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World Journal of Gastroenterology
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1007-9327
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Retrospective Cohort Study Open Access
Copyright: ©Author(s) 2026. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial (CC BY-NC 4.0) license. No commercial re-use. See permissions. Published by Baishideng Publishing Group Inc.
World J Gastroenterol. Nov 28, 2026; 32(44): 120965
Published online Nov 28, 2026. doi: 10.3748/wjg.120965
Histologic remission and arrhythmias in patients with inflammatory bowel disease: A nationwide cohort study
Jiang-Wei Sun, School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen 518107, Guangdong Province, China
Jiang-Wei Sun, Mei-Ling Li, David Bergman, Fahim Ebrahimi, Jonas F Ludvigsson, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17165, Sweden
Mei-Ling Li, Wan-Shui Yang, Department of Nutrition, Center for Big Data and Population Health of IHM, School of Public Health, Anhui Medical University, Hefei 230032, Anhui Province, China
Karl Mårild, Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, Gothenburg 41345, Sweden
Karl Mårild, Department of Pediatrics, Queen Silvia Children’s Hospital, Gothenburg 41685, Sweden
Johan Sundström, Department of Medical Sciences, Uppsala University, Uppsala 75185, Stockholm, Sweden
Johan Sundström, The George Institute for Global Health, University of New South Wales, New South Wales 2052, Australia
Fahim Ebrahimi, Department of Gastroenterology and Hepatology, University Digestive Health Care Center Basel – Clarunis, Basel 4031, Basel-Stadt, Switzerland
Jonas Halfvarson, Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro SE70182, Sweden
Ola Olén, Division of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm 17176, Sweden
Ola Olén, Sachs’ Children and Youth Hospital, Stockholm South General Hospital, Stockholm 11883, Sweden
Jonas F Ludvigsson, Department of Pediatrics, Örebro University Hospital, Örebro 70185, Sweden
Jonas F Ludvigsson, Division of Digestive and Liver Disease, Department of Medicine, Columbia University Medical Center, New York, NY 10032, United States
ORCID number: Jiang-Wei Sun (0000-0003-2252-684X); Mei-Ling Li (0009-0000-1052-8501); Jonas Halfvarson (0000-0003-0122-7234).
Co-corresponding authors: Mei-Ling Li and Jonas F Ludvigsson.
Author contributions: Sun JW was the guarantor, had access to all the data, did all analyses, and designed figures; Sun JW, Li ML, and Ludvigsson JF drafted the manuscript; Li ML and Ludvigsson JF had contributed a lot to this paper as co-corresponding authors; Sun JW and Ludvigsson JF provided funding; Olén O and Ludvigsson JF were involved in the acquisition of data; Sun JW, Li ML, Yang WS, Mårild K, Sundström J, Bergman D, Ebrahimi F, Halfvarson J, Olen O, and Ludvigsson JF authors were involved in the study concept and design; all authors were involved in the interpretation of data and critical revision of the manuscript for important intellectual content and approval of the final version.
AI contribution statement: AI tools (specifically ChatGPT) were used solely for linguistic refinement and formatting assistance. No AI tool was involved in the generation of research data, interpretation of results, or formulation of conclusions. All AI-generated outputs were critically reviewed and revised by the authors.
Supported by Swedish Society for Medical Research, No. PG-23-0315-H-02; European Crohn’s and Colitis Organization; Swedish Society of Medicine; Ruth and Richard Julin Foundation; Karolinska Institutet Research Foundation; National Natural Science Foundation of China; Fundamental Research Funds for Central Universities, Sun Yat-sen University, No. 26hytd011; and Swedish Heart-Lung Foundation.
Institutional review board statement: This study was approved by the Stockholm Ethics Review Board (No. 2014/1287-31/4, No. 2018/972-32, No. 2022-05774-02, No. 2021-06209-01, No. 2022-04384-02, and No. 2023-04868-02).
Informed consent statement: Individual informed consent was waived as the study was register-based.
Conflict-of-interest statement: All authors have completed the ICMJE uniform disclosure form and declare: Sundström J reports direct or indirect stock ownership in companies (Anagram kommunikation AB, Sence Research AB, Symptoms Europe AB, MinForskning AB) providing services to companies and authorities in the health sector including Amgen, AstraZeneca, Bayer, Boehringer, Eli Lilly, Gilead, GSK, Göteborg University, Itrim, Ipsen, Janssen, Karolinska Institutet, LIF, Linköping University, Novo Nordisk, Parexel, Pfizer, Region Stockholm, Region Uppsala, Sanofi, STRAMA, Takeda, TLV, Uppsala University, Vifor Pharma, WeMind. Olén O has been PI on projects at Karolinska Institutet financed by grants from Janssen, Pfizer, AbbVie, Takeda, Galapagos/Alfasigma, Ferring, and Bristol Myer Squibb. Halfvarson J has received consulting and/or advisory board fees from: AbbVie, Alfasigma, Aqilion, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly, Ferring, Galapagos, Gilead, Hospira, Index Pharma, Janssen, Johnson & Johnson, MEDA, Medivir, Medtronic, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Prometheus Laboratories Inc., Sandoz, Shire, STADA, Takeda, Thermo Fisher Scientific, Tillotts Pharma, Vifor Pharma, UCB; and speaker’s fees from: AbbVie, Alfasigma, Bristol Myers Squibb, Celgene, Eli Lilly, Ferring, Galapagos, Gilead, Hospira, Janssen, Johnson & Johnson, Merck Sharp & Dohme, Novartis, Pfizer, Shire, Takeda, Thermo Fisher Scientific, Tillotts Pharma; and research grant support from Janssen, Merck Sharp & Dohme and Takeda. Ebrahimi F has served as an advisory board member for Boehringer Ingelheim. Ludvigsson JF has coordinated a study for the Swedish IBD Quality Register (SWIBREG), which received funding from Janssen Corporation, received financial support from MSD to develop a paper reviewing national healthcare registers in China, has a research collaboration on celiac disease with Takeda and has a research collaboration on fibrosis in IBD with MSD. The other authors report no disclosures relevant to the manuscript.
STROBE statement: The authors have read the STROBE Statement – checklist of items, and the manuscript was prepared and revised according to the STROBE Statement – checklist of items.
Data sharing statement: Under current data protection legislation, the data cannot be shared directly and must be requested from the respective registry holders, Statistics Sweden (information@scb.se) and the Swedish National Board of Health and Welfare (registerservice@socialstyrelsen.se), after approval by the Swedish Ethical Review Authority.
Corresponding author: Jonas F Ludvigsson, Professor, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels Väg 12A, Solna 17165, Sweden. jonasludvigsson@yahoo.com
Received: March 12, 2026
Revised: May 11, 2026
Accepted: July 6, 2026
Published online: November 28, 2026
Processing time: 202 Days and 10 Hours

