PLoS ONE plos plosone PLOS ONE 1932-6203 Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0304624 PONE-D-23-41606 Research Article Medicine and health sciencesGastroenterology and hepatologyGastroesophageal reflux disease Medicine and health sciencesCardiologyArrhythmiaAtrial fibrillation Medicine and health sciencesEpidemiologyMedical risk factors Medicine and health sciencesMedical conditionsCardiovascular diseasesCardiovascular disease risk Medicine and health sciencesCardiologyCardiovascular medicineCardiovascular diseasesCardiovascular disease risk Medicine and health sciencesVascular medicineBlood pressure Medicine and health sciencesEndocrinologyEndocrine disordersDiabetes mellitus Medicine and health sciencesMedical conditionsMetabolic disordersDiabetes mellitus Medicine and health sciencesPulmonologyChronic obstructive pulmonary disease Biology and life sciencesNutritionDietAlcohol consumption Medicine and health sciencesNutritionDietAlcohol consumption Gastroesophageal reflux disease symptoms and risk of atrial fibrillation in a population-based cohort study (the HUNT study) GERD symptoms and risk of AF in a population-based cohort study (the HUNT study) https://orcid.org/0000-0001-9158-4942 Drca Nikola Conceptualization Writing – original draft Writing – review & editing 1 2 * Vegard Malmo Validation Writing – review & editing 3 4 Loennechen Jan Pål Supervision Writing – review & editing 3 4 Janszky Imre Supervision Writing – review & editing 5 6 7 Horn Jens W. Formal analysis Software Writing – review & editing 5 8 Department of Cardiology Karolinska University Hospital, Stockholm, Sweden Heart and Lung Disease Unit, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden Clinic of Circulation and Medical Imaging, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway Department of Cardiology, St. Olavs University Hospital, Trondheim, Norway Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway Regional Center for Health Care Improvement, St Olav’s Hospital, Trondheim, Norway Department of Global Public Health, Karolinska Institutet, Stockholm, Sweden Department of Internal Medicine, Levanger Hospital, Health Trust Nord-Trøndelag, Levanger, Norway Yon Dong Keon Editor Kyung Hee University School of Medicine, REPUBLIC OF KOREA

The authors have declared that no competing interests exist.

 * E-mail: nikola.drca@ki.se 31 5 2024 2024 19 5 e0304624 28 12 2023 14 5 2024 2024 Drca et al This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Aims

Gastroesophageal reflux disease (GERD) may influence the risk of atrial fibrillation (AF). We investigated the association between symptoms of GERD and AF in the Trøndelag Health Study (HUNT).

 Methods

The study cohort comprised 34,120 adult men and women initially free of AF with information on GERD symptoms. Participants were followed from the baseline clinical examination (1 October 2006 to 30 June 2008) to March 31, 2018.

 Results

During a median follow-up of 8.9 years, 1,221 cases of AF were diagnosed. When looking at the whole population, participants with much GERD symptoms did not have an increased risk of AF (HR: 1.01; CI: 95%, 0.82 to 1.24) while participants with little GERD symptoms had a 14% lower risk of AF compared those with no GERD symptoms (HR: 0.86; CI: 95%, 0.76 to 0.97). Among younger participants (<40 years of age), the risk of AF had a trend towards increased risk with increasing symptom load of GERD (little GERD symptoms, HR: 3.09; CI: 95%, 0.74 to 12.94 and much GERD symptoms, HR: 5.40; 95% CI: 0.82 to 35.58). Among older participants (≥65 years of age), we saw a slightly reduced risk of AF in participants with little symptoms (HR: 0.84; CI: 0.72 to 0.97) and no association among those with much GERD symptoms (HR: 1.06; 95% CI: 0.82 to 1.36).

 Conclusion

We did not find support for a clinically important association between symptoms of GERD and AF across all age groups but for some younger people, GERD might play a role in the development of AF. However, our estimates for this age group were very imprecise and larger studies including younger individuals are warranted.

 http://dx.doi.org/10.13039/501100004359 Vetenskapsrådet 2019‐06102 https://orcid.org/0000-0001-9158-4942 Drca Nikola http://dx.doi.org/10.13039/501100004359 Vetenskapsrådet 2021-00202 https://orcid.org/0000-0001-9158-4942 Drca Nikola http://dx.doi.org/10.13039/100007435 Åke Wiberg Stiftelse M19-0424 https://orcid.org/0000-0001-9158-4942 Drca Nikola http://dx.doi.org/10.13039/501100018713 Center for Innovative Medicine 20190797 https://orcid.org/0000-0001-9158-4942 Drca Nikola http://dx.doi.org/10.13039/501100003793 Hjärt-Lungfonden 202110302 https://orcid.org/0000-0001-9158-4942 Drca Nikola Center for Innovative Medicine (https://cimed.ki.se/), Region Stockholm, Grant/Award Number: 20190797, Åke Wibergs Stiftelse (https://ake-wiberg.se/), Grant/Award number: M19-0424, Swedish Heart-Lung Foundation (Hjärt-Lungfonden)(https://www.hjart-lungfonden.se/) Grant/Award Number: 20190301, 20200537, and 202110302 and Swedish research Council (Vetenskapsrådet)(https://www.vr.se/) Grant/Award Number: 2019‐06102 and 2021-00202 to ND. The funders did not have any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data Availability The Trøndelag Health Study (HUNT) has invited persons aged 13–100 years to four surveys between 1984 and 2019. Comprehensive data from more than 140,000 persons having participated at least once and biological material from 78,000 persons are collected. The data are stored in HUNT databank and biological material in HUNT biobank. HUNT Research Centre has permission from the Norwegian Data Inspectorate to store and handle these data. The key identification in the data base is the personal identification number given to all Norwegians at birth or immigration, whilst de-identified data are sent to researchers upon approval of a research protocol by the Regional Ethical Committee and HUNT Research Centre. To protect participants’ privacy, HUNT Research Centre aims to limit storage of data outside HUNT databank, and cannot deposit data in open repositories. HUNT databank has precise information on all data exported to different projects and are able to reproduce these on request. There are no restrictions regarding data export given approval of applications to HUNT Research Centre. For more information see: http://www.ntnu.edu/hunt/data. Introduction

Atrial fibrillation (AF) is the most common cardiac arrhythmia of clinical significance and the prevalence of AF is estimated to be around 3% among adults [1–3]. Patients with AF have an increased risk of premature death, which can be partly explained by an increased incidence of comorbidity such as hypertension, diabetes mellitus, coronary artery disease, heart failure and stroke [4]. There are multiple risk factors and medical conditions that predispose to the development of AF. The mechanisms behind the onset and maintenance of AF are not fully understood, but left atrial remodeling and ectopic triggers, especially in the pulmonary veins are important contributors. The burden of AF is increasing and identifying modifiable risk factors is pivotal for prevention [5].

