation (TLERS) episodes that were associated with gastro-esophageal reflux in upright and recumbent posture, respectively. In upright posture 40 of 58 and 33 of 58 recordings showed middle and distal CV markings, respectively, in contrast to 42 of 51 and 39 of 51 recording in recumbent posture which showed middle and distal CV markings
 Posture
SegmentRecumbent (n = 51 TLESRs)Upright (n = 58 TLESRs)
Average pressureNadir pressurePeak pressureAverage pressureNadir pressurePeak pressure
  1. *P < 0.001 compared with proximal and distal esophageal pressure.

  2. P < 0.05 compared with upright proximal esophageal pressure.

Proximal esophagus−1 ± 1 (n = 10)−4 ± 2 (n = 10)2 ± 2 (n = 10)−2 ± 1 (n = 10)−4 ± 1 (n = 10)0 ± 1 (n = 10)
Middle CV compression10 ± 5* (n = 9)0 ± 3* (n = 9)20 ± 7* (n = 9)5 ± 2* (n = 7)0 ± 2* (n = 7)12 ± 5* (n = 7)
Distal CV compression8 ± 4* (n = 8)3 ± 3* (n = 8)14 ± 6* (n = 8)7 ± 3* (n = 6)2 ± 2* (n = 6)12 ± 5* (n = 6)
Distal esophagus1 ± 2 (n = 10)−3 ± 2 (n = 10)3 ± 2 (n = 10)2 ± 2 (n = 10)−2 ± 2 (n = 10)4 ± 2 (n = 10)
Gastric9 ± 3 (n = 10)8 ± 3 (n = 10)12 ± 4 (n = 10)10 ± 4 (n = 10)9 ± 4 (n = 10)13 ± 4 (n = 10)

Esophageal pressure topography and spread of GER in the recumbent posture

The middle CV compression was present in 9 of 10 subjects and it was located 13 ± 1.5 cm above the LES. On the other hand, the distal CV compression was seen in 8 of 10 subjects and was located 6.5 ± 1 cm above the LES. Detailed pressure and spatial characteristics of these CV compression zones on the esophagus are shown in Table 1. Middle CV compression site has higher peak pressure but lower nadir pressure, as compared with the distal CV compression site. Baseline pressure measurements in the distal esophagus (segment devoid of CV compression) are slightly but not significantly higher than the proximal esophagus (see Table 1).

In the recumbent position, we recorded 45 reflux episodes; 42 (93%) liquid only and 3 (7%) mixed (air + liquid) events. Forty percent (18/45) of the reflux episodes were restricted to the distal esophagus. Average distal and proximal esophageal pressures after the GER (common cavity) in the recumbent posture were 8 ± 3 and 5 ± 2 mmHg respectively. The gastric pressure was the same as distal esophageal pressure. Details of the types of GER and their extension into the proximal esophagus are presented in Table 2. For the GER to spread into the proximal segment, distal esophageal pressure during GER episode needed to overcome middle and distal CV compressions. We analyzed 18 distal GER episodes and 27 proximal reflux episodes associated esophageal pressures in comparison with their respective CV compression pressures. In 89% of the distal-only GER episodes (16/18) average CV compression pressure (higher of middle or distal; e-sleeve pressure across both distal and middle vascular compression segments) was 4 ± 2 mmHg higher than the peak distal esophageal pressure following GER episode (Fig. 2A); in the remaining two episodes, peak CV pressure was higher than peak distal esophageal pressure. On the other hand, in 89% (24/27) of reflux episodes that spread into the proximal esophagus, the peak distal esophageal pressures exceeded average CV compression pressure (both middle and distal, e-sleeve pressure across distal and middle CV compression segments) by 3 ± 1 mmHg (Fig. 2B). In the remaining three proximal reflux episodes, even though the peak distal esophageal pressure did not exceed average CV compression pressure it exceeded nadir CV compression pressure.

Table 2.   Spatial spread and type of GER in different postures
 Reflux type and posture
EsophagusRecumbentUpright
Mixed refluxLiquid onlyAir onlyMixed refluxLiquid only
Air phaseLiquid phaseAir phaseLiquid phase
Distal esophagus121603155
Proximal esophagus21263323111
image

Figure 2.  Spread of gastro-esophageal reflux in recumbent posture; high-resolution manometry and impedance recording are superimposed. In this record, top two white tracings are from impedance sensors located in proximal esophagus, and lower four tracings are from sensors located in the distal esophagus. Purple tracing represents pH measurement, 5 cm above the LES. (A) Liquid reflux episode restricted to the distal esophagus; note that reflux episode is restricted below the middle cardiovascular compression zone. Peak distal esophageal pressure during this TLESR is lower than the average CV compression pressure. (B) Liquid reflux episode extending to proximal esophagus; note that the peak distal esophageal pressure during TLESR is higher than the average CV compression pressure.

