An estimated 1 billion individuals have hypertension worldwide, with 50 million individuals in the United States alone.1 Its prevalence is increasing and, by 2025, it is estimated that the number of adults with hypertension will be around 1.56 billion.2 Obesity or overweight and disorders of lipid and uric acid metabolism are the primary risk factors of essential hypertension. Gastroesophageal reflux disease (GERD), another common medical condition, shares many of the same risk factors with hypertension, such as obesity, male sex, and alcohol drinking. In Western countries, approximately 10% to 20% of adults experience the typical symptoms of GERD—heartburn and/or acid regurgitation—at least once a week.3 GERD has been linked to a number of extraesophageal symptoms and disorders. The Montreal Definition and Classification of GERD have recognized that cough, laryngitis, asthma, and dental erosion can be manifestations of the GERD syndrome.4 Lux et al5 used simultaneous monitoring of esophageal function and electrocardiographic activity to demonstrate that GERD was present in 40% of patients with angiographically proven coronary artery disease (CAD). Studies on the association between GERD and cardiovascular disease have reported conflicting results. Although 1 study demonstrated that GERD was associated with an increased prevalence of hypertension,6 another study found that coronary heart disease and hypertension were not correlated with GERD, although nonvalvular atrial fibrillation was significantly associated with symptomatic GERD.7 Interestingly, Sarnelli et al8 found the prevalence of hypertension to be significantly lower in GERD patients than in non-GERD patients and suggested that GERD might protect against hypertension by inducing changes in the dietary habits of patients.
Many factors are involved in the development of essential hypertension, but whether GERD has an increased risk of hypertension with an increased prevalence of ≥1 hypertension risk factors. The availability of methods such as 24-hour blood pressure (BP) and esophageal impedance and pH monitoring has made investigation of this relationship possible. The aim of this study was to determine whether there was a relationship between GERD and episodes of high BP in patients with essential hypertension, and to assess whether short-term antiacid therapy for GERD could lower BP.
MATERIALS AND METHODS
Compliance With Ethical Standards
Informed consent was obtained from each patient included in the study. The studies have been approved by the First Affiliated Hospital of Zhengzhou University ethics committee and have been performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.
A total of 86 patients with essential hypertension, seeking care in the Cardiology Clinic and Department of Gastroesophageal Reflux Disease in the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China, were recruited consecutively. They included 49 men and 37 women, with a mean age of 53.8 years (age range, 30 to 80 y).
he medical data of all patients with essential hypertension showed mild to moderate hypertension according to the World Health Organization (WHO) criteria at routine examination in adult. According to these criteria, hypertension is defined as systolic BP ≥140 mm Hg and/or diastolic BP ≥90 mm Hg, or history of therapy with antihypertensive medication. Patients with secondary hypertension and target organ damage were excluded from the study.
GERD was diagnosed if the typical symptoms of heartburn and regurgitation were accompanied by endoscopic evidence of esophagitis, or abnormal esophageal pH, a DeMeester score ≥14.72 with symptom correlation of ≥50%, or >73 reflux episodes per day during 24-hour ambulatory impedance monitoring.9 Any patients who had symptoms suggestive of reflux esophagitis and had received 14-day therapy with proton-pump inhibitors (PPIs) were also assumed to have GERD. Patients with large hernias and obstructive sleep apnea syndrome (OSAS) were excluded from the study, because these conditions could cause changes in BP,10,11 interfere with the results of the study.
Pathologic reflux (PR), that is, reflux associated with the onset of symptoms (such as heartburn, regurgitation, chestpain and so on), was indicated by a fall in esophageal pH to <4 for >5 minutes.12
Secondary Study End Points
All patients underwent endoscopy, simultaneous 24-hour continuous BP monitoring, esophageal impedance and pH monitoring. Patients on any form of antiacid therapy were asked to stop treatment for at least 2 weeks before the study. Antihypertensive therapy was not withheld or altered during the study. Twenty-four hour continuous BP monitoring and impedance-pH monitoring were carried out at the same time.