Gastroesophageal reflux disease (GERD), defined by troublesome symptoms of heartburn or regurgitation [6] is a common medical condition with an estimated prevalence in adults in Europe of 8.8%-25.9% [7]. Due to the near anatomical location of the esophagus just behind the left atrium and shared esophageal cardiac neural reflex arches, it has been suggested that the development of AF could be associated with the occurrence of GERD [8]. Local atrial inflammation and irritation caused by esophagitis could potentially trigger AF and increased vagal activity could trigger vagal-mediated AF [9]. Esophageal acid stimulation could reduce coronary flow by neural esophageal-cardiac reflex causing angina and eventually ischemic changes in the atrial tissue promoting AF [10]. GERD could be treated with medication (mainly proton pump inhibitors) or surgical intervention with laparoscopic fundoplication [11]. If an association is found between GERD and AF, it could give us a novel opportunity for prevention of AF in selected patients. Previous studies have shown divergent results and had limited possibilities to adjust for potential confounders [12–16]. We therefore investigated the association between self-reported GERD symptoms and the risk of AF in a large population based study with validated AF diagnoses during the follow up and extensive data on potential confounding factors.

 Methods Study design and population

All residents in Nord-Trøndelag County who were 20 years and older were invited to participate in four consecutive health survey: the HUNT1 Survey (1984–1986), the HUNT2 Survey (1995–1997), the HUNT3 Survey (2006–2008) and the HUNT4 Survey (2018–2019). The HUNT Surveys include questionnaires that cover a wide range of health-related information, including lifestyle factors, and also clinical measurements and analyses of blood and urine samples [17]. In the present study, we used HUNT3 (participants recruited 1 October 2006 to 30 June 2008) as the baseline. A total of 50 804 residents completed questionnaires and underwent a baseline clinical examination. After excluding participants with missing information on GERD (n = 13,407), potential confounders (n = 2,118) and AF diagnosis (n = 1,159) before baseline, it left us with 34,120 individuals for further analysis (Fig 1). Out of these, 24,550 participants reported on GERD symptoms at HUNT2 (participants recruited 1 August 1995 to 30 June 1997) as well.

10.1371/journal.pone.0304624.g001 Final population after excluding participants who did not meet inclusion criteria or with missing information on confounders.

Not mutually exclusive. GERD: Gastroesophageal reflux symptoms; AF: Atrial fibrillation; BMI: Body mass index; COPD: Chronically Obstructive Pulmonary Disease.

The present study was approved by the Regional Committee for Medical and Health Research Ethics Midt-Norway (2016/542 and 2015/2313) and all participants signed a written informed consent before study participation.

 Assessment of GERD (exposure)

In both HUNT2 and HUNT3, information on GERD symptoms was gathered from the participants through a self-administered questionnaire. The participants were asked “To what degree have you had heartburn or acid regurgitation during the previous 12 months?” and were offered three response alternatives “never”, “a little” and “much”. GERD symptoms in the HUNT 2 have been validated showing that 95% of participants reporting much reflux symptoms experience reflux symptoms at least once a week [18].

 Case ascertainment (outcome)

Incident cases of AF were identified through linkage of participants’ Norwegian personal identification number to AF diagnoses (based on ICD-10 code I48) from the two local hospitals in Nord-Trøndelag County from baseline examination date until March 2018. The outcome of AF was defined as either a diagnosis of AF or of atrial flutter because of their close interrelationship. All diagnoses of AF were manually verified by a specialist in cardiology and internal medicine by extracting clinical information and ECG data from the electronic medical records [19].

 Covariates

Information on the participants’ smoking status (never, former, occasional and current), physical activity (inactive, active), alcohol use (abstainers, light, moderate and heavy drinkers), education (≤ 9 years, 10–12, > 12 years), marital status (dichotomized as living alone or not) and medical history of common chronic disease such as angina pectoris, myocardial infarction, chronic obstructive pulmonary disease (COPD), diabetes mellitus and hypertension was gathered by a self-administrated questionnaire in the HUNT3 Survey. Trained nurses conducted a clinical examination where height and weight were measured wearing light clothes without shoes; height was measured to the nearest 1 cm and weight to the nearest 0.5 kg. BMI was calculated as body weight (in kg) divided by the squared value of height (in meters). Systolic and diastolic blood pressure were measured using an automatic sphygmomanometer based on oscillometry, and the average of the second and third measurement was used in the analysis.

 Statistical analysis

Participants were followed from the baseline clinical examination at HUNT3 to the date of diagnosis of AF, death, emigration out of the county, or March 31, 2018, whichever came first. Continuous variables are presented as mean ± SD while categorical variables are presented as numbers (percentage). We categorized the participants into three groups depending on their self-reported level of GERD symptoms during the last 12 months (“never”, “a little” and “much”). Hazard ratios (HR) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards models with age as the underlying time scale. We evaluated the proportional hazards assumption by comparing -ln-ln survival curves and by performing tests on Schoenfeld residuals for each covariate and found no violation of these assumptions. In addition to age at baseline (continuous) and sex, multivariable models were further adjusted for smoking status, alcohol consumption, physical activity level, marital status, education, angina pectoris, myocardial infarction, COPD, diabetes mellitus and hypertension.

Additional analyses were stratified by age (age <40, age ≥ 40 and <65 and, age ≥ 65 years).

All statistical analyses were conducted using Stata 16 for Windows (StataCorp LP, College Station, TX).

 Results

The characteristics of the study population is presented in Table 1. Participants with “much” and “little” symptoms of GERD were older, more often men, had higher BMI, were more often current or former smokers and had more comorbidities such as hypertension, ischemic heart disease, diabetes mellitus and COPD compared to individuals with “never” reflux symptoms. A table comparing the characteristics of in- and excluded participants is presented in the supplementary material. Excluded participants had slightly less cardiovascular diseases and lower prevalence of tertiary education (S1 Table). During a median follow-up of 8.9 years (304,181 person-years), 1,221 cases of AF were diagnosed.