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Esophageal pressure topography and spread of GER in upright posture

Both middle and distal CV compressions are generally less prominent in the upright posture and have somewhat lower pressure (see Table 1). The middle CV compression site was present in 7 of 10 subjects and located 12.5 ± 1.5 cm above LES. The distal CV compression site was present in 6 of 10 subjects and it was located 5.5 ± 1 cm above LES. Middle CV compression segment has higher peak pressure but lower nadir pressure than the distal one. Baseline pressure measurements in the distal esophagus are slightly but significantly higher than the proximal esophagus (Table 1).

In the upright position, we recorded 65 GER episodes; 33 (51%) air only, 26 (40%) mixed reflux and 6 (9%) pure liquid. Only 12% of these GER episodes (8/65) were completely restricted to the distal esophagus. The average distal and proximal esophageal pressures after GER (common cavity) in the upright posture were 6 ± 3 and 3 ± 2 mmHg respectively. Details of the types of GER and their extension into the esophagus are presented in Table 2. In 7 of 8 reflux episodes limited to the distal esophagus (Fig. 3A), average CV compression pressure (higher of middle or distal; e-sleeve pressure across both distal and middle vascular compression segments) was 3 ± 1 mmHg higher than the peak distal esophageal pressure. In the remaining 1 of 8 episode peak CV pressure surpassed peak distal esophageal pressure. On the other hand, 84% (48/57) of GER episodes that spread to the proximal esophageal (Fig. 3B) segment have a peak distal esophageal pressure that is 5 ± 3 mmHg higher than the average CV compression pressure (higher of middle or distal; e-sleeve pressure across both distal and middle vascular compression segments). In the remaining nine episodes peak distal esophageal pressure, even though not higher than the average CV compression pressure, was higher than the nadir compression pressure.

image

Figure 3.  Spread of gastro-esophageal reflux in upright posture; high-resolution manometry and impedance recording are superimposed. Top two white tracings are from impedance sensors in proximal esophagus, and lower four tracings from distal esophageal impedance sensors. Purple tracing is from pH sensor located 5 cm above the LES. (A) Liquid only reflux limited to distal esophagus; impedance recording shows a liquid reflux episode during TLESR, which is restricted to the distal esophagus by CV compression zone. Peak distal esophageal pressure during this TLESR remains less than the average CV compression pressure. (B) Mixed liquid and air reflux extending to proximal esophagus; impedance recording shows a mixed reflux episode during TLESR, which is initially restricted to the distal esophagus by the cardiovascular compression zone but later on spreads to the proximal esophagus. Peak distal esophageal pressure during this TLESR exceeds the average CV compression pressure.

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Intra-esophageal pressure and gastro-esophageal reflux

We reviewed all manometric records in both the distal and the proximal esophageal segments at three different time points: (i) at baseline, i.e., before the onset of TLESR, (ii) during TLESR and before the GER, and (iii) during TLESR and after the GER event. Details of the pressure changes from the baseline and during the TLESR are presented in Fig. 4. In the distal esophagus, after the onset of TLESR and before the onset of the GER event, average esophageal pressures are significantly higher than the preceding baseline pressure (3 ± 1 mmHg and = 0.03 upright, 3 ± 1 mmHg and = 0.002 recumbent). After GER event, distal esophageal pressure showed further increase (= 0.003 upright, < 0.001 recumbent). In the proximal esophagus however, a significant increase in the intra-esophageal pressures during TLESR is only seen after the reflux event spread into this segment (7 ± 2 mmHg and < 0.001, 5 ± 1 mmHg and = 0.003) The above observation suggests that the increase in intra-esophageal pressure during TLESR, commonly referred to as the ‘common cavity’ phenomenon is only a reliable surrogate marker of GER event when present in the proximal but not in the distal esophagus.

image

Figure 4.  Intra-esophageal pressure before TLESR, during TLESR before onset of GER and during TLESR after the onset of GER. Note, in the distal esophagus, there is an increase in the esophageal pressure after the onset of reflux and before the onset of reflux event. On the other hand, in the proximal esophagus, esophageal pressure increase during TLESR only occurs after the onset of reflux event. *P < 0.05 compared with the baseline pressure before TLESR.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author Contributions
  9. Conflict of interests
  10. References

In summary, we describe pressure topography of the CV compression sites on the esophagus in normal healthy subjects in the upright and recumbent positions and show that (i) CV compressions divide esophagus into compartments and restrict the spread of GER, (ii) variations in the CV compression of esophagus with change in the posture and nature of reflux content (liquid or air) determine the proximal spread of reflux into the esophagus. For example in upright posture, due to smaller CV compression pressure and more frequent presence of air in reflux content, the GER commonly spreads into the proximal esophagus, and (iii) changes in the distal esophageal pressure during TLESR may occur in the absence of GER.

