748
Original article
Decreased parasympathetic activity in patients with functional dyspepsia Kursat Dala, Onur S. Devecia, Metin Kucukazmana, Naim Ataa, Omer Senb, Selcuk Ozkanb, Abdullah O. Yeniovaa, Salih Baser ¸ a, Esin Beyana, Yasar ¸ Nazligula, Bunyamin Yavuzb and Derun T. Ertugrula Objective Functional dyspepsia (FD) can be described as the presence of symptoms such as bothersome postprandial fullness, early satiation, epigastric pain, and burning without any evidence of structural disease. The aim of this study was to evaluate the autonomic nervous system using heart rate variability (HRV) in patients with postprandial distress syndrome and epigastric pain syndrome. Patients and methods The study population included 64 consecutive patients with a diagnosis of FD and 62 agematched and sex-matched healthy control individuals with no clinical evidence of gastrointestinal, systemic, or cardiovascular diseases. All patients underwent upper gastrointestinal endoscopy and 24 h Holter monitoring. Results There were 30 patients with postprandial distress syndrome and 34 with epigastric pain syndrome. Twentyfour hour square root of the mean squared differences of the successive normal to normal intervals (RMSSD) (30.5±12.4, 35.8±13.9; P = 0.047), 24 h proportion derived by dividing the number of interval differences of successive normal to normal intervals greater than 50 ms (PNN50) (9.8±3.9, 14.1±7.3; P = 0.017), daytime PNN50 (6.8±1.6, 18.4±13.8; P < 0.001), night SD of the normal to normal intervals (SDNN) (111.4±39.9, 133.4±29.8; P = 0.001),
Introduction Functional dyspepsia (FD) can be described as the presence of symptoms such as bothersome postprandial fullness, early satiation, epigastric pain, and epigastric burning without any evidence of structural disease. According to Rome III criteria, it can be classified as postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS) [1]. Although disturbances in motility of the gastrointestinal system are the major findings in FD, the pathophysiology of these conditions remains controversial. Although several studies have evaluated autonomic nervous system (ANS) activity in FD, the role of the ANS in PDS and EPS subheadings is still unclear. It is known that both gastrointestinal motility and perception are regulated by central and peripheral modulation [2]. Heart rate variability (HRV) reflects sympathetic and parasympathetic balance of the sinus node of the heart. HRV analysis has been used extensively to evaluate autonomic modulation of the sinus node. It is c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0954-691X
and night RMSSD (31.7±12.4, 38.2±17.5; P = 0.019) were significantly lower in patients with FD than controls. Other HRV parameters were not significantly different between the two groups. Changes in these parameters showed a decreased parasympathetic tone and discordance in sympathovagal activity in FD. Conclusion Our study showed decreased parasympathetic activity in the patients with FD. Further studies are required to evaluate the significance of HRV parameters and to clarify the mechanism of decreased parasympathetic activity in patients with FD. Eur J c 2014 Wolters Kluwer Gastroenterol Hepatol 26:748–752 Health | Lippincott Williams & Wilkins. European Journal of Gastroenterology & Hepatology 2014, 26:748–752 Keywords: autonomic nervous system, functional dyspepsia, heart rate variability, parasympathetic activity Departments of aInternal Medicine and bCardiology, Kecioren Teaching and Research Hospital, Ankara, Turkey Correspondence to Bunyamin Yavuz, MD, Department of Cardiology, Kecioren Teaching and Research Hospital, Kecioren, Ankara 06280, Turkey Tel: + 903123569000; fax: + 903123569002; e-mail: [email protected] Received 31 January 2014 Accepted 25 March 2014
also used to identify patients at risk for increased cardiac morbidity and mortality. It has been shown to reflect the sympathovagal balance in autonomic control of the cardiovascular system and has been used previously to define the role of ANS activity in certain disorders [3]. The aim of this study is to evaluate the ANS using HRV in patients with PDS and EPS.
Patients and methods The study population included 64 consecutive patients with the diagnosis of FD and 62 age-matched and sexmatched healthy volunteer control individuals with no clinical evidence of gastrointestinal, systemic, or cardiovascular diseases. All controls had normal ECGs and normal blood pressure. Patients with FD were evaluated according to Rome III Diagnostic Criteria for Functional Gastrointestinal Disorders [1]. There were 30 patients with PDS and 34 patients with EPS. We excluded patients with PDS/EPS overlap. All patients underwent DOI: 10.1097/MEG.0000000000000111
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Decreased parasympathetic activity Dal et al. 749
upper gastrointestinal endoscopy for exclusion of structural disease. Twenty-four hour Holter monitoring, transthoracic echocardiography, abdominal ultrasonography, ECG, biochemical analysis, and complete blood count were performed in all study populations.
Analysis of heart rate variability parameters
Exclusion criteria were the presence of coronary artery disease, atrial fibrillation, heart failure, chronic obstructive pulmonary disease, valvular heart disease, diabetes mellitus, hypertension, chronic hepatic disease, abnormal abdominal ultrasonography, patients with low ejection fraction (< 55%), presence of symptoms suggesting irritable bowel syndrome, and other systemic disease. The protocol of this study was approved by the local ethics committee, and informed consent was obtained from every participant in this study.
All 24 h, night, and daytime periods were used to investigate HRV parameters. Daytime and night-time were defined as 6 a.m. to 10 p.m. and 10 p.m. to 6 a.m. For the time-domain analysis of HRV, each QRS complex resulting from sinus node depolarization was detected and normal to normal (NN) intervals were determined.