Abstract
BACKGROUND

The risk of arrhythmias during periods of histologic and clinical activity of inflammatory bowel disease (IBD) remains unknown.

AIM

To investigate the association of histologic inflammation (vs remission) and clinically active IBD (vs quiescent IBD) with arrhythmias risk.

METHODS

We conducted a nationwide cohort study in Sweden including patients with histologic disease activity (n = 61383; 1969-2017) and clinical activity (n = 96154; 1969-2020). The primary outcome was incident arrhythmias (atrial fibrillation/flutter, bradyarrhythmias, other supraventricular arrhythmias, and ventricular arrhythmias/cardiac arrest) that occurred within 2 years after documented histologic inflammation (vs remission) or clinically active IBD (vs quiescent IBD). Poisson regression model estimated incidence rates of arrhythmias and Cox proportional hazards model estimated adjusted hazard ratios (aHRs) and 95%CIs.

RESULTS

Histologic inflammation was associated with an increased risk of arrhythmias compared to histologic remission [incidence rate: 62.0 vs 47.2 per 10000 person-years; aHR = 1.35 (1.18-1.54)], corresponding to one additional event of arrhythmia per 338 (95%CI: 233-625) IBD patients within 2 years after histologic inflammation. The increased risk of arrhythmia was observed in patients with Crohn’s disease [aHR = 1.28 (0.99-1.66)] and ulcerative colitis [aHR = 1.42 (1.21-1.67)], but not in IBD-unclassified [aHR = 0.97 (0.54-1.77)]. In patients with clinically quiescent IBD, histologic inflammation was still associated with an increased risk of arrhythmias [aHR = 1.16 (1.00-1.36)].

CONCLUSION

Both histologic and clinical activity of IBD were associated with a modestly increased risk of arrhythmias.

Key Words: Inflammatory bowel disease; Histologic remission; Clinical activity; Arrhythmia; Cohort

Core Tip: Inflammatory bowel disease (IBD) is associated with multiple cardiovascular complications, but the relationship between histologic inflammation and arrhythmia risk remains unclear. This nationwide cohort study found that, compared with histologic remission, histologic inflammation was associated with an increased risk of arrhythmias; similarly, clinically active IBD compared with clinically quiescent IBD was linked to modestly higher arrhythmia risk. Even among patients with clinically quiescent IBD, histologic inflammation remained associated with higher arrhythmia risk.
INTRODUCTION

Inflammatory bowel disease (IBD), encompassing Crohn’s disease (CD), ulcerative colitis (UC), and IBD-unclassified (IBD-U), is a chronic inflammatory disease primarily affecting the gastrointestinal tract[1-3]. IBD typically follows a relapsing-remitting course, characterized by repeated inflammatory injuries to the intestinal mucosa. Between flares, the mucosa may undergo healing, although complete restoration of normal structure and function is often not achieved[4].

Evidence suggests that IBD is associated with a range of extraintestinal complications, including cardiovascular diseases (CVD)[5]. Previous studies have linked active phase of IBD to myocardial infarction[6,7], stroke[6,8], ischemic heart and cerebrovascular disease[9], arterial vascular disease[10], and heart failure[11]. Although arrhythmias, affecting 1.5%-5% of the general population[12,13], are associated with elevated risks of heart failure, stroke, and mortality[14,15], the association between active IBD and arrhythmias remains unclear. To date, one Danish study has reported an increased risk of atrial fibrillation during active stages of IBD[8]. However, since histologic inflammation may still persist without clinical symptoms and during periods without endoscopic activity[16], achieving histologic remission is increasingly recognized as a potential therapeutic goal in the management of IBD (for example in patients with UC[17]). Previous studies have suggested a link between histologic remission and a reduced risk of relapse, hospitalization, surgery, and colorectal cancer[18,19]. Given that chronic inflammation may trigger or exacerbate arrhythmias by cardiac structural remodeling, electrophysiological alterations, and autonomic nervous system dysfunction[20,21], it is clinically important to investigate whether histologic inflammation (vs histologic remission) and clinically active IBD (vs quiescent IBD) are associated with arrhythmias in patients with IBD, and whether histologic inflammation remains associated with arrhythmia risk in patients with clinically quiescent IBD.