Several investigators have observed the CV compression of esophagus in both normal subjects and patients with dysphagia. Left atrium enlargement in association with mitral valve disease and congestive heart failure may compress the distal esophagus, as observed on barium swallows studies, and in some patients may cause mild dysphagia.22,23 Cardiovascular compression of the esophagus in association with aberrant subclavian artery causing dysphagia is referred to as ‘Dysphagia Lusoria’.24 Atherosclerosis and calcification of the distal thoracic aorta in the elderly individuals may compress distal esophagus to cause ‘Dysphagia Aortica’.17 Interestingly, pulsatile marking on the esophagus, at multiple sites, are observed routinely in patients who have no symptoms of dysphagia, the reasons for which is not entirely clear. We describe in detail the topography of CV compression sites in the esophagus in normal healthy subjects. The distal CV compression site revealed a waveform with double peaks in each cardiac cycle (similar to diastolic and systolic atrial pressure tracings) in contrast to the proximal CV compression which has only one peak (corresponding to the systolic pressure) which suggests that the proximal CV compression is more likely to be related to aorta and the distal one to the left atrium (Fig. 1D). It is interesting that the changes in posture affect the CV compression sites, however we observed that even in the recumbent posture there can be changes in the amplitude of compression pressure; the reason for which we suspect may be related to minor change in the subject’s posture.

The major finding of our study is that the CV compression of esophagus restricts the spread of GER into proximal esophagus. High-resolution manometry allows measurement of esophageal pressures with an accuracy of 1 mmHg and impedance recording is a sensitive technique to detect liquid and gas reflux in the esophagus. Therefore, simultaneous HRM and impedance recordings made it possible to determine the precise relationship between amplitude of CV compression pressure and intra-esophageal pressures at various locations in the esophagus and their relationship to GER. We observed that in the recumbent position large numbers of GER episodes were restricted to distal esophagus because distal esophageal pressure during GER did not exceed the CV compression pressure. Those GER episodes that did spread to the proximal esophagus show distal esophageal pressure to be higher than the CV compression pressure proving that CV compression indeed determines the proximal spread of GER. The higher incidence of GER in the proximal esophagus in the upright posture is related to two reasons: (i) incidence of CV compression of the esophagus in upright position is lower than in the recumbent position and (ii) air is major content of the refluxate in the upright position and air can escape more easily and rapidly into proximal esophagus during inspiration-related decreases in the CV compression pressure. Several investigators have observed that the frequency of GER and acid exposure, especially in the proximal esophagus is higher in the upright position as compared with the recumbent position.25–28 The latter appears counterintuitive because movement of reflux contents against gravity, in the upright position, should be lower than in the recumbent position. Our findings provide explanation for these counterintuitive observations.

What determines intra-esophageal pressure during GER? It is commonly believed that with relaxation of LES during TLESR, esophagus and stomach become one cavity and there is equalization of pressures in the two cavities. For the pressure equalization to occur, gastric contents (air or liquid) must move into esophagus. Similar to our earlier reports, we observed that the pressure in distal esophagus can increase before arrival of GER in the distal esophagus.29 How can that occur? Recently, we and others found longitudinal muscle contraction of distal esophagus in association with TLESR.30,31 Longitudinal muscle contraction occurs prior to the onset of TLESR; it starts distally and spreads toward the proximal or oral direction. It is likely that the longitudinal muscle contraction, which renders esophagus stiff and non-compliant and causes shortening of the esophagus, is the cause of increased esophageal pressure initially. Later part of TLESR, as LES relaxes completely and there is LES opening, equalization of gastric and esophageal pressures results in a true gastroesophageal common cavity.

In summary, our study, for the first time, describes the role of CV compression of esophagus in restricting spread of GER along the esophagus in normal healthy subjects. Future studies should investigate whether patients with reflux disease show findings similar or different as compared to normal subjects. Furthermore, the role of CV compression in the proximal spread of reflux in the esophagus of elderly patients with CV disorders and hypertension deserves further investigation.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author Contributions
  9. Conflict of interests
  10. References

This study was funded by US National Institute of Health grant support RO1-DK060733 to Dr. Ravinder K. Mittal.

Author Contributions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author Contributions
  9. Conflict of interests
  10. References

Dr. Arash Babaei was involved in all aspects of the study including study design and concept, acquisition of data, analysis and interpretation of data, statistical analysis, drafting of the manuscript and critical revision of the manuscript for important intellectual content. Dr. Ravinder Mittal provided essential tools, space and funding for the study; he played a major role in study concept and design, supervision of study and critical review of the manuscript for important intellectual content.

Conflict of interests

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author Contributions
  9. Conflict of interests
  10. References

None of the authors have any conflict of interest to disclose.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author Contributions
  9. Conflict of interests
  10. References
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