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Keywords:

  • antral contraction;
  • cardiovascular function;
  • functional dyspepsia;
  • modified sham feeding;
  • postprandial distress syndrome

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest and funding
  8. References

Background  Impaired vagal function has been reported to be important in some patients with functional dyspepsia (FD). However, the pathophysiologic mechanisms influencing the cephalic phase of vagal activity in FD are incompletely understood. The aim of this study was to investigate the gastric response to modified sham feeding (MSF) on ultrasound and cardiovascular autonomic function in FD patients.

Methods  Nineteen patients with postprandial distress syndrome (PDS, 11 men and eight women; mean age: 48.2 years) and 26 healthy subjects (HS, 13 men and 13 women; mean age: 45.0 years) were studied prospectively. Firstly, cardiovascular autonomic function was assessed by spectral analysis of RR interval variability. Antral contraction was then evaluated by ultrasonography after MSF was performed to stimulate the cephalic phase of vagal activity.

Key Results  Spectral analysis of RR interval variability showed that the high-frequency component was significantly smaller in the patients than in the HS (< 0.01). The frequency of antral contraction in response to MSF over 15 min was also significantly lower in the PDS patients than in the HS. The 15-min integrated antral contractile response (area under the contraction vs time curve) was significantly smaller in the PDS patients than in the HS (P < 0.01). Univariate analysis revealed a modest correlation between the high-frequency component of RR interval variability and the area under the contraction vs time curve (n = 46, r = 0.49, P < 0.01).

Conclusions & Inferences  Autonomic abnormalities affecting the cephalic phase of vagal activity may be important in the pathogenesis of FD.


Abbreviations:
ANS

autonomic nervous system

CNS

central nervous system

ECG

electrocardiography

FD

functional dyspepsia

HRV

heart rate variability

ICR

integrated antral contractile response

MSF

modified sham feeding

PDS

postprandial distress syndrome

RR-HF

high frequency component

RR-LF

low frequency component

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest and funding
  8. References

Functional dyspepsia (FD) is a heterogeneous gastrointestinal disorder that shows a high prevalence in the general population.1,2 While dyspepsia symptoms can interfere with numerous aspects of daily activities and well-being, dysmotility-like symptoms are reported to have the greatest negative impact on health-related quality of life.3,4

Several factors have been implicated in the pathophysiology of FD, although the underlying etiology remains obscure. Some studies have suggested that functional abnormalities of the autonomic nervous system (ANS) may be important in the pathogenesis of FD,5,6 because vagal dysfunction has been suggested as a cause of antral dysmotility, impaired gastric accommodation, and visceral hypersensitivity, which are abnormalities frequently found in these patients.7,8 Activation of vagal function during meals begins with the cephalic phase, during which thinking about, seeing, smelling, and tasting food stimulate gastrointestinal secretion, gastrointestinal motility, and hormone release.9,10 The central nervous system (CNS) influences all major gastrointestinal functions, including secretion, motility, blood flow, and defense against injury. Specific gastrointestinal responses occur after administration of a wide range of neurotransmitters to defined CNS regions. A study by Wicks et al. have shown that an unpleasant bitter taste causes delayed gastric emptying.11 Lorena et al. have demonstrated that anxiety is related to abnormal antral retention of food in patients with FD.12 In addition, a recent study by Lunding et al. have revealed that vagal stimulation by sham feeding improves antral motility in FD patients given a meal of soup.13 These findings suggest that the gastrointestinal tract and the CNS interact with each other. Thus, the possibility exists that the cephalic phase of vagal activity is important for the pathogenesis of gastric motility disturbances in patients with FD. However, the pathophysiologic mechanisms that influence the cephalic phase of vagal activity in FD are incompletely understood.

Power spectral analysis of beat-to-beat heart rate variability (HRV) data derived from electrocardiograms has provided useful insights into the function of the ANS in animals and in humans.14,15 There have already been some studies into the relationship between ANS and FD.12,16 Breathing exercises with vagal biofeedback have been shown to increase drinking capacity and improve the quality of life for FD patients.16 It is not completely clear, however, whether changes of cardiovascular autonomic function are confined to the neurocardiac fibers or whether there is generalized regulation of vagal activity. Similarly, it is not known whether there is a correlation between cardiovascular autonomic activity and the cephalic phase of vagal activity. Among various methods used for evaluation of autonomic nervous function, sham feeding is considered to be the most physiologic way to stimulate the cephalic phase of vagal activity. However, there have not been many studies of the response of gastric motility to sham feeding in FD, even though gastric symptoms are the major complaint of these patients.