10.1371/journal.pone.0304624.t001 Characteristics of the study population (n = 34,120).
Degree of reported symptoms on Gastroesophageal reflux
Nevern = 19,387 A littlen = 12,314 Muchn = 2,419
Female, n (%) 11,363 58.6 6,421 52.1 1,321 54.6
Age at Baseline, years (SD) 51.4 15.0 54.6 14.4 54.6 14.1
BMI (kg/m2) (SD) 26.4 4.2 28.0 4.4 28.9 4.5
Hypertension, n (%) 6,611 34.1 5,527 44.9 1,104 45.6
Diabetes mellitus, n (%) 747 3.9 656 5.3 118 4.9
C-reactive protein (mg/l) (SD) 2.31 4.85 2.95 6.00 3.37 7.03
High-density lipoprotein (mmol/l) (SD) 1.39 0.36 1.31 0.34 1.29 0.34
Total cholesterol (mmol/l) (SD) 5.46 1.10 5.59 1.09 5.67 1.17
COPD, n (%) 435 2.2 527 4.3 127 5.3
Angina pectoris, n (%) 444 2.3 503 4.1 137 5.7
Myocardial infarction, n (%) 426 2.2 434 3.5 83 3.4
Alcohol consumption
    Abstainers, n (%) 3,743 19.3 2,404 19.5 524 21.7
    Light drinkers, n (%) 11,821 61.0 7,455 60.5 1,417 58.6
    Moderate drinkers, n (%) 3,548 18.3 2,293 18.6 429 17.7
    Heavy drinkers, n (%) 275 1.4 162 1.3 49 2.0
Smoking status
    Never, n (%) 9,132 47.1 4,746 38.5 818 33.8
    Former, n (%) 5,932 30.6 4,524 36.7 973 40.2
    Occasionally, n (%) 1,300 6.7 896 7.3 176 7.3
    Current, n (%) 3,023 15.6 2,148 17.4 452 18.7
Physical inactivity
    Inactive, n (%) 3,539 18.3 2,733 22.2 647 26.8
    Active, n (%) 15,848 81.8 9,581 77.8 1,772 73.3
Education
    Lower secondary, n (%) 3,667 18.9 3,073 25.0 674 27.9
    Upper secondary, n (%) 9,477 48.9 6,198 50.3 1,255 51.9
    Tertiary, n (%) 6,243 32.2 3,043 24.7 490 20.3
Marital Status
    Single, n (%) 4,482 23.1 2,397 19.5 441 18.2
    Married, Cohabitant, n (%) 11,806 60.9 7,710 62.6 1,503 62.1
    Widow, Divorced, Separated, n (%) 3,099 16.0 2,207 17.9 475 19.6

Values are presented as mean ± standard deviation or number (percentages). BMI body mass index. COPD chronic obstructive lung diseases. n = number.

In our main analyses we saw those patients reporting little symptoms of GERD had a multivariable HR of 0.86 (95% CI: 0.76 to 0.97) while patients reporting much had a HR of 1.01 (95% CI: 0.82 to 1.24) compared to patients who never had any GERD symptoms, indicating a U-shaped association (Table 2). Dichotomization of GERD symptoms into just two groups resulted in a HR of 1.08 (95% CI: 0.88 to 1.32) for “Much” GERD symptoms compared to “Never or a little”. In a sensitivity analyzes where we excluded all participants who reported cardiac angina, infarction, or COPD symptoms, we observed no relevant changes of the estimates. Additional adjustment for lipids and CRP resulted in no appreciable changes in the estimates (data not shown).

10.1371/journal.pone.0304624.t002 Gastroesophageal reflux disease symptoms and risk for atrial fibrillation.
GERD Symptoms n = 34,120 Events1,221 Person years304,181 HR* 95% CI HR‡ 95% CI HR# 95% CI
Never 19,387 645 173,360 1 (Ref) 1 (Ref) 1 (Ref)
A little 12,314 470 109,338 0.93 0.82–1.04 0.88 0.78–0.99 0.86 0.76–0.97
Much 2,419 106 21,482 1.12 0.91–1.38 1.02 0.83–1.26 1.01 0.82–1.24
Never or a little 31,701 1,115 282,699 1 (Ref) 1 (Ref) 1 (Ref)
Much 2,419 106 21,482 1.16 0.95–1.41 1.08 0.89–1.32 1.08 0.88–1.32

N = number

HR = Hazard Ratio

CI = Confidence interval

*Model 1: Adjusted for age at baseline (continuous) and sex.

‡Model 2: Adjusted as Model 1 and additional for body mass index (continuous), smoking status (never, former, current), alcohol consumption (abstain, light drinkers, moderate drinkers, heavy drinkers), physical activity (inactive, active), education (lower secondary education, upper secondary education, tertiary education) and marital status (unmarried, married/cohabitant, widowed/divorced/separated).

#Model 3: Adjusted as Model 2 and additional blood pressure (dichotomized hypertension: systolic blood pressure>140mmHg or diastolic blood pressure >90 mmHg or use of blood pressure lowering medication), diabetes mellitus (patient indicated to have diabetes mellitus or non-fasting glucose >11.1 mmol/l), chronic obstructive pulmonary disease.

In the age stratified analyses, among younger participants (<40 years of age), the risk of AF had a trend towards increased risk with increasing symptom load of GERD (little GERD symptoms, HR: 3.09; CI: 95%, 0.74 to 12.94 and much GERD symptoms, HR: 5.40; 95% CI: 0.82 to 35.58). However, due to few events at younger age, the estimates were imprecise with wide Cis. Among older participants (≥65 years of age), we saw a similar U-shaped association as in our main analyses: a slightly reduced risk of AF in participants with little symptoms (HR: 0.84; CI: 0.72 to 0.97) and no association among those with much GERD symptoms (HR: 1.06; 95% CI: 0.82 to 1.36) (Table 3).

10.1371/journal.pone.0304624.t003 Gastroesophageal reflux disease symptoms and risk for atrial fibrillation stratified for 3 age groups.
Age <40 Age ≥ 40 and <65 Age ≥ 65
n(7,089) Events(11) HR 95% CI n(19,761) Events(390) HR 95% CI n(7,270) Events(820) HR 95% CI
Never 4,673 3 1 (Ref) 10,975 205 1 (Ref) 3,739 437 1 (Ref)
A little 2,035 6 3.09 0.74–12.94 7,296 152 0.87 0.70–1.07 2,983 312 0.84 0.72–0.97
Much 381 2 5.40 0.82–35.58 1,490 33 0.88 0.61–1.28 548 71 1.06 0.82–1.36

n = number; HR = Hazard Ratio; CI = Confidence interval

Adjusted for age at baseline (continuous), sex, body mass index (continuous), smoking status (never, former, current), alcohol consumption (abstain, light drinkers, moderate drinkers, heavy drinkers), physical activity (inactive, active), education (lower secondary education, upper secondary education, tertiary education), marital status (unmarried, married/cohabitant, widowed/divorced/separated), blood pressure (dichotomized hypertension: systolic blood pressure>140mmHg or diastolic blood pressure >90 mmHg or use of blood pressure lowering medication), diabetes mellitus (patient indicated to have diabetes mellitus or non-fasting glucose >11.1 mmol/l) and chronic obstructive pulmonary disease. (Model 3).