We therefore undertook a nationwide register-based cohort study to investigate the associations between histologic and clinical activity of IBD and risk of arrhythmias. We hypothesized that arrhythmias risk would be increased during periods of histologic inflammation and active IBD.

MATERIALS AND METHODS
Data source and study population

This study was based on Swedish national registers (Supplementary material). Briefly, IBD patients were identified as those having either ≥ 2 International Classification of Disease codes in the National Patient Register (NPR)[22] or ≥ 1 International Classification of Disease code plus ≥ 1 IBD-indicative biopsy in ESPRESSO (Epidemiology Strengthened by histoPathology Reports in Sweden[23], Supplementary Table 1). This definition has a validated positive predictive value (PPV) of 93%-95%[24,25]. To avoid immortal time bias, we set IBD diagnosis date when both criteria were met. We classified IBD into three subtypes (i.e., CD, UC, and IBD-U) and used the Montreal classification criteria to define IBD phenotypes at diagnosis, including CD location and perianal disease modifier, UC extent, and presence of primary sclerosing cholangitis or other extraintestinal manifestations (Supplementary Table 2).

We explored the association of histologic activity with arrhythmias in 61383 patients diagnosed from 1969 to 2017 with histology data and studied the link of clinical activity with arrhythmias in 96154 patients diagnosed from 1969 to 2020 and residing in Sweden after 2006 with data indicative of clinical activity.

Exposures

Following expert consensus[26,27] and prior studies[28,29], we defined histologic inflammation (primary exposure) as having ≥ 1 SNOMED (the Swedish version of the Systematized Nomenclature of Medicine) code for ileocolorectal inflammation or ulceration/erosion (Supplementary Table 3). Histologic remission was identified as having ileocolorectal histopathology codes M00100/M00110 (normal mucosa)[23] and no SNOMED codes indicating inflammation or ulceration/erosion. While recognizing the variability in disease progression in IBD[4], we hypothesized that histologic inflammation could persist up to 12 months after the biopsy[28].

Based on previous publications[28,29], IBD-related surgery (Supplementary Table 4), IBD-related hospitalization, and ≥ 1 budesonide or corticosteroid dispensation (either oral or topical therapy), initiation of immunomodulators, or advanced therapies were used as surrogate events for clinically active IBD (see Supplementary Table 5 for their definitions). A clinically active period persisted 3 months after date of IBD-related surgery/hospitalization or after the end date of the treatment period. The treatment period encompassed days covered by the abovementioned IBD medications. The period would extend for another 3 months if an additional surrogate event occurred within 3 months of the prior event[28,29]. A quiescent period was defined as absence of any surrogate event of clinically active IBD. IBD medications were identified from the NPR[22], the Prescribed Drug Register (PDR)[30], and the Swedish Quality Register for IBD (SWIBREG) (Supplementary Table 5). We restricted the clinical activity study to January 2006 and onwards to capture at least 6 months of drug usage data, since the PDR has only been available since July 2005.

Outcomes and follow-up

The primary outcome was overall arrhythmias, a composite outcome defined as ≥ 1 diagnosis of any secondary outcome: (1) Atrial fibrillation/flutter; (2) Bradyarrhythmias; (3) Other supraventricular arrhythmias; and (4) Ventricular arrhythmias/cardiac arrest (Supplementary Table 6). We identified individuals with arrhythmias from the NPR (considering both primary and secondary diagnoses) and from the Cause of Death Register (only for ventricular arrhythmias/cardiac arrest), with a high PPV of 97% for atrial fibrillation/flutter[31]. If one individual was diagnosed with more than one of the secondary outcomes, this individual contributed to the analysis for each outcome with the respective diagnosis date.

We set date of histologic inflammation/remission and date of clinically active/quiescent IBD as the index date. Individuals with a diagnosis of any arrhythmia before the index date were excluded. Follow-up started from the index date until the diagnosis of an incident arrhythmia, emigration from Sweden, 2 years after the index date, or end of follow-up on 31 December 2021, whichever occurred first. Follow-up was censored at the time of any change in exposure status (i.e., histology and clinical disease activity) during follow-up period. We assumed that the effect of histologic inflammation on the risk of arrhythmia would persist up to 2 years and therefore defined incident arrhythmias occurred within 2 years after the index date as our main analysis. Additionally, to address the potentially arbitrary assumption regarding the duration of the histologic inflammation effect, we conducted a sensitivity analysis to assess the risk of incident arrhythmias within 5 years after the index date.

Covariates

We considered age at IBD diagnosis, sex, and calendar year at index date in model 1 and additionally adjusted for county of residence, educational attainment, country of birth, number of health care visits, and history of CVD-related comorbidities (including hypertension, diabetes, obesity, dyslipidemia, chronic kidney disease, and chronic obstructive pulmonary disease) in model 2 (see Supplementary material for details and Supplementary Table 6 for their definitions). Except for age at IBD diagnosis, sex, and country of birth, all other covariates were treated as time-varying and were updated at each index date (i.e., the start of a new exposure period).

Statistical analysis

Cox proportional hazards model was applied to estimate hazard ratios (HRs) with 95%CIs of overall and specific arrhythmias after histologic inflammation (vs histologic remission) and clinically active IBD (vs quiescent IBD), with age at index date as the underlying time scale. We treated competing events (e.g., death) as censoring events. We used Poisson regression to estimate incidence rates (IRs) of outcomes and applied robust standard errors to account for within-individual correlations across periods.