Laboratory measurements
Fasting blood samples were obtained by the venipuncture of the large antecubital veins of the patients studied without stasis after a 12-h fast. The samples were then centrifuged immediately; the plasma was separated and stored at – 801C. Fasting serum total cholesterol, triglycerides, low-densitylipoprotein cholesterol, high-density-lipoprotein cholesterol (lot no.: B302, Konelab; Thermo Fisher Scientific Inc., Vantaa, Finland), g-glutamyltransferase (lot no.: C331, Konelab), alanine aminotransferase (lot no.: C239, Konelab), and aspartate aminotransferase (lot no.: C372, Konelab) concentrations were measured enzymatically using an automatic analyzer (Konelab 60i). Total cholesterol (lot no.: B540, Konelab) and triglycerides (lot no.: C186, Konelab) were measured by enzymatic colorimetric tests; low-density-lipoprotein cholesterol (lot no.: C435, Konelab) and high-density-lipoprotein cholesterol (lot no.: C136, Konelab) were measured using the homogeneous enzymatic colorimetric test. Serum creatinine was measured using the alkaline picrate (Jaffe) method (lot no.: C092, Konelab). The stool antigen test was used to evaluate Helicobacter pylori infection in all patients. Endoscopy
Esophagogastroduodenoscopy was performed using a Fujinon EG-450WR5 (Fujinon, Saitama, Japan) videogastroscope in each endoscopic examination. Holter monitoring
Twenty-four hour Holter monitoring was performed for all participants. Recordings were obtained using threechannel analog recorders and analyzed using the DMS 300-7L Holter system [DM Systems (Beijing) Co. Ltd, Beijing, China]. Cardioscan premier DM Holter software was used to calculate HRV parameters. The investigators who analyzed the ECG parameters were blinded to control/patient status.
For HRV analyses, the evaluated parameters were defined according to the Task Force of European Society of Cardiology and the North American Society of Pacing and ECG on HRV [4].
The following standard parameters were calculated from the time series: (1) SD of the normal to normal intervals (SDNN): SD of intervals between two normal R-waves. SDNN provides an impression of the overall circulatory dynamics. (2) The square root of the mean squared differences of successive normal to normal intervals (RMSSD): the square root of square of the mean square differences of successive NN intervals. Higher values indicate higher vagal activity. (3) The proportion derived by dividing the number of interval differences of successive normal to normal intervals greater than 50 ms (PNN50): the proportion derived by dividing NN50 (the number of interval differences of successive NN intervals > 50 ms) by the total number of NN intervals. Again, higher values indicate higher vagal activity. Spectral analysis of HRV included total power, high-frequency (HF) component (0.15–0.40 Hz), low-frequency (LF) component (0.04–0.15 Hz), and very low-frequency component (0–0.04 Hz). LF/HF ratio = low-frequency power/ high-frequency power was calculated to yield the relative changes in HRV in the frequency domain. Transthoracic echocardiography
Transthoracic echocardiographic examination was performed in all participants using a System Five (GE Vingmed Ultrasound; GE Healthcare, Horten, Norway) cardiac ultrasound scanner and 2.5–3.5 MHz transducers to determine left ventricular systolic functions, cardiac valvular disease, and myocardial contraction abnormalities. Left ventricular ejection fraction (%) was measured from crosssectional echocardiographic images of the left ventricle. Statistical analyses
Distribution of the continuous variables was determined using the Kolmogorov–Smirnov test. Continuous variables with a normal distribution were expressed as mean±SD, variables with skew distribution were expressed as median (minimum–maximum), and categorical variables were expressed as percentage. Means were compared
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
750
European Journal of Gastroenterology & Hepatology 2014, Vol 26 No 7
Table 1 Demographic features of the patients and control participants Parameters Age (years) Sex (F/M) (%) LVEF (%) Hemoglobin (g/dl) WBC Platelets ALT AST TC (mg/dl) LDL-C (mg/dl) HDL-C (mg/dl) Triglycerides (mg/dl)
Heart rate variability parameters in functional dyspepsia and controls
Table 2
FD (n = 64)
Controls (n = 62)
P
40.2±7.4 49/15 (77/23) 65.7±3.2 13.1±2.9 5.6±1.1 103 320±16 103 19.9±8.9 21.5±3.9 205.5±27.9 103.6±36.7 62.5±8.0 149.9±38.9
38.1±10.9 45/17 (73/27) 64.1±3.4 13.8±1.9 6.8±2.4 103 351±20 103 22.5±8.4 19.8±3.1 201.8±29.1 114.8±33.4 64.1±5.2 142.5±28.4
NS NS NS NS NS NS NS NS NS NS NS NS
ALT, alanine aminotransferase; AST, aspartate aminotransferase; F/M, female/ male; FD, functional dyspepsia; HDL-C, high-density-lipoprotein cholesterol; LDLC, low-density-lipoprotein cholesterol; LVEF, left ventricular ejection fraction; TC, total cholesterol; WBC, white blood cells.
using analysis of variance or the Mann–Whitney U-test. For all statistics, a two-sided P value less than 0.05 was considered statistically significant. All analyses were carried out using SPSS 10.0 (SPSS Inc., Chicago, Illinois, USA) for Windows.