P-value for age-GERD interaction < 0.001.

To investigate if long-lasting sustained GERD symptoms influence the risk AF, we categorized the population into four groups: Never GERD (No GERD symptoms in HUNT2 and HUNT3)(Reference), Newly Developed GERD (much or little symptoms of GERD in HUNT 3 but no symptoms in HUNT2), Sustained GERD (much or little symptoms of GERD in both HUNT2 and HUNT 3), Regressed GERD (much or little symptoms of GERD in HUNT2 but no symptoms in HUNT 3). Sustained GERD (HR: 0.90; 95% CI: 0.77 to 1.04) or newly developed GERD (HR: 0.94; 95% CI: 0.79 to 1.11) was not associated with an increased risk for AF. In participants with regression of GERD symptoms, we saw a weak association with a HR of 1.26 (95% CI: 1.01 to 1.56) in the age and sex-adjusted model, which decreased after further adjustment for potential confounders (HR: 1.14; CI: 0.92 to 1.42) (Table 4).

10.1371/journal.pone.0304624.t004 Long lasting gastroesophageal reflux disease symptoms from HUNT2 to HUNT3 and risk for atrial fibrillation.
Long Lasting GERD Symptoms n Events Person years HR* 95% CI HR‡ 95% CI HR# 95% CI
Reference. Never GERD symptoms HUNT2 and HUNT3 11,811 449 105,456 1 (Ref) 1 (Ref) 1 (Ref)
Group 1. Newly Developed GERD symptoms HUNT3 5,117 208 45,432 1.00 0.84–1.17 0.95 0.81–1.12 0.94 0.79–1.11
Group 2. Sustained GERD symptoms HUNT2 and HUNT3 5,769 286 50,830 1.00 0.86–1.16 0.91 0.78–1.05 0.90 0.77–1.04
Group 3. Regressed GERD symptoms HUNT2 1,853 99 16,196 1.26 1.01–1.56 1.16 0.93–1.45 1.14 0.92–1.42

N = number, HR = Hazard Ratio, CI = Confidence interval

Long Lasting GERD symptoms definition: Reference: Never GERD symptoms in HUNT2 and HUNT3, Group 1: Newly Developed GERD symptoms: Never GERD symptoms in HUNT2 but HUNT3 (little or much), Group 2: Sustained GERD symptoms: HUNT2 and HUNT3 (little or much), Group 3: Regressed GERD symptoms: HUNT2 (little or much) but never in HUNT3.

*Model 1: Adjusted for age at baseline (continuous) and sex.

‡Model 2: Adjusted as Model 1 and additional for body mass index (continuous), smoking status (never, former, current), alcohol consumption (abstain, light drinkers, moderate drinkers, heavy drinkers), physical activity (inactive, active), education (lower secondary education, upper secondary education, tertiary education) and marital status (unmarried, married/cohabitant, widowed/divorced/separated).

#Model 3: Adjusted as Model 2 and additional blood pressure (dichotomized hypertension: systolic blood pressure>140mmHg or diastolic blood pressure >90 mmHg or use of blood pressure lowering medication), diabetes mellitus (patient indicated to have diabetes mellitus or non-fasting glucose >11.1 mmol/l), chronic obstructive pulmonary disease.

 Discussion

In this large population-based cohort study with validated data on AF diagnosis and robust data on potential confounders, we were able to find a complex association between GERD symptoms and AF. Our main analyses showed a U-shaped association between the risk of AF and the degree of GERD symptoms. In our age stratified analyses, we saw the same U-shaped association among older individuals. Among younger individuals, we saw a trend towards increasing risk of AF with increasing symptom load of GERD. However, since AF was rare among young participants, the estimates obtained in these analyses were imprecise.

These findings concur with a recent register-based population study that investigated whether objectively determined esophagitis or Barrett’s esophagus increases the risk of AF [12]. The investigators found an increased risk of AF among patients younger than 60 years of age who had a HR of 1.55 (95% CI, 1.27 to 1.88) within the first year of diagnosis but the excess risk decreased afterward (HR: 1.14; 95% CI, 1.06 to 1.22). Older patients (age ≥60 years) did not show an increased risk of AF.

A recent meta-analysis summarized prior research on GERD and AF risk not including the study discussed above. The analyses were based on three cohort and one case-control study (total participants: n = 228 305, participants with GERD: n = 80 171) and did not find support for GERD increasing the risk of AF. The summary RR was 1.06 (95% CI, 0.86 to 1.31) [20]. The three cohort studies included in this meta-analysis showed divergent results. Jeffrey S. Kunz and colleagues showed a weak association between GERD and AF after adjusting for several confounders (RR: 1.08; 95% CI, 1.02 to 1.13) [14] and Chin-Chou Huang and associates were able to reproduce these findings with a HR of 1.31 (95% CI, 1.06 to1.61) [13]. They further saw that patients with GERD symptoms who received proton pump inhibitory (PPI) therapy had the highest risk of AF. This could suggest that patients with the worst symptoms taking PPI therapy also had the highest risk of AF. The third cohort study by Bunch et al. found instead an inverse relationship between the presence of GERD and AF (HR: 0.81; 95% CI, 0.68 to 0.96) after adjusting for other risk factors [15]. In their study, diagnosis of esophagitis seemed to increase the risk for AF (HR: 1.94; 95% CI, 1.35 to 2.78), but after adjusting for age, gender, hypertension, and heart failure the authors reported that the hazard ratio was no longer statistically significant without specifying the point estimate. In an unadjusted survival analysis, they also found a U-shaped association of GERD symptoms and the risk of AF with the highest risk in patients reporting frequent daily symptoms and patients reporting no symptoms. The lowest risk was seen in patients reporting some or weekly GERD symptoms. None of these studies made any age stratified analyses.