The 24-hour BP monitoring device consisted of an inflatable cuff attached to a small computer, which weighed about 500 grams. It was worn over the shoulder or on a belt. On the basis of study of Dobrzycki et al12 and Lam et al,13 hypertension provoked by GERD was defined as elevation of systolic BP to ≥140 mm Hg and/or diastolic BP to ≥90 mm Hg during and for up to 10 minutes after a PR episode. In our methodology, BP monitoring was set to monitor once every 10 minutes over a 24-hour time period. Information on the BP measurements was recorded on tape and could be downloaded to a computer. The following variables were assessed: daytime (awake activity) BP, nocturnal (sleep) BP, diurnal average systolic and diastolic BP, and the percentage fall in nocturnal BP (ie, average daytime BP—average nocturnal BP/average daytime BP). According to the percentage fall in nocturnal BP, patients could be classified as “dippers” (those with 10% to 20% fall in BP at night) and “nondippers” (those with <10% fall in BP at night). When the decrease in systolic BP and diastolic BP were discordant, only the systolic BP was considered.
Esophageal impedance-pH was measured with an antimon electrode catheter (Syntetics, Sweden). For each patient, the electrode catheter was placed 5 cm above lower esophageal sphincter. The indicators and standards for impedance-pH monitoring were adapted from Kim.14 The following parameters were evaluated: (1) total duration for which pH remained <4, (2) percentage duration for which pH was <4 in the upright position, (3) percentage duration for which pH was <4 in the recumbent position, and (4) number of times pH decreased to <4.
Primary Study End Points
All cases of high BP recorded during a PR episode were considered time-dependent on PR. Patients who had at least 1 episode of high BP in response to PR were identified. The relationship between GERD and hypertension was evaluated by episode of PR and high BP. These patients were then administered a 14-day course of omeprazole (20 mg twice a day). On the 14th day of the therapy, simultaneous continuous esophageal impedance-PH and BP monitoring was repeated at the similar external environment (eg, similar time of sleep, daily activity, etc.).
Statistical analysis was performed using SPSS 17.0 (SPSS Inc., Chicago, IL) and GraphPad InStat version 3.06 (GraphPad Software, San Diego, CA). The data were reported as maximum, minimum, mean, and SD for normally distributed variables. The nonparametric Mann-Whitney U test was used when the data were not normally distributed. Regression analysis was used to determine the relationship between hypertension and GERD. Pearson χ2 test or matched-pairs t test were used to compare BP and esophageal pH variables before and after antiacid therapy. A difference was considered statistically significant at P≤0.05.
Among the 86 patients with hypertension, 38 patients (44.2%) had GERD (Fig. 1); however, only 24 patients satisfied the criteria that at least 1 high BP episode was time-dependent on the occurrence of PR (Fig. 1). Of these 38 patients who met GERD and hypertension criteria, 25 patients first showed GERD symptoms and the emergence of hypertension were 1 to 10 years later; 13 patients first showed hypertension and the emergence of GERD were 0.8 to 6 years later. The duration of GERD were (8.2±5.6) years and of hypertension were (6.4±4.0) years. There were no differences in mean age, sex distribution, body mass index (BMI), prevalence of smoking, and antihypertensive drug medication between patients with GERD versus those without GERD (P>0.05 in all cases). The proportion of patients taking different types of antihypertensive drugs (eg, β-blocker, calcium channel antagonist, angiotensin converting enzyme inhibitor, or angiotensin II receptor blocker) were also comparable in both groups. However, there were no statistical difference in both groups (Table 1).
The incidence of esophagitis was significantly higher in GERD group than the control group (P=0; Table 1). There were 494 PR episodes and 684 high BP episodes in the 38 patients with GERD. Of these, 317 PR episodes and 339 high BP episodes occurred at night, whereas 177 PR episodes and 345 high BP episodes occurred at daytime. The PR episodes were significantly more common at night when supine (P=0.003), occurring predictably around 2:00 AM (Fig. 2). There was no difference between daytime and nighttime in the incidence of high BP episodes (P=0.934), however, there significantly increased during early AM or waking hours than other time periods (P<0.05).