24 h SDNN (ms) RMSSD (ms) PNN50 (%) LF/HF Daytime SDNN (ms) RMSSD (ms) PNN50 (%) LF/HF Night-time SDNN (ms) RMSSD (ms) PNN50 (%) LF/HF
FD (n = 64)
Controls (n = 62)
P
144.1±33.3 30.5±12.4 9.8±3.9 2.9±1.6
142.1±25.9 35.8±13.9 14.1±7.3 2.8±1.3
NS 0.047 (S) 0.017 (S) NS
122.3±33.1 25.9±10.5 6.8±1.6 3.1±1.2
131.9±22.9 27.7±10.5 18.4±13.8 3.2±1.4
NS NS < 0.001 (S) NS
111.4±39.9 31.7±12.4 16.5±14.7 2.7±1.6
133.4±29.8 38.2±17.5 16.3±11.7 2.5±1.0
0.001 (S) 0.019 (S) NS NS
FD, functional dyspepsia; LF/HF ratio, low-frequency/high-frequency ratio; PNN50, proportion derived by dividing the number of interval differences of successive normal to normal intervals greater than 50 ms; RMSSD, square root of the mean squared differences of successive normal to normal intervals; S, significant; SDNN, SD of the normal to normal intervals.
Fig. 1
80.00
Results
On the basis of the results of the Holter analysis, all participants were detected to have sinus rhythm, without episodes of sustained atrial or ventricular arrhythmias and sinus node dysfunction or atrioventricular block. Twentyfour hour RMSSD (30.5±12.4, 35.8±13.9; P = 0.047), 24 h PNN50 (9.8±3.9, 14.1±7.3; P = 0.017), daytime PNN50 (6.8±1.6, 18.4±13.8; P < 0.001), night SDNN (111.4±39.9, 133.4±29.8; P = 0.001), and night RMSSD (31.7±12.4, 38.2±17.5; P = 0.019) were significantly lower in patients with FD than in the controls. Other HRV parameters were not significantly different between the two groups (Table 2). Changes in these parameters showed a decreased parasympathetic tone and discordance in sympathovagal activity in FD. Box plot graphics of 24 h RMSSD and 24 h PNN50 are presented in Figs 1 and 2. Daytime PNN50 (5.9±1.4, 7.6±1.8, and 18.4±13.8, respectively) and night SDNN (115.4±48.9, 107.1±26.6, and 133.4±29.8) were significantly lower in the EPS and PDS groups than in the controls (Table 3). Other HRV
60.00 24 h RMSSD
A total of 64 patients with FD and 62 control participants were examined. Patients with FD were classified into two subgroups as PDS and EPS. There were 30 patients with PDS and 34 with EPS. Demographic data of the FD [mean age: 40.2±7.4 years; 49 (77%) women] and control groups [mean age: 38.1±10.9 years; 45 (73%) women] were similar (Table 1). None of the participants had hypertension, diabetes mellitus, heart failure, coronary artery disease, or valvular heart disease. The ratio of H. pylori infection was 63% (40 patients) in the FD group and 66% (41 individuals) in the control group.
40.00
20.00
0.00 Controls
FD
Box plot graphic of 24 h RMSSD in patients with functional dyspepsia (FD) and controls. RMSSD, square root of the mean squared differences of successive normal to normal intervals.
parameters were not significantly different between the three groups.
Discussion This study showed that patients with FD had decreased parasympathetic tone and discordance in sympathovagal activity. To the best of our knowledge, there is only one study that has examined the relationship between FD and ANS activity. We evaluated ANS activity using HRV. HRV is a reliable quantitative method for evaluation of ANS activity [3]. This method is used in general cardiology practice for evaluation of ANS activity and risk of arrhythmia in patients with coronary heart disease,
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Decreased parasympathetic activity Dal et al. 751
heart failure, hypertension, diabetes mellitus, and other disorders [4]. Lorena et al. [5] evaluated ANS activity in a small number of patients with FD. They found that the values of parameters reflecting vagal activity were significantly lower in patients with FD. The results of our study are similar to their findings. They studied a very small sample size. We had a larger sample size compared with their study. We used the new classification criteria to evaluate patients with FD. We evaluated the HRV parameters PDS and EPS separately. The power of our study was high. The power of their study was unknown. The major sensory nerve supply of the gastrointestinal tract arises from the abdominal vagus nerve. Stimulation
Fig. 2
60.00
∗
24 h PNN50
50.00 40.00 30.00 20.00 10.00 0.00 Controls
FD
Box plot graphic of 24 h PNN50 in patients with functional dyspepsia (FD) and controls. PNN50, proportion derived by dividing the number of interval differences of successive NN intervals greater than 50 ms. *P = 0.017.
Table 3
of the abdominal vagal nerve or its peripheral fields induce a complex physiological response of heart and vessels. Some studies have reported gastric vagal neuropathy to be strongly related to cardiac autonomic neuropathy in diabetic patients [6]. These physiological and pathological findings support the concept that cardiovascular autonomic responses also reflect the function of the abdominal vagus. There are several explanations for low vagal tone in patients with FD. Low vagal tone in patients with FD was associated with mental stress and personality factors [7]. However, it seems plausible that other mechanisms may contribute toward the autonomic dysfunction in these patients. The relationship between decreased vagal activity and motor dysfunction in FD is still controversial. Hausken et al. [8] suggested a relation between decreased vagal tone and antral dysmotility in patients with FD. Greydanus et al. [9] found that abnormal transit was sometimes associated with disorders of extrinsic neural control, but the latter are also found in patients with normal transit. Consequently, further descriptive studies are required to establish the real impact of the observed parasympathetic dysfunction on the gastrointestinal motor function in FD. In our study, although patients were well matched in terms of sex and age, there were a number of other factors that could have affected HRV that were not controlled for in this study including anxiety, depression, sleep state, of abuse, symptom severity, menstruation, and BMI. It is likely that these may have influenced the outcomes as these are parameters that have differed between groups in previous studies, for example, FD has been associated with anxiety in a number of studies and, similarly, the PDS subtype has been more associated with anxiety [10]. FD has also been associated with sleep disturbances in some series [11]. These factors were some of the limitations of our study.