Subgroup and sensitivity analysis: Subgroup analyses were conducted by IBD subtypes (i.e., CD, UC, and IBD-U), sex, age at IBD diagnosis, age at index date, calendar period at IBD diagnosis, IBD duration (0 years, 0-5 years, and > 5 years), number of health care visits, and history of CVD-related comorbidities before index date. To examine the impact of the introduction of modern IBD therapy, we stratified the analysis by calendar period. To assess the influence of disease phenotypes, we stratified the analysis by CD location, UC extent, and the occurrence of primary sclerosing cholangitis or other extraintestinal manifestations. As all subgroup analyses were pre-specified, we did not account for multiple testing, therefore findings from subgroup analyses are exploratory.

To test the robustness of our results, in a sensitivity analysis, we changed the presumed duration of histologic inflammation from 12 months to 6 months and clinically active IBD from 3 months to 6 months. Moreover, to estimate the possible incremental effect of residual histologic inflammation on arrhythmias risk, we assessed 2-year risk of arrhythmias in histologic inflammation (vs remission) during quiescent IBD periods. Furthermore, to explore the association of histologic inflammation and arrhythmias beyond the time around IBD diagnosis, we discarded the first three months or first one year after IBD diagnosis from the analysis.

Data analyses were performed using SAS version 9.4 and R version 3.6.0. A two-sided P ≤ 0.05 was considered statistically significant.

RESULTS
Histologic inflammation vs remission

We identified 61383 eligible patients with IBD (median age at diagnosis: 37.2 years), including 17594 with CD, 40421 with UC, and 3368 with IBD-U (Supplementary Table 7). At date of IBD diagnosis, 11.0% were childhood-onset IBD, 47.7% were female, 92.9% were born in the Nordic countries, and 53.9% were diagnosed since 2002 (Supplementary Table 7). Some 27779 patients contributed 47462 remission periods (median age at index date: 46.3 years; median duration of remission: 2.0 years) and 53719 contributed to 102904 inflammation periods (43.7 years; median duration of inflammation: 1.0 year) (Table 1). The majority remission periods were recorded after 2001 (Table 1). Nearly 30% of histologic inflammation periods were observed within 3 months after IBD diagnosis (Supplementary Figure 1).

Table 1 Characteristics of inflammatory bowel disease patients during periods of histologic inflammation and histologic remission in 1969-2017, n (%)/mean (interquartile range)/mean ± SD.
Item
Histologic remission
Histologic inflammation
Histologic inflammation in subtypes of IBD
CD
UC
IBD-U
Number of periods4746210290426168709625774
Number of patients277795371915021356783020
Number of patients by number of periods
    117224 (62.0)30142 (56.1)8930 (59.5)19412 (54.4)1800 (59.6)
    25927 (21.3)11806 (22.0)3436 (22.9)7775 (21.8)595 (19.7)
    32443 (8.8)5561 (10.4)1418 (9.4)3891 (10.9)252 (8.3)
    ≥ 42185 (7.9)6210 (11.6)1237 (8.2)4600 (12.9)373 (12.4)
Age (years)1
mean ± SD45.9 ± 16.644.3 ± 17.641.3 ± 17.745.4 ± 17.445.5 ± 18.0
Median (IQR)46.3 (33.4-58.6)43.7 (30.5-57.6)39.9 (26.9-54.8)44.8 (31.8-58.5)45.6 (31.0-59.3)
    < 182319 (4.9)6011 (5.8)2300 (8.8)3345 (4.7)366 (6.3)
    18-4015345 (32.3)38169 (37.1)10836 (41.4)25417 (35.8)1916 (33.2)
    40-6019158 (40.4)36778 (35.7)8437 (32.2)26220 (37.0)2121 (36.7)
    ≥ 6010640 (22.4)21946 (21.3)4595 (17.6)15980 (22.5)1371 (23.7)
Calendar period1
    1969-1989 1257 (2.7)6379 (6.2)1721 (6.6)4074 (5.7)584 (10.1)
    1990-20017970 (16.8)29924 (29.1)7426 (28.4)20962 (29.5)1536 (26.6)
    2002-200915568 (32.8)32606 (31.7)8201 (31.3)23042 (32.5)1363 (23.6)
    2010-201722667 (47.8)33995 (33.0)8820 (33.7)22884 (32.3)2291 (39.7)
Educational attainment1
    0-9 years9182 (19.4)22003 (21.4)5701 (21.8)14995 (21.1)1307 (22.6)
    10-12 years20606 (43.4)43549 (42.3)11217 (42.9)30001 (42.3)2331 (40.4)
    ≥ 13 years14868 (31.3)26509 (25.8)5932 (22.7)19280 (27.2)1297 (22.5)
    Missing2806 (5.9)10843 (10.5)3318 (12.7)6686 (9.4)839 (14.5)
IBD duration (years)1
mean ± SD9.3 ± 8.66.6 ± 8.06.5 ± 8.36.5 ± 7.77.8 ± 9.5
Median (IQR)7.4 (2.1-13.8)3.5 (0.0-10.7)3.1 (0.0-10.6)3.7 (0.0-10.6)3.6 (0.0-13.2)
    01969 (4.2)28345 (27.6)7495 (28.6)19334 (27.3)1516 (26.3)
    0-516646 (35.1)29172 (28.4)7554 (28.9)20007 (28.2)1611 (27.9)
    > 528847 (60.8)45387 (44.1)11119 (42.5)31621 (44.6)2647 (45.8)
Number of health care visits2
    015871 (33.4)46294 (45.0)11082 (42.4)32667 (46.0)2545 (44.1)
    110057 (21.2)20178 (19.6)4790 (18.3)14269 (20.1)1119 (19.4)
    2-39999 (21.1)18351 (17.8)4738 (18.1)12611 (17.8)1002 (17.4)
    ≥ 411535 (24.3)18081 (17.6)5558 (21.2)11415 (16.1)1108 (19.2)
Disease history1
    Hypertension4076 (8.6)7128 (6.9)1642 (6.3)4906 (6.9)580 (10.1)
    Diabetes2232 (4.7)4272 (4.2)839 (3.2)3092 (4.4)341 (5.9)
    Obesity810 (1.7)1357 (1.3)405 (1.6)860 (1.2)92 (1.6)
    Dyslipidemia1195 (2.5)1728 (1.7)308 (1.2)1303 (1.8)117 (2.0)
    Chronic kidney diseases518 (1.1)925 (0.9)259 (1.0)590 (0.8)76 (1.3)
    COPD605 (1.3)1510 (1.5)379 (1.5)1008 (1.4)123 (2.1)
1Measured at index date. Index date was defined as date of histologic inflammation or remission.
2Measured between 2 years and 6 months before the index date.
CD: Crohn’s disease; COPD: Chronic obstructive pulmonary disease; IBD: Inflammatory bowel disease; IBD-U: Inflammatory bowel disease-unclassified; UC: Ulcerative colitis; IQR: Interquartile range.
Open in New Tab Full Size Table