A possible explanation for divergent results in studies investigating the association between GERD and AF could be that GERD may have a bigger impact on the risk of AF among younger persons who have a low underlying risk for AF and where vagal nerve stimulation have been found to have a stronger impact on induction of AF [21]. In older individuals, where established risk factors for AF like overweight, hypertension, and age are predominant, and important for AF development it might be difficult to show any eventual additive influence of GERD on the risk of AF.

The observed small risk reduction of AF in older individuals with little GERD symptoms might reflect that treatment of GERD may lead to reduced risk of AF in those individuals. The risk reduction was not observed in older individuals with more severe GERD symptoms.

Study strengths and limitations

Compared to previous register-based studies, we were able to adjust for several important confounding factors such as BMI, alcohol consumption and physical activity. Our study population was stable and homogeneous. The diagnosis of AF was carefully verified and validated by extracting clinical information and ECG data from the electronic medical records which minimized the risk for misclassification and ensured an almost complete follow-up.

The main limitation of the study is the possibility of exposure misclassification. In our study, GERD was evaluated only based on self-reported symptoms. No gastroscopic examination or pH monitoring was used to assess the presence of esophagitis, reflux or gastric ulcer. Furthermore, we did not have any information on medications such as non-steroidal anti-inflammatory drugs or hormone therapy that could potentially influence the risk. If patients with “much” GERD were treated with anti-reflux medication such as proton pump inhibitors, it could decrease reflux and inflammation and thus possibly prevent AF. There is also a possibility that patients reporting GERD symptoms were seeking medical attention more often and by that increasing their chance of getting an AF diagnosis. We cannot rule out that our results were affected by uncontrolled or residual confounding. For example, we did not have information on different types of food or stress.

 Conclusion

In conclusion, our study did not find support for a strong, clinically important association between symptoms of GERD and AF across all age groups but for some younger people, GERD might play a role in the development of AF. However, our estimates for this age group were very imprecise and larger studies including younger individuals are warranted.

 Supporting information Characteristics of in- and excluded study population.

(DOCX)

The Trøndelag Health Study (HUNT) is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology NTNU), Trøndelag County Council, Central Norway Regional Health Authority, and the Norwegian Institute of Public Health. We thank the Department for Research and Development, and clinicians at the Medical Department, Nord-Trøndelag Hospital Trust, Norway, for extracting the data from the patient registers.

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Gut. 2014;63(6):871–80. doi: 10.1136/gutjnl-2012-304269 23853213 Linz D, Hohl M, Vollmar J, Ukena C, Mahfoud F, Bohm M. Atrial fibrillation and gastroesophageal reflux disease: the cardiogastric interaction. Europace. 2017;19(1):16–20. doi: 10.1093/europace/euw092 27247004 Huang TC, Lo LW, Yamada S, Chou YH, Lin WL, Chang SL, et al. Gastroesophageal reflux disease and atrial fibrillation: Insight from autonomic cardiogastric neural interaction. J Cardiovasc Electrophysiol. 2019;30(11):2262–70. doi: 10.1111/jce.14181 31515888 Chauhan A, Mullins PA, Taylor G, Petch MC, Schofield PM. Cardioesophageal reflex: a mechanism for "linked angina" in patients with angiographically proven coronary artery disease. J Am Coll Cardiol. 1996;27(7):1621–8. doi: 10.1016/0735-1097(96)00041-1 8636546 Katz PO, Dunbar KB, Schnoll-Sussman FH, Greer KB, Yadlapati R, Spechler SJ. ACG Clinical Guideline for the Diagnosis and Management of Gastroesophageal Reflux Disease. Am J Gastroenterol. 2022;117(1):27–56. doi: 10.14309/ajg.0000000000001538 34807007 Maret-Ouda J, Santoni G, Xie S, Rosengren A, Lagergren J. Objectively confirmed gastroesophageal reflux disease and risk of atrial fibrillation: a population-based cohort study in Sweden. Eur J Gastroenterol Hepatol. 2022;34(11):1116–20. doi: 10.1097/MEG.0000000000002419 36052701 Huang CC, Chan WL, Luo JC, Chen YC, Chen TJ, Chung CM, et al. Gastroesophageal reflux disease and atrial fibrillation: a nationwide population-based study. PLoS One. 2012;7(10):e47575. doi: 10.1371/journal.pone.0047575 23077642 Kunz JS, Hemann B, Edwin Atwood J, Jackson J, Wu T, Hamm C. Is there a link between gastroesophageal reflux disease and atrial fibrillation? Clin Cardiol. 2009;32(10):584–7. doi: 10.1002/clc.20660 19911354 Bunch TJ, Packer DL, Jahangir A, Locke GR, Talley NJ, Gersh BJ, et al. Long-term risk of atrial fibrillation with symptomatic gastroesophageal reflux disease and esophagitis. Am J Cardiol. 2008;102(9):1207–11. doi: 10.1016/j.amjcard.2008.06.048 18940293 Floria M, Bărboi O, Grecu M, Cijevschi Prelipcean C, Balan G, Drug VL. Atrial fibrillation and sympathovagal balance in patients with gastroesophageal reflux disease. Turk J Gastroenterol. 2017;28(2):88–93. doi: 10.5152/tjg.2017.16540 28134128 Krokstad S, Langhammer A, Hveem K, Holmen TL, Midthjell K, Stene TR, et al. Cohort Profile: the HUNT Study, Norway. Int J Epidemiol. 2013;42(4):968–77. doi: 10.1093/ije/dys095 22879362 Nilsson M, Johnsen R, Ye W, Hveem K, Lagergren J. Obesity and estrogen as risk factors for gastroesophageal reflux symptoms. Jama. 2003;290(1):66–72. doi: 10.1001/jama.290.1.66 12837713 Malmo V, Langhammer A, Bønaa KH, Loennechen JP, Ellekjaer H. Validation of self-reported and hospital-diagnosed atrial fibrillation: the HUNT study. Clin Epidemiol. 2016;8:185–93. doi: 10.2147/CLEP.S103346 27354826 Xu L, Zhang Y, Xie J, Liu Y, Xu L. Association between gastroesophageal reflux disease and atrial fibrillation: a systematic review and meta-analysis. Rev Esp Enferm Dig. 2019;111(11):874–9. doi: 10.17235/reed.2019.5389/2017 31617365 Chen PS, Tan AY. Autonomic nerve activity and atrial fibrillation. Heart rhythm: the official journal of the Heart Rhythm Society. 2007;4(3 Suppl):S61–4. doi: 10.1016/j.hrthm.2006.12.006 17336887 10.1371/journal.pone.0304624.r001 Decision Letter 0 Yon Dong Keon Academic Editor 2024 Dong Keon Yon This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version 0

23 Jan 2024

PONE-D-23-41606Association between Atrial fibrillation and Gastroesophageal reflux disease in a population-based cohort study (the HUNT study)PLOS ONE

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# Please receive the English editing service.