Heart rate variability parameters in patients with postprandial distress syndrome, epigastric pain syndrome, and controls
Parameters 24 h SDNN (ms) RMSSD (ms) PNN50 (%) LF/HF ratio Daytime SDNN (ms) RMSSD (ms) PNN50 (%) Night-time SDNN (ms) RMSSD (ms) PNN50 (%)
EPS (n = 34)
PDS (n = 30)
Controls (n = 62)
Pa
Pb
Pc
146.8±36.8 29.7±12.3 9.0±6.9 3.1±1.6
140.9±28.1 31.3±12.6 10.7±4.9 2.8±1.6
142.1±25.9 35.8±13.9 14.1±7.3 2.8±1.3
NS NS NS NS
NS 0.039 (S) 0.048 (S) NS
123.6±36.0 25.3±10.3 5.9±1.4
120.8±30.0 26.8±10.9 7.6±1.8
131.9±22.9 27.7±10.5 18.4±13.8
NS NS NS
NS NS < 0.001 (S)
NS NS < 0.001 (S)
115.4±48.9 31.7±10.1 15.7±14.2
107.1±26.6 33.7±12.1 17.4±13.6
133.4±29.8 38.2±17.5 16.3±11.7
NS NS NS
< 0.001 (S) 0.031 (S) NS
0.003 (S) NS NS
NS NS NS NS
EPS, epigastric pain syndrome; LF/HF ratio, low-frequency/high-frequency ratio; PDS, postprandial distress syndrome; PNN50, proportion derived by dividing the number of interval differences of successive normal to normal intervals greater than 50 ms; RMSSD, square root of the mean squared differences of successive normal to normal intervals; S, significant; SDNN, SD of the normal to normal intervals. a P value between EPS and PDS. b P value between EPS and controls. c P value between PDS and controls.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
752 European Journal of Gastroenterology & Hepatology
2014, Vol 26 No 7
In patients with FD, the first step of treatment is eradication of H. pylori, if present, according to the Maastricht criteria [12]. After this step, if symptoms of FD persist, proton pump inhibitors and prokinetic drugs are used for treatment. However, these drugs do not affect the physiopathology of FD. This study aimed to examine the physiopathology of FD. We found decreased parasympathetic activity in the patients with FD. To identify novel treatment methods and drugs, researchers should focus on decreased parasympathetic activity. The rate of H. pylori infection was very high in our study population. However, there was no significant difference in patients with FD and the controls. Conclusion
Our study showed decreased parasympathetic activity in patients with FD. Further studies are required to evaluate the significance of HRV parameters and to clarify the mechanism of decreased parasympathetic activity in patients with FD.
Acknowledgements Conflicts of interest
There are no conflicts of interest.
References 1
Drossman DA. The functional gastrointestinal disorders and the Rome III process. Gastroenterology 2006; 130:1377–1390.
2
Thompson DG. Modulation of gastric perception and motility in man. Current concepts and correlation with symptoms. Dig Dis Sci 1994; 39 (Suppl): 48S–50S. 3 Pumprla J, Howorka K, Groves D, Chester M, Nolan J. Functional assessment of heart rate variability: physiological basis and practical applications. Int J Cardiol 2002; 84:1–14. 4 Task Force of European Society of Cardiology and the North American Society of Pacing and Electrophysiology on Heart Rate Variability. Standards of measurement, physiological interpretation, and clinical use. Eur Heart J 1996; 17:354–381. 5 Lorena SL, Figueiredo MJ, Almeida JR, Mesquita MA. Autonomic function in patients with functional dyspepsia assessed by 24-hour heart rate variability. Dig Dis Sci 2002; 47:27–31. 6 Buysschaert M, Donckier J, Dive A, Ketelslegers JM, Lambert AE. Gastric acid and pancreatic polypeptide responses to sham feeding are impaired in diabetic subjects with autonomic neuropathy. Diabetes 1985; 34: 1181–1185. 7 Haug TT, Svebak S, Hausken T, Wilhelmsen I, Berstad A, Ursin H. Low vagal activity as mediating mechanism for the relationship between personality factors and gastric symptoms in functional dyspepsia. Psychosom Med 1994; 56:181–186. 8 Hausken T, Svebak S, Wilhelmsen I, Haug TT, Olafsen K, Pettersson E, et al. Low vagal tone and antral dysmotility in patients with functional dyspepsia. Psychosom Med 1993; 55:12–22. 9 Greydanus MP, Vassallo M, Camilleri M, Nelson DK, Hanson RB, Thomforde GM. Neurohormonal factors in functional dyspepsia: insights on pathophysiological mechanisms. Gastroenterology 1991; 100:1311–1318. 10 Tse AW, Lai LH, Lee CC, Tsoi KK, Wong VW, Chan Y, et al. Validation of self-administrated questionnaire for psychiatric disorders in patients with functional dyspepsia. J Neurogastroenterol Motil 2010; 16:52–60. 11 Vege SS, Locke GR 3rd, Weaver AL, Farmer SA, Melton LJ 3rd, Talley NJ. Functional gastrointestinal disorders among people with sleep disturbances: a population-based study. Mayo Clin Proc 2004; 79:1501–1506. 12 Malfertheiner P, Megraud F, O’Morain CA, Atherton J, Axon AT, Bazzoli F, et al. European Helicobacter Study Group. Management of Helicobacter pylori infection – the Maastricht IV/Florence consensus report. Gut 2012; 61:646–664.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Original article