A total of 647 newly diagnosed arrhythmias were observed after histologic inflammation (IR: 62.0/10000 person-years), compared with 382 after remission (IR = 47.2), with an IR difference of 14.8 (95%CI: 8.0-21.5) (Figure 1A and Supplementary Table 8). These rates corresponded to one additional arrhythmia per 338 (95%CI: 233-625) IBD patients over 2 years after histologic inflammation, with an adjusted HR (aHR) of 1.35 (1.18-1.54). A statistically increased risk was observed for atrial fibrillation/flutter [aHR = 1.38 (1.18-1.62)] and ventricular arrhythmias/cardiac arrest [aHR = 1.73 (1.22-2.44)], but not for bradyarrhythmias [aHR = 1.10 (0.69-1.74)] and other supraventricular arrhythmias [aHR = 1.30 (0.90-1.90)]. Histologic inflammation was also associated with arrhythmias in patients with CD [aHR = 1.28 (0.99-1.66)] and UC [aHR = 1.42 (1.21-1.67)], but not in IBD-U [aHR = 0.97 (0.54-1.77)] (Supplementary Table 9).

Figure 1
Open in New Tab   Full Size Figure   Download Figure
Figure 1 Incidence rates and hazard ratios for the 2-year risk of arrhythmias in histologic inflammation (vs remission) and clinically active inflammatory bowel disease (vs quiescent inflammatory bowel disease), with 95%CIs. A: Histologic inflammation (vs remission); B: Clinically active inflammatory bowel disease (vs quiescent inflammatory bowel disease). The hazard ratios were estimated from the Cox proportional hazard model based on model 2. IR: Incidence rate; IBD: Inflammatory bowel disease.

In subgroup analyses, the IR for arrhythmias increased with age and calendar years as well as was higher in those with a history of CVD-related comorbidity (Supplementary Table 10). For example, in the histologic inflammation group, the IR per 10,000 person-years across calendar year at IBD diagnosis was 49.7 for 1969-1989, 58.7 for 1990-2001, 72.0 for 2002-2009, and 76.6 for 2010-2017, respectively, although no clear temporal pattern was observed for aHR. Histologic inflammation was associated with a higher relative risk of arrhythmias in those with IBD diagnosed ≥ 40 years old, with low/middle education level, and with higher numbers of healthcare visits (Supplementary Table 10). Due to the small number of events, no significant differences were seen between IBD phenotype strata (Supplementary Table 11).

In sensitivity analyses, robust results for arrhythmias were observed when extending the follow-up to 5 years [aHR = 1.38 (1.24-1.54), Supplementary Table 12] and assuming a histologic inflammation duration of 6 months [aHR = 1.46 (1.25-1.70), Supplementary Table 13]. Histologic inflammation was also linked to a higher risk of any arrhythmias [aHR = 1.16 (1.00-1.36), P = 0.054] and atrial fibrillation/flutter [aHR = 1.22 (1.02-1.45)] in patients with clinically quiescent IBD (Supplementary Table 14). After discarding the first 3 months [aHR = 1.26 (1.10-1.44)] or 1 year [aHR = 1.26 (1.08-1.45)] following IBD diagnosis from the analysis, we still observed a positive association between histologic inflammation and arrhythmias (Supplementary Table 15).

Clinically active vs quiescent IBD

This analysis included 96154 IBD patients diagnosed 1969-2020 (31967 CD patients, 56704 UC patients, and 7483 IBD-U patients (Supplementary Table 16). They contributed to 293289 quiescent IBD periods (median age at index date: 49.2 years; median duration of quiescent IBD: 0.5 years) and 290860 active IBD periods (49.7 years; median duration of active IBD: 0.5 years) (Table 2). The characteristics of both groups at the index date were comparable (Table 2).