# Hazard ratios (HR) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards models with age as underlying time scale.

Please cite the statistical guideline (DOI: https://doi.org/10.54724/lc.2023.e8).

# Please add the sentence.

"A two-sided P less than 0.05 considered significance." -> in Method.

# Reference is too short to draw the conclusion.

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Reviewer #1: Partly

Reviewer #2: Yes

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Reviewer #1: No

Reviewer #2: Yes

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Reviewer #1: This study aimed to investigate the longitudinal association between GERD and AF using data from the HUNT Study.

I have the following comments:

1: It should be clear in the title that the authors investigated the association between GERD (exposure) and AF (outcome). The title (association between AF and GERD) may give the impression that the authors applied AF as an exposure and GERD as an outcome.

2: Lines 57-61: A reference is needed.

3: Line 66: GERD was already spelled out previously.

4: Line 87: > 30% of participants were excluded for having missing data about GERD. The sociodemographic and clinical data should be compared between those who were excluded and those who were included. The potential discrepancy might have affected the representativeness.

5: Line 88: I recommend the authors to reconsider their complete case analysis approach. They may consider imputation or dummy variable analysis.

6: Line 103: ICD-10 code I48 includes atrial flutter. This should be clarified.

7: The authors have provided data about cholesterol levels and CRP in Table 1, yet they did not adjust for these variables in the regression analysis. This should be reconsidered.

8: BP cut-off for hypertension is either 140/90 mmHg per the European guidelines or 130/80 mmHg per the US guidelines. The application of 130/85 mmHg should have a reference.

9: Table 3: The authors do not have to stratify results by age using the value of median. Age results are usually stratified based on clear definitions, older adults versus young and middle-aged adults for example, with a cut-off of 60 or 65 to define older adults.

10: The main limitation of this study is that GERD was self-reported. Was that diagnosis validated in the HUNT Study or any other studies with similar socio-demographic characteristics? This is a very important point that should be further discussed.

11: GERD and AF have so many common risk factors such as age, obesity, smoking, diabetes, dyslipidemia, heavy alcohol consumption, and dyslipidemia. Stratifying the results by these confounders is essential. The authors may consider performing interaction analyses as well.

12: Lines 210-216: This explanation is not based on scientific evidence. Further, participants aged 54 are not older adults. You may consider this explanation after the analysis is stratified by a different age group cut-off.

13: I recommend adding a 3rd GERD category (any) involving those with any GERD symptoms. Given that the authors have no data about GERD endoscopy or medication history, it is so presumptive to accept that the symptom severity suggested by the participants truly reflected their medical condition.

14: Lines 217-221: To test this hypothesis, the authors should revise their data to see whether GERD patients really improved their lifestyle within the following years.

15: Line 236-238: The conclusion gives the impression that there is a kind of association but not so strong, while no association could be attained. I recommend rephrasing this section.

16: GERD is associated with certain foods and drinks, stress and anxiety, pregnancy, NSAIDs, hormonal therapies, and gastric ulcers. These variables were not controlled in this study. The authors should raise this point in their limitation section.

Reviewer #2: Thank you for the opportunity to review this manuscript. This study investigates the association between conscious levels of gastroesophageal reflux symptoms and the risk of atrial fibrillation in individuals aged 20 years and older. The findings reveal a lack of evidence supporting this association and indicate different trends in this association between younger and older participants. The manuscript is well written, and the sample size is notably large. The ethical information and competing interests have been reported.

The reviewer has several comments.

Major comments:

In general, reports of gastroesophageal reflux disease and atrial fibrillation are not uncommon. Therefore, the content of differences compared to previous findings (interaction with age) becomes more important, which reflects the new information of this research field.

Regarding stratified analysis on age grouping, my perspective is that instead of using the median age to stratify, it is preferable to use age intervals that hold clinical significance. The median age only represents the current demographic of the data in wave 3 of the HUNT study. Using age intervals that have clinical significance, such as 20-39 years, 40-64 years, and 65 years and above, can enhance the applicability of the findings to clinical practice. Individuals aged 20-39 are generally considered to have low risks of cardiovascular diseases and atrial fibrillation (as the authors mentioned in line 182, 210), while the elderly population aged 65 and above exhibits significantly elevated risks of them. In contrast, conscious symptoms of gastroesophageal reflux disease are more common in younger individuals, while older individuals usually have fewer conscious symptoms, but more severe conditions and complications (lead to more misclassifications and possibly null association).

The age interaction is a clever entry point. My suggestion is to present more age-related information, such as the proportion of conscious symptoms in different age groups, and to add more content discussing why individuals of different ages may have different findings. I know the authors have already discussed this aspect, but I feel the content is a bit limited. It would be better to add more information, and mention this interaction in the Abstract and Introduction sections.

Moreover, it is preferable to show the interaction effect between age and gastroesophageal reflux disease levels alongside this stratified analysis.

Another suggestion is to use self-reported/ conscious symptoms of gastroesophageal reflux disease to describe exposure in title and other sections. My concern is that this study identified a weak association, which may be due to self-reporting rather than objective measurement (as the authors mentioned in line 228). Using a precise description can accurately convey the findings.

Minor comments:

1. Atrial fibrillation is the outcome of interest, so it is preferable to put it to the back and change the title to: Association between gastroesophageal reflux disease and incident atrial fibrillation…, or use a similar expression of your preference.

2. The expression “(n = 1,221)” in line 106 is unclear. It is preferable to add details and rephrase it as follows: During the follow-up, 1,221 cases of atrial fibrillation (AF) were diagnosed, or use a similar expression, or delete it because you have already mentioned it in line 141 of the Result section.

3. The expression “Degree of reported symptoms…” in Table 1 is not a column name for participants characteristics, so it is preferable to put it on the top of Never/ A little / Much columns. Besides, these numbers in Never/ A little / Much columns have a same column distance, it is preferable to make related numbers (eg. female n 11,363 and % 58.6) close together or merge them, such as 11,363 (58.6%), which is easier to understand. It is better to change the expression “Age at HUNT3” to “Age at baseline”, I think it's easier to understand. The above is my personal suggestion; the authors can choose to modify it based on their own judgment.