Decreased parasympathetic activity in patients with functional dyspepsia Kursat Dala, Onur S. Devecia, Metin Kucukazmana, Naim Ataa, Omer Senb, Selcuk Ozkanb, Abdullah O. Yeniovaa, Salih Baser ¸ a, Esin Beyana, Yasar ¸ Nazligula, Bunyamin Yavuzb and Derun T. Ertugrula Objective Functional dyspepsia (FD) can be described as the presence of symptoms such as bothersome postprandial fullness, early satiation, epigastric pain, and burning without any evidence of structural disease. The aim of this study was to evaluate the autonomic nervous system using heart rate variability (HRV) in patients with postprandial distress syndrome and epigastric pain syndrome. Patients and methods The study population included 64 consecutive patients with a diagnosis of FD and 62 agematched and sex-matched healthy control individuals with no clinical evidence of gastrointestinal, systemic, or cardiovascular diseases. All patients underwent upper gastrointestinal endoscopy and 24 h Holter monitoring. Results There were 30 patients with postprandial distress syndrome and 34 with epigastric pain syndrome. Twentyfour hour square root of the mean squared differences of the successive normal to normal intervals (RMSSD) (30.5±12.4, 35.8±13.9; P = 0.047), 24 h proportion derived by dividing the number of interval differences of successive normal to normal intervals greater than 50 ms (PNN50) (9.8±3.9, 14.1±7.3; P = 0.017), daytime PNN50 (6.8±1.6, 18.4±13.8; P < 0.001), night SD of the normal to normal intervals (SDNN) (111.4±39.9, 133.4±29.8; P = 0.001),
Introduction Functional dyspepsia (FD) can be described as the presence of symptoms such as bothersome postprandial fullness, early satiation, epigastric pain, and epigastric burning without any evidence of structural disease. According to Rome III criteria, it can be classified as postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS) [1]. Although disturbances in motility of the gastrointestinal system are the major findings in FD, the pathophysiology of these conditions remains controversial. Although several studies have evaluated autonomic nervous system (ANS) activity in FD, the role of the ANS in PDS and EPS subheadings is still unclear. It is known that both gastrointestinal motility and perception are regulated by central and peripheral modulation [2]. Heart rate variability (HRV) reflects sympathetic and parasympathetic balance of the sinus node of the heart. HRV analysis has been used extensively to evaluate autonomic modulation of the sinus node. It is c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0954-691X
and night RMSSD (31.7±12.4, 38.2±17.5; P = 0.019) were significantly lower in patients with FD than controls. Other HRV parameters were not significantly different between the two groups. Changes in these parameters showed a decreased parasympathetic tone and discordance in sympathovagal activity in FD. Conclusion Our study showed decreased parasympathetic activity in the patients with FD. Further studies are required to evaluate the significance of HRV parameters and to clarify the mechanism of decreased parasympathetic activity in patients with FD. Eur J c 2014 Wolters Kluwer Gastroenterol Hepatol 26:748–752 Health | Lippincott Williams & Wilkins. European Journal of Gastroenterology & Hepatology 2014, 26:748–752 Keywords: autonomic nervous system, functional dyspepsia, heart rate variability, parasympathetic activity Departments of aInternal Medicine and bCardiology, Kecioren Teaching and Research Hospital, Ankara, Turkey Correspondence to Bunyamin Yavuz, MD, Department of Cardiology, Kecioren Teaching and Research Hospital, Kecioren, Ankara 06280, Turkey Tel: + 903123569000; fax: + 903123569002; e-mail: [email protected] Received 31 January 2014 Accepted 25 March 2014
also used to identify patients at risk for increased cardiac morbidity and mortality. It has been shown to reflect the sympathovagal balance in autonomic control of the cardiovascular system and has been used previously to define the role of ANS activity in certain disorders [3]. The aim of this study is to evaluate the ANS using HRV in patients with PDS and EPS.
Patients and methods The study population included 64 consecutive patients with the diagnosis of FD and 62 age-matched and sexmatched healthy volunteer control individuals with no clinical evidence of gastrointestinal, systemic, or cardiovascular diseases. All controls had normal ECGs and normal blood pressure. Patients with FD were evaluated according to Rome III Diagnostic Criteria for Functional Gastrointestinal Disorders [1]. There were 30 patients with PDS and 34 patients with EPS. We excluded patients with PDS/EPS overlap. All patients underwent DOI: 10.1097/MEG.0000000000000111
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Decreased parasympathetic activity Dal et al. 749
upper gastrointestinal endoscopy for exclusion of structural disease. Twenty-four hour Holter monitoring, transthoracic echocardiography, abdominal ultrasonography, ECG, biochemical analysis, and complete blood count were performed in all study populations.
Analysis of heart rate variability parameters
Exclusion criteria were the presence of coronary artery disease, atrial fibrillation, heart failure, chronic obstructive pulmonary disease, valvular heart disease, diabetes mellitus, hypertension, chronic hepatic disease, abnormal abdominal ultrasonography, patients with low ejection fraction (< 55%), presence of symptoms suggesting irritable bowel syndrome, and other systemic disease. The protocol of this study was approved by the local ethics committee, and informed consent was obtained from every participant in this study.
All 24 h, night, and daytime periods were used to investigate HRV parameters. Daytime and night-time were defined as 6 a.m. to 10 p.m. and 10 p.m. to 6 a.m. For the time-domain analysis of HRV, each QRS complex resulting from sinus node depolarization was detected and normal to normal (NN) intervals were determined.