Table 2 Characteristics of inflammatory bowel disease patients during periods of clinically active and quiescent inflammatory bowel disease in 2006-2020, n (%)/mean (interquartile range)/mean ± SD.
Item
Quiescent IBD
Active IBD
Active IBD in subtypes of IBD
CD
UC
IBD-U
Number of periods29328929086010862516341718818
Number of patients891148576330092490616610
Number of patients by number of periods
    130440 (34.2)28012 (32.7)9301 (30.9)16000 (32.6)2711 (41.0)
    218002 (20.2)17135 (20.0)5765 (19.2)10007 (20.4)1363 (20.6)
    312023 (13.5)11701 (13.6)4090 (13.6)6787 (13.8)824 (12.5)
    ≥ 428649 (32.2)28915 (33.7)10936 (36.3)16267 (33.2)1712 (25.9)
Age (years)1
mean ± SD49.1 ± 18.549.4 ± 18.948.4 ± 18.950.1 ± 18.649.5 ± 20.3
Median (IQR)49.2 (34.0-63.9)49.7 (34.0-64.4)48.9 (32.8-63.5)50.1 (34.9-64.8)51.3 (31.6-65.9)
    < 189177 (3.1)10442 (3.6)4716 (4.3)4565 (2.8)1161 (6.2)
    18-4093218 (31.8)89971 (30.9)34371 (31.6)50145 (30.7)5455 (29.0)
    40-6097569 (33.3)95268 (32.8)35715 (32.9)54173 (33.2)5380 (28.6)
    ≥ 6093325 (31.8)95179 (32.7)33823 (31.1)54534 (33.4)6822 (36.3)
Calendar period1
    2006-200959205 (20.2)58641 (20.2)22324 (20.6)33571 (20.5)2746 (14.6)
    2010-2020234084 (79.8)232219 (79.8)86301 (79.5)129846 (79.5)16072 (85.4)
Educational attainment1
    0-9 years57630 (19.7)58420 (20.1)22824 (21.0)31452 (19.3)4144 (22.0)
    10-12 years134083 (45.7)131664 (45.3)49786 (45.8)73827 (45.2)8051 (42.8)
    ≥ 13 years89008 (30.4)86096 (29.6)29736 (27.4)51397 (31.5)4963 (26.4)
    Missing12568 (4.3)14680 (5.1)6279 (5.8)6741 (4.1)1660 (8.8)
IBD duration (years)1
mean ± SD10.8 ± 10.311.1 ± 10.411.9 ± 11.210.7 ± 9.69.9 ± 12.0
Median (IQR)8.1 (2.4-16.1)8.4 (2.7-16.5)8.9 (2.8-18.1)8.5 (3.0-15.7)4.8 (0.6-15.1)
    026271 (9.0)31739 (10.9)12445 (11.5)15632 (9.6)3662 (19.5)
    0-581444 (27.8)70892 (24.4)24951 (23.0)40040 (24.5)5901 (31.4)
    > 5185574 (63.3)188229 (64.7)71229 (65.6)107745 (65.9)9255 (49.2)
Number of health care visits2
    061932 (21.1)63613 (21.9)22132 (20.4)37306 (22.8)4175 (22.2)
    155308 (18.9)55407 (19.1)20357 (18.7)32021 (19.6)3029 (16.1)
    2-371211 (24.3)70586 (24.3)25853 (23.8)40455 (24.8)4278 (22.7)
    ≥ 4104838 (35.8)101254 (34.8)40283 (37.1)53635 (32.8)7336 (39.0)
Disease history1
    Hypertension48248 (16.5)46986 (16.2)16920 (15.6)26097 (16.0)3969 (21.1)
    Diabetes20635 (7.0)20188 (6.9)6228 (5.7)12357 (7.6)1603 (8.5)
    Obesity10753 (3.7)10531 (3.6)3982 (3.7)5671 (3.5)878 (4.7)
    Dyslipidemia12545 (4.3)12076 (4.2)3426 (3.2)7671 (4.7)979 (5.2)
    Chronic kidney diseases7353 (2.5)7400 (2.5)2937 (2.7)3831 (2.3)632 (3.4)
    COPD12405 (4.2)12488 (4.3)5020 (4.6)6369 (3.9)1099 (5.8)
1Measured at index date. Index date was defined as date of clinically active or quiescent IBD.
2Measured between 2 years and 6 months before the index date.
CD: Crohn’s disease; COPD: Chronic obstructive pulmonary disease; IBD: Inflammatory bowel disease; IBD-U: Inflammatory bowel disease-unclassified; UC: Ulcerative colitis; IQR: Interquartile range.
Open in New Tab Full Size Table

We identified 2248 (IR = 108.4/10000 person-years) vs 1724 (IR = 67.4) incident arrhythmias in active vs quiescent IBD, respectively, resulting in an IR difference of 41.1 (35.6-46.6). These rates corresponded to one additional arrhythmia per 122 (107-140) IBD patients over 2 years following active IBD, with an aHR of 1.77 (1.66-1.88) (Figure 1B and Supplementary Table 17). Active IBD was significantly associated with all secondary outcomes except for bradyarrhythmias. Patients with CD [aHR = 1.70 (1.52-1.91)], UC [aHR = 1.78 (1.64-1.93)], and IBD-U [aHR = 2.04 (1.62-2.58)] were at an increased risk of arrhythmias during active IBD period (Supplementary Table 18). Elevated risks for secondary outcomes (except for bradyarrhythmias) were also noted in active IBD across IBD subtypes (Supplementary Table 18).

Subgroup analyses revealed notable differences in the IR of arrhythmi with similar relative risk increases (Supplementary Table 19). The IR for arrhythmias increased with age and number of health care visits but decreased with educational attainment. Additionally, it was higher among individuals with CVD-related comorbidity before index date. The relative risk for developing arrhythmias was higher in males [aHR = 1.86 (1.70-2.02)] and was highest at IBD diagnosis [IBD duration = 0; aHR = 2.94 (2.37-3.65)] but persisted even in active IBD that occurred > 5 years after diagnosis [aHR = 1.68 (1.56-1.81)] (Supplementary Table 19). Significant association for arrhythmias was also observed in the analysis by CD location, UC extent, and the occurrence of other extraintestinal manifestations (Supplementary Table 20).