In the present study, we investigated the gastric response to modified sham feeding (MSF) in patients with postprandial distress syndrome (PDS) in order to evaluate the cephalic phase of vagal activity. We also assessed cardiovascular autonomic function, and investigated whether it showed a correlation with vagal activity.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest and funding
  8. References

Subjects

We studied 19 patients with FD (11 men and eight women with a mean age of 48.2 years; range: 16–69 years) who had recurrent mid-upper abdominal discomfort characterized by at least two of the following symptoms: bothersome postprandial fullness, early satiety, and/or bloating. Their symptoms had been present for at least 6 months before diagnosis, so the symptom pattern was compatible with PDS as defined by the ROME III Committee.17

The patients were not taking any medications known to affect gastrointestinal motor function, cardiovascular function, or autonomic function. No patient had a history of gastrectomy, collagen vascular disease, diabetes mellitus, or autonomic neuropathy as assessed by direct inquiry, physical examination, blood tests, and ultrasonography. We also endoscopically confirmed the absence of local pathological lesions such as ulcers or cancers before the study in all patients. Twenty-six healthy controls were also studied (13 men and 13 women with a mean age of 45.0 years; range: 19–73 years). The controls had no symptoms and were without any evidence of gastrointestinal disease.

This study was approved by our institutional review board, and informed consent was obtained from all of the participants.

Heart rate variability

To evaluate cardiovascular autonomic function, heart rate (R-R interval) variability was tested by two examiners (MH and JH), and the data were assessed by one examiner (MH) who was blinded to subject characteristics. Subjects were studied in a quiet room maintained at a comfortable temperature (22–24 °C) and investigated before the MSF procedure on the same day. After an overnight fast, each subject was studied in the supine position after breathing smoothly at a rate of 10–15 min−1 for 15 min in order to achieve acclimatization. After the acclimatization period, electrocardiography (ECG) recording was started for 15 min. Heart rate variability data were derived from the ECG by measuring the beat-to-beat variation of the R-R interval. Standard silver/silver chloride cutaneous electrodes were applied to the lower left chest in the midaxillary line and to the right and left supraclavicular regions. A single ECG channel was recorded at a sampling rate of 6000 Hz and was analyzed after being downsampled to 500 Hz. The R-R intervals were calculated, resampled, and interpolated by computer software (ANS 508; Nihon-Kohrin, Aichi, Japan). Segments without artifacts or ectopic beats for a duration of 120 s were selected for spectral analysis. Power spectral analysis of HRV was then performed with fast Fourier transformation and the power values of the high frequency component (RR-HF: 0.15–0.40 Hz), the low frequency component (RR-LF: 0.04–0.15 Hz), and the LF/HF ratio were calculated by the computer incorporated into the equipment.18,19 The RR-LF component represents sympathetic activity and some parasympathetic activity, while vagal efferent activity is considered to be the major contributor to the RR-HF component. In addition, the LF/HF ratio is considered to reflect the sympatho-vagal balance.20,21 In the present study, we used the power spectrum of RR-HF as an index of vagal tone, and the LF/HF ratio as an indicator of the sympatho-vagal balance.

Gastric response to modified sham feeding

After we assessed HRV, we evaluated the gastric response to MSF. In a quiet room that was maintained at a comfortable temperature (22–24 °C), the subject sat in a chair leaning slightly backward. A 3.75-MHz convex probe was positioned on the anterior abdominal wall in the epigastic region to simultaneously visualize the antrum, superior mesenteric artery, and abdominal aorta.

Before MSF, antral contraction was observed to confirm phase I of motor activity (quiescent without contractions) for more than 10 min. If phase II (isolated contractions) or III (a burst of peristaltic contractions) was observed, we waited for the next phase I period, which usually followed phase III.