Laboratory measurements
Fasting blood samples were obtained by the venipuncture of the large antecubital veins of the patients studied without stasis after a 12-h fast. The samples were then centrifuged immediately; the plasma was separated and stored at – 801C. Fasting serum total cholesterol, triglycerides, low-densitylipoprotein cholesterol, high-density-lipoprotein cholesterol (lot no.: B302, Konelab; Thermo Fisher Scientific Inc., Vantaa, Finland), g-glutamyltransferase (lot no.: C331, Konelab), alanine aminotransferase (lot no.: C239, Konelab), and aspartate aminotransferase (lot no.: C372, Konelab) concentrations were measured enzymatically using an automatic analyzer (Konelab 60i). Total cholesterol (lot no.: B540, Konelab) and triglycerides (lot no.: C186, Konelab) were measured by enzymatic colorimetric tests; low-density-lipoprotein cholesterol (lot no.: C435, Konelab) and high-density-lipoprotein cholesterol (lot no.: C136, Konelab) were measured using the homogeneous enzymatic colorimetric test. Serum creatinine was measured using the alkaline picrate (Jaffe) method (lot no.: C092, Konelab). The stool antigen test was used to evaluate Helicobacter pylori infection in all patients. Endoscopy
Esophagogastroduodenoscopy was performed using a Fujinon EG-450WR5 (Fujinon, Saitama, Japan) videogastroscope in each endoscopic examination. Holter monitoring
Twenty-four hour Holter monitoring was performed for all participants. Recordings were obtained using threechannel analog recorders and analyzed using the DMS 300-7L Holter system [DM Systems (Beijing) Co. Ltd, Beijing, China]. Cardioscan premier DM Holter software was used to calculate HRV parameters. The investigators who analyzed the ECG parameters were blinded to control/patient status.
For HRV analyses, the evaluated parameters were defined according to the Task Force of European Society of Cardiology and the North American Society of Pacing and ECG on HRV [4].
The following standard parameters were calculated from the time series: (1) SD of the normal to normal intervals (SDNN): SD of intervals between two normal R-waves. SDNN provides an impression of the overall circulatory dynamics. (2) The square root of the mean squared differences of successive normal to normal intervals (RMSSD): the square root of square of the mean square differences of successive NN intervals. Higher values indicate higher vagal activity. (3) The proportion derived by dividing the number of interval differences of successive normal to normal intervals greater than 50 ms (PNN50): the proportion derived by dividing NN50 (the number of interval differences of successive NN intervals > 50 ms) by the total number of NN intervals. Again, higher values indicate higher vagal activity. Spectral analysis of HRV included total power, high-frequency (HF) component (0.15–0.40 Hz), low-frequency (LF) component (0.04–0.15 Hz), and very low-frequency component (0–0.04 Hz). LF/HF ratio = low-frequency power/ high-frequency power was calculated to yield the relative changes in HRV in the frequency domain. Transthoracic echocardiography
Transthoracic echocardiographic examination was performed in all participants using a System Five (GE Vingmed Ultrasound; GE Healthcare, Horten, Norway) cardiac ultrasound scanner and 2.5–3.5 MHz transducers to determine left ventricular systolic functions, cardiac valvular disease, and myocardial contraction abnormalities. Left ventricular ejection fraction (%) was measured from crosssectional echocardiographic images of the left ventricle. Statistical analyses
Distribution of the continuous variables was determined using the Kolmogorov–Smirnov test. Continuous variables with a normal distribution were expressed as mean±SD, variables with skew distribution were expressed as median (minimum–maximum), and categorical variables were expressed as percentage. Means were compared
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
750
European Journal of Gastroenterology & Hepatology 2014, Vol 26 No 7
Table 1 Demographic features of the patients and control participants Parameters Age (years) Sex (F/M) (%) LVEF (%) Hemoglobin (g/dl) WBC Platelets ALT AST TC (mg/dl) LDL-C (mg/dl) HDL-C (mg/dl) Triglycerides (mg/dl)
Heart rate variability parameters in functional dyspepsia and controls
Table 2
FD (n = 64)
Controls (n = 62)
P
40.2±7.4 49/15 (77/23) 65.7±3.2 13.1±2.9 5.6±1.1 103 320±16 103 19.9±8.9 21.5±3.9 205.5±27.9 103.6±36.7 62.5±8.0 149.9±38.9
38.1±10.9 45/17 (73/27) 64.1±3.4 13.8±1.9 6.8±2.4 103 351±20 103 22.5±8.4 19.8±3.1 201.8±29.1 114.8±33.4 64.1±5.2 142.5±28.4
NS NS NS NS NS NS NS NS NS NS NS NS
ALT, alanine aminotransferase; AST, aspartate aminotransferase; F/M, female/ male; FD, functional dyspepsia; HDL-C, high-density-lipoprotein cholesterol; LDLC, low-density-lipoprotein cholesterol; LVEF, left ventricular ejection fraction; TC, total cholesterol; WBC, white blood cells.
using analysis of variance or the Mann–Whitney U-test. For all statistics, a two-sided P value less than 0.05 was considered statistically significant. All analyses were carried out using SPSS 10.0 (SPSS Inc., Chicago, Illinois, USA) for Windows.