A significantly higher incidence of the high BP episodes was observed in GERD patients than in non-GERD patients [22.58 (SD 6.33) vs. 14.82 (SD 5.44); P=0.016]. GERD patients also had significantly higher average nocturnal BP than non-GERD patients (P=0.026 and P=0.020 for systolic BP and diastolic BP, respectively). However, daytime BP and mean BP were not significantly different between patients with and without GERD (P>0.05; Fig. 3). The percentage of reduced nocturnal BP (nondippers) was 6.5%.
Among 38 GERD and hypertension patients, there was correlation in the frequencies of high BP and PR episodes in 24-hour period (R 2=0.259, P=0.011, Fig. 2). Twenty-four patients who at least 1 high BP episode was time-dependent on the occurrence of PR. Two patients had only 1 high BP episodes related to PR, the other 22 patients had at least 2 episodes. Manual correlation of the time of the high BP episodes to the time of the PR episodes revealed 102 (14.9%) high BP episodes to be PR dependent. The 24 patients who high BP episodes related to PR were administered 14 days of PPI therapy with omeprazole (20 mg bid). Esophageal pH parameters of GERD patients gathered before and after treatment with omeprazole are shown in Table 2. As expected, the DeMeester score, the total duration for which pH remained <4, the percentage duration for which pH was <4 in the upright position, the percentage duration for which pH was <4 in the recumbent position, the number of times pH decreased to <4, the number of PR episodes, and the number of PR-dependent high BP episodes were all significantly decreased on the 14th day of the therapy (P<0.05 in all cases). Omeprazole therapy also resulted in a statistically significant reduction of BP; the mean BP, daytime BP, and nighttime BP were significantly lower after therapy (P<0.05; Table 2 and Fig. 4).
This study mainly considers the relationship between GERD and hypertension. The use of 24-hour continuous BP monitoring provides a clear picture of an individual’s BP because it is unaffected by the phenomenon of “white coat hypertension”; allows identification of hidden hypertension; can assess degree of arised BP or short-term variations in BP and the circadian rhythm; and so on. Similarly, 24-h esophageal impedance and pH monitoring detects not just acid reflux but also helps distinguish between weak acid reflux and nonacid reflux.
Gastroesophageal reflux (GER) during sleep can lead to the development of extra-esophageal complications such as asthmatic attacks and idiopathic pulmonary fibrosis.15 A large national survey in the United States that evaluated the prevalence of nocturnal GER and its effect on quality of life found that 10% of respondents have symptoms of nocturnal GER.16 In a recent prospective study of 331 obstructive sleep apnea patients, nocturnal GER was present in 62% of patients before the start of continuous positive airway pressure treatment.17 Consistent with previous studies, our study also showed that episodes of GER were more common in the nighttime, especially when supine (Fig. 2). This could be because of increased vagal activity at night, which can increase gastric acid production, delay esophageal clearance, and reduce lower esophageal sphincter tension. In addition, in the recumbent posture, the position of the esophagus and stomach increases the chances of reflux.
The defined of large HH was size of hernia sac >6 cm, or >30% of the stomach herniated into the chest cavity.18 Large HH could compress the left atrium and result in hemodynamic changes.10 OSAS is defined as an apneahypopnea index (AHI) >5, along with excessive daytime somnolence.19 The similar epidemiological and biochemical variables raises the possibility of considerable co-morbidity between hypertension and OSAS. The numerous epidemiological datas support a causal relationship between OSAS and hypertension.20–22 These results led to the exclusion of large HH and OSAS patients.