A cup of Chinese noodles (4.4 g of protein, 10.0 g of fat, and 25.8 g of carbohydrate with a total caloric value of 211 kcal or 882.0 kJ) was prepared in a kitchen separate from the laboratory. Before starting MSF, the subject was told to chew each bite of the test meal six to seven times and then spit it into a plastic bag. Subjects were instructed to avoid swallowing the test meal. The MSF was performed for a 90-s period, after which the weights of noodles in the cup and the contents of the bag were compared to confirm that the test meal had not been swallowed. We ascertained that none of the subjects was troubled by performing this procedure.

From immediately after MSF, antral contractions were counted for 15 min by ultrasonography (SSA-390A; Toshiba Medical Systems, Nasu, Japan) using a previously reported method.22 The frequency of antral contractions was defined as the number of contractions per 3-min period during the 15-min observation time and contractions were counted on videotapes that were coded to blind the readers to each subject’s identity. The antral response to MSF was assessed from the frequency of contractions and also from the 15-min integrated antral contraction rate (ICR), which was defined as the area under the contraction vs time curve. Antral contraction was defined as transient luminal narrowing accompanied by wall thickening (Fig. 1). All measurements were reviewed by two examiners (NM and KN) with gastrointestinal expertise, who agreed with each other for 42/45 subjects. When there was no consensus about the frequency of antral contractions between the two examiners (3/45 subjects), the videotapes were reviewed and discussed to reach a consensus.

image

Figure 1.  Ultrasonographic images of antral contraction in response to modified sham feeding (3.75-MHz convex probe). Antral contraction was defined as transient luminal narrowing accompanied by wall thickening.

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Statistical analysis

Data are expressed as the mean ± standard error of the mean (SEM). The statistical significance of differences between two groups was assessed by using Student’s t-test. Correlations were investigated by Pearson’s correlation analysis method. In all procedures, = 0.05 was accepted as indicating significance.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest and funding
  8. References

Heart rate variability

The power of the RR-HF component indicating vagal tone was significantly lower in PDS patients than in normal subjects (P < 0.01) (Fig. 2A). On the other hand, the LF/HF ratio (sympatho-vagal balance) was not significantly different between the two groups (P = 0.24) (Fig. 2B).

image

Figure 2.  Spectral analysis of R-R interval variability in the two groups: (A) *The power of the RR-HF component was significantly lower in dysmotility-like functional dyspepsia patients than in normal subjects (< 0.01). (B) However, the LF/HF ratio was not significantly different between the two groups (= 0.24).

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Gastric response to sham feeding

The gastric antrum was visualized clearly by ultrasonography in every subject. In the healthy controls, antral contraction was seen at a rate of 2–3 cycles min−1 after MSF. In contrast, few antral contractions were observed in the patients with PDS (Fig. 3). The ICR was significantly lower in the PDS patients (12.9 ± 4.6) than in the healthy controls (68.9 ± 5.8, P < 0.01).

image

Figure 3.  Antral contraction after modified sham feeding. Fewer antral contractions were observed in patients with dysmotility-like functional dyspepsia.

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Relation between RR-HF and gastric response to sham feeding

Fig. 4 shows the correlation between the power of RR-HF and the antral response to MSF indicated by the ICR. There was a modest, but significant, correlation between these two parameters (n = 46, r = 0.49, P < 0.01).

image

Figure 4.  Relation between RR-HF and the gastric response to sham feeding as shown by the integrated antral contractile response. There was a modest correlation between these parameters (n = 46, r = 0.49, P < 0.01). Solid lines represent the regression lines (predictors for a given x-axis value), and broken lines are the 95% confidence limits for the regression lines.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest and funding
  8. References

This study demonstrated an impaired gastric response to MSF in patients with PDS, which suggests the existence of some abnormality in the cephalic phase of vagal function.

Modified sham feeding is thought to stimulate gastric acid secretion23–25 and gastric motility via vagal pathways,9 and has been used to evaluate the success of vagotomy for peptic ulcer disease26 and the role of the vagus nerve in the secretion of IgA from the normal gastric mucosa.27 However, few studies have assessed the effect of vagal activity on gastric motility.9,28,29 With regard to MSF, the test meal content and timing have differed between studies. In our study, we chose noodles and a sham feeding time of 90 s to reduce the chance of swallowing the meal. Manometric studies have shown that sham feeding delays the reappearance of phase III activity,29 but this finding is not consistent with our results. Although we lack a definitive explanation for this discrepancy, differences in the test meal used and in the sensitivity of the modality employed to detect contractions may explain the different findings. Stern et al. performed electrogastrography and found an increase in contractions of 3 cycles min−1 during and after sham feeding,28 which is in agreement with our data except for the different duration of sustained motor activity.