24 h SDNN (ms) RMSSD (ms) PNN50 (%) LF/HF Daytime SDNN (ms) RMSSD (ms) PNN50 (%) LF/HF Night-time SDNN (ms) RMSSD (ms) PNN50 (%) LF/HF
FD (n = 64)
Controls (n = 62)
P
144.1±33.3 30.5±12.4 9.8±3.9 2.9±1.6
142.1±25.9 35.8±13.9 14.1±7.3 2.8±1.3
NS 0.047 (S) 0.017 (S) NS
122.3±33.1 25.9±10.5 6.8±1.6 3.1±1.2
131.9±22.9 27.7±10.5 18.4±13.8 3.2±1.4
NS NS < 0.001 (S) NS
111.4±39.9 31.7±12.4 16.5±14.7 2.7±1.6
133.4±29.8 38.2±17.5 16.3±11.7 2.5±1.0
0.001 (S) 0.019 (S) NS NS
FD, functional dyspepsia; LF/HF ratio, low-frequency/high-frequency ratio; PNN50, proportion derived by dividing the number of interval differences of successive normal to normal intervals greater than 50 ms; RMSSD, square root of the mean squared differences of successive normal to normal intervals; S, significant; SDNN, SD of the normal to normal intervals.
Fig. 1
80.00
Results
On the basis of the results of the Holter analysis, all participants were detected to have sinus rhythm, without episodes of sustained atrial or ventricular arrhythmias and sinus node dysfunction or atrioventricular block. Twentyfour hour RMSSD (30.5±12.4, 35.8±13.9; P = 0.047), 24 h PNN50 (9.8±3.9, 14.1±7.3; P = 0.017), daytime PNN50 (6.8±1.6, 18.4±13.8; P < 0.001), night SDNN (111.4±39.9, 133.4±29.8; P = 0.001), and night RMSSD (31.7±12.4, 38.2±17.5; P = 0.019) were significantly lower in patients with FD than in the controls. Other HRV parameters were not significantly different between the two groups (Table 2). Changes in these parameters showed a decreased parasympathetic tone and discordance in sympathovagal activity in FD. Box plot graphics of 24 h RMSSD and 24 h PNN50 are presented in Figs 1 and 2. Daytime PNN50 (5.9±1.4, 7.6±1.8, and 18.4±13.8, respectively) and night SDNN (115.4±48.9, 107.1±26.6, and 133.4±29.8) were significantly lower in the EPS and PDS groups than in the controls (Table 3). Other HRV
60.00 24 h RMSSD
A total of 64 patients with FD and 62 control participants were examined. Patients with FD were classified into two subgroups as PDS and EPS. There were 30 patients with PDS and 34 with EPS. Demographic data of the FD [mean age: 40.2±7.4 years; 49 (77%) women] and control groups [mean age: 38.1±10.9 years; 45 (73%) women] were similar (Table 1). None of the participants had hypertension, diabetes mellitus, heart failure, coronary artery disease, or valvular heart disease. The ratio of H. pylori infection was 63% (40 patients) in the FD group and 66% (41 individuals) in the control group.
40.00
20.00
0.00 Controls
FD
Box plot graphic of 24 h RMSSD in patients with functional dyspepsia (FD) and controls. RMSSD, square root of the mean squared differences of successive normal to normal intervals.
parameters were not significantly different between the three groups.
Discussion This study showed that patients with FD had decreased parasympathetic tone and discordance in sympathovagal activity. To the best of our knowledge, there is only one study that has examined the relationship between FD and ANS activity. We evaluated ANS activity using HRV. HRV is a reliable quantitative method for evaluation of ANS activity [3]. This method is used in general cardiology practice for evaluation of ANS activity and risk of arrhythmia in patients with coronary heart disease,
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Decreased parasympathetic activity Dal et al. 751
heart failure, hypertension, diabetes mellitus, and other disorders [4]. Lorena et al. [5] evaluated ANS activity in a small number of patients with FD. They found that the values of parameters reflecting vagal activity were significantly lower in patients with FD. The results of our study are similar to their findings. They studied a very small sample size. We had a larger sample size compared with their study. We used the new classification criteria to evaluate patients with FD. We evaluated the HRV parameters PDS and EPS separately. The power of our study was high. The power of their study was unknown. The major sensory nerve supply of the gastrointestinal tract arises from the abdominal vagus nerve. Stimulation
Fig. 2
60.00
∗
24 h PNN50
50.00 40.00 30.00 20.00 10.00 0.00 Controls
FD
Box plot graphic of 24 h PNN50 in patients with functional dyspepsia (FD) and controls. PNN50, proportion derived by dividing the number of interval differences of successive NN intervals greater than 50 ms. *P = 0.017.
Table 3
of the abdominal vagal nerve or its peripheral fields induce a complex physiological response of heart and vessels. Some studies have reported gastric vagal neuropathy to be strongly related to cardiac autonomic neuropathy in diabetic patients [6]. These physiological and pathological findings support the concept that cardiovascular autonomic responses also reflect the function of the abdominal vagus. There are several explanations for low vagal tone in patients with FD. Low vagal tone in patients with FD was associated with mental stress and personality factors [7]. However, it seems plausible that other mechanisms may contribute toward the autonomic dysfunction in these patients. The relationship between decreased vagal activity and motor dysfunction in FD is still controversial. Hausken et al. [8] suggested a relation between decreased vagal tone and antral dysmotility in patients with FD. Greydanus et al. [9] found that abnormal transit was sometimes associated with disorders of extrinsic neural control, but the latter are also found in patients with normal transit. Consequently, further descriptive studies are required to establish the real impact of the observed parasympathetic dysfunction on the gastrointestinal motor function in FD. In our study, although patients were well matched in terms of sex and age, there were a number of other factors that could have affected HRV that were not controlled for in this study including anxiety, depression, sleep state, of abuse, symptom severity, menstruation, and BMI. It is likely that these may have influenced the outcomes as these are parameters that have differed between groups in previous studies, for example, FD has been associated with anxiety in a number of studies and, similarly, the PDS subtype has been more associated with anxiety [10]. FD has also been associated with sleep disturbances in some series [11]. These factors were some of the limitations of our study.