In sensitivity analyses, we noted robust associations of active IBD and arrhythmias when extending the follow-up to 5 years [aHR = 1.73 (1.64-1.83), Supplementary Table 21] and assuming a 6-month duration of clinically active IBD [aHR = 1.81 (1.69-1.94), Supplementary Table 22].

DISCUSSION

In this nationwide cohort study, both histologic inflammation and clinically active IBD were associated with an increased risk of incident arrhythmias. The link between histologic inflammation and arrhythmias persisted even when follow-up started over a year after IBD diagnosis. Histologic inflammation was also linked to an elevated risk of arrhythmias in patients with clinically quiescent IBD. These findings suggest that achieving histologic and clinical remission may reduce the risk of arrhythmias in patients with IBD.

Comparison with earlier literature

Histologic remission is increasingly recognized as a potential therapeutic target in IBD management, particularly in UC. Several studies have demonstrated that histologic inflammation and/or clinically active IBD is associated with an increased risk of multiple adverse outcomes. For example, histologic inflammation has been linked to reduced fertility[28], increased risk of preterm birth[29], fractures[32], and serious infections[33] in patients with IBD. A study from Denmark reported an overall increased risk of atrial fibrillation among patients with IBD [incidence rate ratio (IRR) = 1.26 (1.16-1.36)], primarily during IBD flares [IRR = 2.63 (2.26-3.06)] and persistent activity [IRR = 2.06 (1.67-2.55)][8]. The authors used three markers to define IBD flare: (1) Corticosteroid prescriptions; (2) IBD-related hospital admissions; and (3) Initiation of biological treatment. However, this study focused on atrial fibrillation and used the general population as the reference group, without evaluating other arrhythmia subtypes or investigating the role of histologic activity on arrhythmias.

Our study is the first in the same study population to evaluate the influence of both histologic and clinical activity of IBD on arrhythmias, indicating that both forms of disease activity are linked to arrhythmias. Among patients with clinically quiescent disease, histologic inflammation remained associated with an elevated arrhythmia risk [aHR = 1.16 (1.00-1.36)]. Moreover, the association between histologic inflammation and arrhythmias persisted even when we started follow-up from one year after IBD diagnosis, implying a potential long-term impact of intestinal inflammation on arrhythmia risk. The positive association was mainly observed in patients with UC and CD, rather than in patients with IBD-U, which may be due to limited sample size and a small number of events in IBD-U. Our findings indicate that targeting histologic remission in patients with IBD may benefit cardiovascular health.

In this study, the IR was higher during clinically quiescent IBD periods than during histologic remission, and the IR difference between active and quiescent periods was higher than that between histologic inflammation and remission. This discrepancy may partly reflect differences in the time periods used for the two comparisons. For example, data for disease activity were mostly from more recent years and with shorter follow-up. Therefore, direct comparison between absolute IR differences should be cautious.

Potential mechanisms

Several potential mechanisms may explain the observed association between IBD and arrhythmias. Chronic inflammation is a key element in the pathogenesis of arrhythmias[20]. During the active periods of the disease, the enhanced inflammatory status may trigger arrhythmia[34]. Elevated levels of pro-inflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1β, and interleukin-6, can induce atrial structural remodeling and abnormal calcium handling in cardiomyocytes, which are critical pathophysiologic substrates for atrial fibrillation[21,35,36]. Chronic inflammation may also induce autonomic dysregulation (e.g., increased sympathetic tone and decreased parasympathetic tone), which could reduce heart rate variability and prolong QTc interval and lead to arrhythmogenesis[37]. Notably, the association was strongest for ventricular arrhythmias/cardiac arrest, which may be partly explained by the dependence of ventricular arrhythmias on myocardial electrophysiological stability. A previous study has shown that, at the ventricular level, patients with IBD commonly exhibit prolonged QTc interval and increased QT dispersion, suggesting altered ventricular repolarization and increased electrophysiological instability[38]. Increased QT dispersion is regarded as a marker of myocardial electrical instability and has been associated with a higher susceptibility to ventricular arrhythmias and sudden cardiac death[39].

Beyond inflammation, as suggested in our findings, clinical features during active IBD (e.g., corticosteroid therapy, surgery, and hospitalization) may further increase the risk of arrhythmias. For example, previous studies have shown that corticosteroids may induce electrolyte imbalances (e.g., hypokalemia) and increase sympathetic nervous tone, both of which are established pro-arrhythmic factors[40-43]. Moreover, long-term use of moderate to high doses of corticosteroids may speed up the development of atherosclerosis, further raising the risk of cardiovascular events and arrhythmias[40]. In addition, surgery and hospitalization may increase the risk of infection[44], which may contribute to the development of arrhythmias[45].

Furthermore, IBD-related gut dysbiosis could promote the release of pro-inflammatory cytokines, thereby triggering immune responses and amplifying systemic inflammation[46]. During active IBD period, gut microbiota is commonly shifted, characterized by a reduction in short-chain fatty acid (SCFA)-producing bacteria (e.g., Faecalibacterium prausnitzii and Roseburia hominis)[47,48] alongside an enrichment of pro-inflammatory or opportunistic taxa (e.g., Ruminococcus gnavus, Enterococcus, and Streptococcus anginosus)[49,50]. These alterations may lead to reduced SCFA production, impaired gut barrier integrity, and amplification of inflammatory signalling. Another possible mechanism involves SCFA, particularly butyrate and propionate, which are key microbial metabolites that maintain intestinal immune homeostasis and promote regulatory T cell differentiation[51,52]. We hypothesize that SCFA depletion during active IBD may contribute to systemic inflammation and immune dysregulation, potentially increasing susceptibility to arrhythmias[53,54].