4. All continuous variables are presented as mean ± standard deviation in Table 1, which is not appropriate. For continuous variables with a normal distribution, presenting them with a mean and standard deviation is acceptable. However, for variables with a non-normal distribution, such as C-reactive protein, it is more appropriate to display them with an interquartile range, as the standard deviation is not a meaningful statistical measure for variables with non-normal distribution.

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Reviewer #2: No

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 10.1371/journal.pone.0304624.r002 Author response to Decision Letter 0 Submission Version 1

21 Apr 2024

We would like to thank the editor and reviewers for their insightful input which was very helpful in improving the manuscript. Below we provide a point-to-point reply to the comments and suggestions.

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Response: We have adjusted the manuscript to PLOS ONE's style requirements to the best of our ability.

2. We note that you have indicated that there are restrictions to data sharing for this study. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For more information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

Before we proceed with your manuscript, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., a Research Ethics Committee or Institutional Review Board, etc.). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

Response: It is not possible to share data. These are sensitive patient data, and we are not allowed to share them with third parties due to laws and regulation.

The Trøndelag Health Study (HUNT) has invited persons aged 13 - 100 years to four surveys between 1984 and 2019. Comprehensive data from more than 140,000 persons having participated at least once and biological material from 78,000 persons are collected. The data are stored in HUNT databank and biological material in HUNT biobank. HUNT Research Centre has permission from the Norwegian Data Inspectorate to store and handle these data. The key identification in the data base is the personal identification number given to all Norwegians at birth or immigration, whilst de-identified data are sent to researchers upon approval of a research protocol by the Regional Ethical Committee and HUNT Research Centre. To protect participants’ privacy, HUNT Research Centre aims to limit storage of data outside HUNT databank, and cannot deposit data in open repositories. HUNT databank has precise information on all data exported to different projects and are able to reproduce these on request. There are no restrictions regarding data export given approval of applications to HUNT Research Centre. For more information see: http://www.ntnu.edu/hunt/data

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. For a list of recommended repositories, please see

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We will update your Data Availability statement on your behalf to reflect the information you provide.

Response: The Trøndelag Health Study (HUNT) has invited persons aged 13 - 100 years to four surveys between 1984 and 2019. Comprehensive data from more than 140,000 persons having participated at least once and biological material from 78,000 persons are collected. The data are stored in HUNT databank and biological material in HUNT biobank. HUNT Research Centre has permission from the Norwegian Data Inspectorate to store and handle these data. The key identification in the data base is the personal identification number given to all Norwegians at birth or immigration, whilst de-identified data are sent to researchers upon approval of a research protocol by the Regional Ethical Committee and HUNT Research Centre. To protect participants’ privacy, HUNT Research Centre aims to limit storage of data outside HUNT databank, and cannot deposit data in open repositories. HUNT databank has precise information on all data exported to different projects and are able to reproduce these on request. There are no restrictions regarding data export given approval of applications to HUNT Research Centre. For more information see: http://www.ntnu.edu/hunt/data

Additional Editor Comments:

Thank you for submitting your manuscript. The reviewers and I believe it is of potential value for our readers. However, the reviewers have raised a number of very important issues, and their excellent comments will need to be adequately addressed in a revision before the acceptability of your manuscript for publication in the Journal can be determined. We cannot guarantee that your revised paper will be chosen for publication; this would be solely based on how satisfactorily you have addressed the reviewer comments.

# Please receive the English editing service.

Response: We have carefully checked and revised the language of our manuscript

# Hazard ratios (HR) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards models with age as underlying time scale.

Please cite the statistical guideline (DOI: https://doi.org/10.54724/lc.2023.e8).

Response: We have added the citation as suggested.

# Please add the sentence.

"A two-sided P less than 0.05 considered significance." -> in Method.

Response: Instead of hypothesis testing, we relied on estimation, and accordingly we provided the point estimates together with confidence intervals. Thus, we did not claim statistical significance for our findings. We recognize that opinions differ regarding the concept of statistical significance but we agree with those who strongly argue against its use in typical biomedical research where no immediate decision is required (see for example https://www.nature.com/articles/d41586-019-00857-9 or the statement of the American Statistical Association: Wasserstein RL, Lazar NA. The ASA’s statement on p-values: context, process and purpose. Am Stat. 2016;70(2):129–133.)

# Reference is too short to draw the conclusion.

Response: We were not able to understand this comment.

Responses to Reviewer # 1

Reviewer #1: This study aimed to investigate the longitudinal association between GERD and AF using data from the HUNT Study.

I have the following comments:

1: It should be clear in the title that the authors investigated the association between GERD (exposure) and AF (outcome). The title (association between AF and GERD) may give the impression that the authors applied AF as an exposure and GERD as an outcome.

Response: Response: We have changed the title to “Gastroesophageal reflux disease symptoms and risk for atrial fibrillation in a population-based cohort study (the HUNT Study)”

2: Lines 57-61: A reference is needed.

Response: We have added a reference (5). “Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomstrom-Lundqvist C, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J. 2021;42(5):373-498.”

3: Line 66: GERD was already spelled out previously.

Response: We have changed to just the abbreviation “GERD”.

4: Line 87: > 30% of participants were excluded for having missing data about GERD. The sociodemographic and clinical data should be compared between those who were excluded and those who were included. The potential discrepancy might have affected the representativeness.

Response: We have included a table in the supplementary material showing the characteristics of in- and excluded study populations and a comment in the Results: “A table comparing the characteristics of in- and excluded participants is presented in the supplementary material. Excluded participants had slightly less cardiovascular diseases and a lower prevalence of tertiary education (Supplemental Table 1)”. Also, participants in the HUNT Study received two main packages of questions, referred to as Questionnaire 1 and Questionnaire-2. GERD symptoms were asked in Questionnaire 2. The response rate for GERD reflected closely the overall response rate of its package which makes systematic missingness for GERD-related reasons unlikely.

5: Line 88: I recommend the authors to reconsider their complete case analysis approach. They may consider imputation or dummy variable analysis.

Response: Additional analyses with multiple imputations of missing covariates for the main analyses only changed the estimates marginally. The total number increased from 34,120 to 36,238, number of cases from 1,221 to 1,339. The HR for “Much GERD symptoms” in the fully adjusted model (Model 3) changed from HR 1.01 95% CI 0.82-1.24 to HR 0.99 95% CI, 0.81-1.21.

These analyses and data are not added or shown in the current version of the manuscript but can be included if so requested.

6: Line 103: ICD-10 code I48 includes atrial flutter. This should be clarified.