Heart rate variability parameters in patients with postprandial distress syndrome, epigastric pain syndrome, and controls
Parameters 24 h SDNN (ms) RMSSD (ms) PNN50 (%) LF/HF ratio Daytime SDNN (ms) RMSSD (ms) PNN50 (%) Night-time SDNN (ms) RMSSD (ms) PNN50 (%)
EPS (n = 34)
PDS (n = 30)
Controls (n = 62)
Pa
Pb
Pc
146.8±36.8 29.7±12.3 9.0±6.9 3.1±1.6
140.9±28.1 31.3±12.6 10.7±4.9 2.8±1.6
142.1±25.9 35.8±13.9 14.1±7.3 2.8±1.3
NS NS NS NS
NS 0.039 (S) 0.048 (S) NS
123.6±36.0 25.3±10.3 5.9±1.4
120.8±30.0 26.8±10.9 7.6±1.8
131.9±22.9 27.7±10.5 18.4±13.8
NS NS NS
NS NS < 0.001 (S)
NS NS < 0.001 (S)
115.4±48.9 31.7±10.1 15.7±14.2
107.1±26.6 33.7±12.1 17.4±13.6
133.4±29.8 38.2±17.5 16.3±11.7
NS NS NS
< 0.001 (S) 0.031 (S) NS
0.003 (S) NS NS
NS NS NS NS
EPS, epigastric pain syndrome; LF/HF ratio, low-frequency/high-frequency ratio; PDS, postprandial distress syndrome; PNN50, proportion derived by dividing the number of interval differences of successive normal to normal intervals greater than 50 ms; RMSSD, square root of the mean squared differences of successive normal to normal intervals; S, significant; SDNN, SD of the normal to normal intervals. a P value between EPS and PDS. b P value between EPS and controls. c P value between PDS and controls.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
752 European Journal of Gastroenterology & Hepatology
2014, Vol 26 No 7
In patients with FD, the first step of treatment is eradication of H. pylori, if present, according to the Maastricht criteria [12]. After this step, if symptoms of FD persist, proton pump inhibitors and prokinetic drugs are used for treatment. However, these drugs do not affect the physiopathology of FD. This study aimed to examine the physiopathology of FD. We found decreased parasympathetic activity in the patients with FD. To identify novel treatment methods and drugs, researchers should focus on decreased parasympathetic activity. The rate of H. pylori infection was very high in our study population. However, there was no significant difference in patients with FD and the controls. Conclusion
Our study showed decreased parasympathetic activity in patients with FD. Further studies are required to evaluate the significance of HRV parameters and to clarify the mechanism of decreased parasympathetic activity in patients with FD.
Acknowledgements Conflicts of interest
There are no conflicts of interest.
References 1
Drossman DA. The functional gastrointestinal disorders and the Rome III process. Gastroenterology 2006; 130:1377–1390.
2
Thompson DG. Modulation of gastric perception and motility in man. Current concepts and correlation with symptoms. Dig Dis Sci 1994; 39 (Suppl): 48S–50S. 3 Pumprla J, Howorka K, Groves D, Chester M, Nolan J. Functional assessment of heart rate variability: physiological basis and practical applications. Int J Cardiol 2002; 84:1–14. 4 Task Force of European Society of Cardiology and the North American Society of Pacing and Electrophysiology on Heart Rate Variability. Standards of measurement, physiological interpretation, and clinical use. Eur Heart J 1996; 17:354–381. 5 Lorena SL, Figueiredo MJ, Almeida JR, Mesquita MA. Autonomic function in patients with functional dyspepsia assessed by 24-hour heart rate variability. Dig Dis Sci 2002; 47:27–31. 6 Buysschaert M, Donckier J, Dive A, Ketelslegers JM, Lambert AE. Gastric acid and pancreatic polypeptide responses to sham feeding are impaired in diabetic subjects with autonomic neuropathy. Diabetes 1985; 34: 1181–1185. 7 Haug TT, Svebak S, Hausken T, Wilhelmsen I, Berstad A, Ursin H. Low vagal activity as mediating mechanism for the relationship between personality factors and gastric symptoms in functional dyspepsia. Psychosom Med 1994; 56:181–186. 8 Hausken T, Svebak S, Wilhelmsen I, Haug TT, Olafsen K, Pettersson E, et al. Low vagal tone and antral dysmotility in patients with functional dyspepsia. Psychosom Med 1993; 55:12–22. 9 Greydanus MP, Vassallo M, Camilleri M, Nelson DK, Hanson RB, Thomforde GM. Neurohormonal factors in functional dyspepsia: insights on pathophysiological mechanisms. Gastroenterology 1991; 100:1311–1318. 10 Tse AW, Lai LH, Lee CC, Tsoi KK, Wong VW, Chan Y, et al. Validation of self-administrated questionnaire for psychiatric disorders in patients with functional dyspepsia. J Neurogastroenterol Motil 2010; 16:52–60. 11 Vege SS, Locke GR 3rd, Weaver AL, Farmer SA, Melton LJ 3rd, Talley NJ. Functional gastrointestinal disorders among people with sleep disturbances: a population-based study. Mayo Clin Proc 2004; 79:1501–1506. 12 Malfertheiner P, Megraud F, O’Morain CA, Atherton J, Axon AT, Bazzoli F, et al. European Helicobacter Study Group. Management of Helicobacter pylori infection – the Maastricht IV/Florence consensus report. Gut 2012; 61:646–664.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