GERD has been identified in 40% of patients with angiographically proven coronary artery disease,5 and cardiac arrhythmias have also been found to be significantly correlated with GERD episodes.7 An earlier study had shown that hypertension occurred more frequently in patients with BE and RE, GERD was associated with an increased prevalence of hypertension.6 The study underwent at the similar external conditions. So, we did not consider heart rate, and used BP as the only surrogate in pathologic esophageal acid reflux. We used 24-hour esophageal impedance and pH and BP monitoring and found that there was significant association between hypertension and GERD (R 2=0.259, Fig. 2), with episodes of PR being associated with elevation of both systolic and diastolic BP (Fig. 3). Among 684 high BP episodes in the 38 patients with GERD, manual correlation of the time of the high BP episodes to the time of the PR episodes revealed 102 (14.9%) high BP episodes to be PR dependent. This method was arbitrarily selected time window, which could be free of time dependent analysis shortcomings. Although a minority of BP episodes was related to PR, it was important significance to clinical research. Although our findings may be true, the interrelated mechanisms are not known.
The common risk factors for hypertension and GERD are one of the possible explanations for the relationship between these 2 conditions. A higher prevalence of GERD and CAD has been reported in elders, smokers, and patients with excess abdominal fat.23,24 In our study population there was no significant difference between GERD patients and non-GERD patients in mean BMI or in the distribution of male sex or obesity and so it is unlikely that these factors were responsible for the GER associated with hypertension (Table 1), which was the samilar as a previous study.6
β-Blockers and calcium channel blockers, both of which are commonly used in patients with hypertension, may increase GER by reducing the tone of the lower esophageal sphincter and by diminishing esophageal clearance. This may be one of mechanisms responsible for the relatively high prevalence of GERD in patients with hypertension. Another possible mechanism could be a neural reflex between the esophagus and the cardiovascular system, with GER causing chest pain, and the reflex sympathetic activity induced by chest pain leading to hypertension. Recently, a new theory has been put forward that could also explain the relationship between GERD and hypertension. The theory postulates that under the regulation of caudal solitary complex neurons, cardiorespiratory and digestive reflexes are activated concurrently by the same stimuli. The most notable of which are hypercapnic acidosis and orexin.25
The PPI test is a useful method for the diagnosis and treatment of patients with GERD.26 Current guidelines advise anti-acid therapy with once-daily PPI for those with typical GERD symptoms (ie, regurgitation, heartburn) and twice-daily PPI for those with extra-esophageal symptoms.27,28 PPI therapy has shown ability to improve asthma symptoms29 and performance on pulmonary function tests30 thus allowing reductions in asthma medications.31 Short-term, high-dose PPI therapy has also been successful in controlling non-cardiac chest pain.32,33 Therefore, based on the proven anti-acid effect of PPI, we hypothesized that reduction in GER could be used as an adjunctive therapy for patients with essential hypertension. In this study, we administered 14-day PPI therapy to 24 patients with essential hypertension and assessed how change in esophageal pH affected the BP. Our results clearly demonstrated that antiacid drug therapy could reduce systolic and diastolic BP of patients with both GERD and essential hypertension (Table 2 and Fig. 4).
This study has several limitations: First, hypertension occurred before or after the start of PR could not be assessed. Second, we did not analyze factors known to increase BP and GERD, such as high alcohol, stress and lifestyle. Third, the study sample was small, which precluded subgroup analysis for different factors. Finally, there was no control group in the second part of the study where PPI treatment was administered; it was not clear whether GERD therapy has long lasting effects on hypertension; the lower BP levels detected post treatment may have been related to decrease stress as the patients had already undergone monitoring previously.
This study demonstrated that parts of reflux episodes might be associated with BP elevation. Antiacid therapy restored esophageal pH to normal and significantly lowered elevated BP, which suggested that treatment of GERD could be useful for normalizing BP in essential hypertension patients. Multicenter randomized controlled trials are required to confirm our findings and clarify the underlying mechanisms.
We are indebted to Dr L.X. Gu for assistance with the statistical analysis. The trial has not been registered, because the study is not a randomized controlled trial, and we begin to engage in research in this area recently.
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Keywords:Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
GERD; hypertension; blood pressure monitoring; esophageal impedance and pH monitoring