According to the present study, the RR-HF component was significantly smaller in the patients with PDS than in the healthy subjects (HS). The RR-HF is considered to represent parasympathetic activity,18,30,31 and the present results obtained by the spectral analysis of heart rate (R-R interval) variability are in keeping with previous reports.5,32,33 We used spectral analysis of HRV for evaluation of vagal cardiac efferent activity. The heart rate is influenced by autonomic activity associated with respiration and hemodynamics, and it fluctuates periodically. Spectral analysis of HRV permits the separation of frequency components attributed to the sympathetic and parasympathetic nervous systems, and the clinical significance of changes in these components has been examined in patients with heart disease,30 cerebrovascular disease,18 and diabetes mellitus.31 This method of evaluation is considered to be non-invasive, convenient, and highly accurate.

Previous studies have indicated that autonomic dysfunction is important in the pathogenesis of FD. Hausken et al. found significantly lower vagal tone in 25 dyspeptic patients compared with 23 HS (based on assessment of respiratory sinus arrhythmia).34 Greydanus et al. studied four patients with slow transit dyspepsia and reported that the maximum increased of plasma pancreatic polypeptide during sham feeding was markedly smaller in two patients and slightly reduced in a third.35 These findings are consistent with our results. However, such changes may be influenced by distress, as demonstrated by a recent report of an elevated level of anxiety.36 Although we did not investigate the presence of anxiety among the FD patients in this study, none of the patients had a history of anxiety or depression and we used non-invasive methods such as ultrasonography and ECG, as autonomic function is markedly affected by sensory stimuli including emotional discomfort. Therefore, we consider that anxiety/emotional distress did not influence our results.

A variety of factors may be responsible for FD, and autonomic dysfunction cannot be considered as the sole or even the main cause of this condition. However, the high prevalence of dysfunction of the cephalic phase of vagal efferent activity that we observed among our patients with PDS may lead to better a understanding of this disorder and ultimately to more effective treatment. A recent study showed that correction of impaired vagal efferent activity improved antral motility in FD patients.13 That study targeted impaired vagal efferent activity for treatment of FD, which supports our concept of the condition.

In this study, we found that there was modest correlation between the power of RR-HF and the gastric response to MSF, as indicated by the ICR. The cell bodies for the great majority of the parasympathetic efferent fibers projecting to the stomach originate along the entire rostro-caudal extent of the dorsal motor nucleus of the vagus.37 In contrast, cell bodies of cardiac vagal preganglionic neurons have been found throughout the dorsal motor nucleus following the injection of retrograde tracers into cardiac ganglia.38 Thus, it is likely that the efferent projections originating from the dorsal motor nucleus of vagus differ between the heart and the stomach. However, there was a recent report of a significant correlation between the gastric motility index and the LF/HF ratio after electroacupuncture.39 The authors of that report concluded that the dorsal motor nucleus of vagus regulates the physiological function of both the heart and stomach, which supports our results, although further studies in a larger population will be necessary to confirm these findings.

In this study, we did not investigate the correlation between antral contraction after a meal and the antral response to MSF. A previous study using electrogastrography showed that the increase in the power of the dominant frequency after a meal is well correlated with the response to sham feeding.40 Taking these findings together, we can speculate that postprandial gastric emptying is slower in patients with PDS than in HS, because significantly fewer antral contractions occurred after MSF in our FD patients than in our healthy controls.

In this study, cardiovascular autonomic function and dyspeptic symptoms were not investigated after MSF. Increasing vagal activity by breathing exercises has been reported to increase drinking capacity and improve the quality of life for FD patients.16 In addition, a recent study has shown that correction of impaired vagal efferent activity improves antral motility in FD patients.13 However, it is not completely clear whether MSF can improve vagal activity, antral motility, or dyspeptic symptoms. A large-scale study will be needed to evaluate these effects of MSF in order to assess the mechanisms involved.

In conclusion, autonomic dysfunction affecting the cephalic phase of vagal activity might be involved in the pathogenesis of FD.

Conflict of interest and funding

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest and funding
  8. References

The authors have no conflicts of interests. The authors alone are responsible for the content and writing of the paper.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest and funding
  8. References