Response: We have clarified in the manuscript under “Case ascertainment (Outcome)” (Methods) that I48 includes atrial flutter. “The outcome of AF was defined as either a diagnosis of AF or of atrial flutter because of their close interrelationship”.

7: The authors have provided data about cholesterol levels and CRP in Table 1, yet they did not adjust for these variables in the regression analysis. This should be reconsidered.

Response: We have originally refrained from adjusting for these factors as they might be on the causal pathway. However, further adjustment with CRP and cholesterol left the results largely unchanged: (See table in Word-file)

Table for reviewers. Gastroesophageal reflux disease symptoms and risk for atrial fibrillation including additionally total cholesterol and CRP

GERD Symptoms n*=34,120

(including n of cases) HR* 95% CI n‡=33,356

(including n of cases) HR‡ 95% CI n#=33,339

(including n of cases) HR# 95% CI

Never 19,387(645) 1 (Ref) 18,972(633) 1 (Ref) 18,962(633) 1 (Ref)

A little 12,314(470) 0.88 0.78-0.99 12,033(459) 0.87 0.77-0.98 12,028(459) 0.87 0.77-0.98

Much 2,419(106) 1.02 0.83-1.26 2,351(100) 0.98 0.79-1.22 2,349(100) 0.97 0.79-1.20

N= number

HR= Hazard Ratio

CI= Confidence interval

* Model 2: Adjusted as Model 1 and additional for body mass index (continuous), smoking status (never, former, current), alcohol consumption (abstain, light drinkers, moderate drinkers, heavy drinkers), physical activity (inactive, active), education (lower secondary education, upper secondary education, tertiary education) and marital status (unmarried, married/cohabitant, widowed/divorced/separated).

‡Sensitivity analysis with total cholesterol additionally included

#Sensitivity analysis with total cholesterol and C-reactive protein additionally included

These data are not shown in the manuscript, but we can certainly include these data if so requested.

In the manuscript, we have written under “Results”: “Additional adjustment for lipids and CRP resulted in no appreciable changes in the estimates (data not shown)”

8: BP cut-off for hypertension is either 140/90 mmHg per the European guidelines or 130/80 mmHg per the US guidelines. The application of 130/85 mmHg should have a reference.

Response: We have changed the BP cut-off to 140/90 and redone all the analyses which resulted in only minor changes in the estimates.

9: Table 3: The authors do not have to stratify results by age using the value of median. Age results are usually stratified based on clear definitions, older adults versus young and middle-aged adults for example, with a cut-off of 60 or 65 to define older adults.

Response: We have redone the age-stratified analyses by dividing the population into three age groups as suggested by Reviewer 1 (this comment and comment 12) and by the first comment raised by Reviewer 2: age <40, age ≥ 40 and <65 and, age ≥ 65.

New results are presented in Table 3 and the manuscript.

10: The main limitation of this study is that GERD was self-reported. Was that diagnosis validated in the HUNT Study or any other studies with similar socio-demographic characteristics? This is a very important point that should be further discussed.

Response: We have added information from a validation study performed on participants from the HUNT Study.

“GERD symptoms in the HUNT 2 have been validated showing that 95% of participants reporting much reflux symptoms experience reflux symptoms at least once a week.”

Reference (18): Nilsson M, Johnsen R, Ye W, Hveem K, Lagergren J. Obesity and estrogen as risk factors for gastroesophageal reflux symptoms. Jama. 2003;290(1):66-72

11: GERD and AF have so many common risk factors such as age, obesity, smoking, diabetes, dyslipidemia, heavy alcohol consumption, and dyslipidemia. Stratifying the results by these confounders is essential. The authors may consider performing interaction analyses as well.

Response: We have adjusted for these variables which is statistically equivalent but more efficient than stratification. Extensive stratification in order to find stronger or weaker effects in certain subgroups, i.e., to find interactions, in the absence of a priori hypotheses, is generally not recommended, see for example: Wittes J. On looking at subgroups. Circulation. 2009 Feb 24;119(7):912-5. doi: 10.1161/CIRCULATIONAHA.108.836601. PMID: 19237669.

However, if so requested, we are willing to consider further stratified analyses where subgroup differences can be expected based on prior data and/or biological mechanisms.

12: Lines 210-216: This explanation is not based on scientific evidence. Further, participants aged 54 are not older adults. You may consider this explanation after the analysis is stratified by a different age group cut-off.

Response: Based on this comment and comment 9 from Reviewer 1 and Comment 1 by Reviewer 2, we have redone the age-stratified analyses by dividing them into three age groups: age <40, age ≥ 40 and <65 and, age ≥ 65 years.

New results are presented in Table 3 and the manuscript.

13: I recommend adding a 3rd GERD category (any) involving those with any GERD symptoms. Given that the authors have no data about GERD endoscopy or medication history, it is so presumptive to accept that the symptom severity suggested by the participants truly reflected their medical condition.

Response: We have added an analysis to our main analysis where we dichotomize symptoms of GERD into just two groups “Never or a little” versus “Much”. GERD symptoms in the HUNT 2 have been validated showing that 95% of participants reporting “Much” reflux symptoms experience reflux symptoms at least once a week while among participants reporting “little” symptoms only 25% had symptoms at least once a week. We believe that the group with “little” GERD symptoms resembles more “never” than “much” GERD symptoms (Nilsson M, Johnsen R, Ye W, Hveem K, Lagergren J. Obesity and estrogen as risk factors for gastroesophageal reflux symptoms. Jama. 2003;290(1):66-72) and therefore we prefer this categorization instead of the suggested one.

14: Lines 217-221: To test this hypothesis, the authors should revise their data to see whether GERD patients really improved their lifestyle within the following years.

Response: We have looked at the changes (see the results at the end of the answer to this comment), but the picture is not very clear, and we have therefore deleted this part on changes explaining the results from the discussion. (See table in the Word-file)

15: Line 236-238: The conclusion gives the impression that there is a kind of association but not so strong

Submitted filename: Response to Reviewers_GERD and AF_PLOS_v2.docx

 10.1371/journal.pone.0304624.r003 Decision Letter 1 Yon Dong Keon Academic Editor 2024 Dong Keon Yon This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version 1

15 May 2024

Gastroesophageal reflux disease symptoms and risk of atrial fibrillation in a population-based cohort study (the HUNT Study)

PONE-D-23-41606R1

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 10.1371/journal.pone.0304624.r004 Acceptance letter Yon Dong Keon Academic Editor 2024 Dong Keon Yon This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

20 May 2024

PONE-D-23-41606R1

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