Strengths and limitations

Strengths included a large, nationwide, population-based cohort with prospectively collected data, which could greatly minimize selection and recall bias. Besides, histopathological data provided an objective measure of disease activity beyond clinical assessments, allowing for a more nuanced evaluation of the association between inflammation and arrhythmia risk. Moreover, the high PPVs for both IBD and atrial fibrillation ensured the accuracy of disease identification[24,25,31], and linking multiple national registers enabled adjustment for potential confounders such as sociodemographic factors and comorbidities.

Several limitations should be acknowledged. First, our definition of arrhythmias did not include cases diagnosed only in primary care or not attended by healthcare at all. Thus, the findings apply only to arrhythmia requiring specialist care. Moreover, since the NPR was founded in 1964 and covers nationwide inpatient care since 1987 and outpatient care since 2001, therefore the IR of arrhythmias is likely to be underestimated. Second, our definitions of histologic and clinical disease activity have not been validated, and we lacked endoscopic and biochemical data, limiting our ability to comprehensively assess disease activity outside histologic and clinical activity. Therefore, future studies are warranted to validate our two definitions and findings. Third, our definition of histology activity was not based on a histologic scoring system (e.g., the Nancy index[26]) and lacked information on inflammation severity or its cumulative impact over time. Although the Swedish national guideline suggests grading the inflammation, such grading has not been extensively used in routine healthcare. Moreover, our definition of clinical activity was primarily based on corticosteroid prescriptions (accounting for approximately 70% of active cases), thus the findings may partly reflect the cardiovascular effects of corticosteroids[42]. Besides, patients classified as clinically quiescent may still have endoscopic activity given that only IBD-related surgery, hospitalization and treatment initiation were used as proxies of clinically active disease. The inclusion of dose escalation and the addition of rectal 5-aminosalicylic acid might have further refined our definition. Fourth, exposure misclassification may occur, particularly in CD patients, where histologic inflammation is often segmental, stenotic, or submucosal in nature. Besides, when lesions are in biopsy-inaccessible regions such as the ileocecal area, histologic assessment may also be limited. Furthermore, the PDR is available since June 2005, and only patients residing in Sweden from 2006 onward were included in the clinical activity study, which might lead to the misclassification of clinical activity. Fifth, although we adjusted for related comorbidities (e.g., obesity, chronic obstructive pulmonary disease, hypertension, diabetes, and dyslipidemia) in the model, lifestyle factors (e.g., smoking, diet, physical activity, and body mass index) were not available in the register, therefore residual confounding cannot be fully excluded. Sixth, subgroup analyses were exploratory, and no formal interaction tests were conducted. As such, differences across subgroups should be interpreted with caution. Lastly, our study population was predominantly Caucasian, limiting the generalizability to other settings.

Implications

The risk elevation for arrhythmias in IBD was moderate, with an absolute increase of 14.8/10000 person-years and a relative increase of 35% for histologic inflammation. The corresponding numbers were 41.1/10000 person-years and 77% for active IBD. Given globally over seven million people may live with IBD[55], IBD prevalence is rising, and arrhythmias are usually associated with adverse CVD outcomes, our findings have important implications. Clinicians should be aware of the higher arrhythmia risk during histologic inflammation and active IBD periods, especially in patients aged 40 or older, with lower education, more healthcare visits, or CVD-related comorbidities, which may help to identify high-risk individuals for arrhythmias at early stage. For patients at high risk, targeted interventions such as reducing body weight, increasing physical activity, smoking cessation, limiting alcohol consumption, and optimizing the control of diabetes and hypertension are recommended to reduce the risk of arrhythmias, in line with current clinical guidelines[56,57], given the established long-term association between IBD and arrhythmias[5] and the expected increase in arrhythmias risk burden with age.

CONCLUSION

In conclusion, both histologic and clinical activities of IBD were associated with a higher risk of arrhythmias, and even in clinically quiescent patients, histologic inflammation was linked to an increased arrhythmia risk. Future studies are warranted to validate our definition of disease activity and to investigate the potential benefits of achieving histologic remission in patients with IBD.

ACKNOWLEDGEMENTS

We thank the Swedish national registry for providing data, the ESPRESSO and SWIBREG project staff for their support, and all study participants for their contributions.

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57.  Writing Committee Members; Joglar JA, Chung MK, Armbruster AL, Benjamin EJ, Chyou JY, Cronin EM, Deswal A, Eckhardt LL, Goldberger ZD, Gopinathannair R, Gorenek B, Hess PL, Hlatky M, Hogan G, Ibeh C, Indik JH, Kido K, Kusumoto F, Link MS, Linta KT, Marcus GM, McCarthy PM, Patel N, Patton KK, Perez MV, Piccini JP, Russo AM, Sanders P, Streur MM, Thomas KL, Times S, Tisdale JE, Valente AM, Van Wagoner DR. 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2024;83:109-279.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 660]  [Cited by in RCA: 695]  [Article Influence: 347.5]  [Reference Citation Analysis (0)]
Footnotes

Peer review: Externally peer reviewed.

Peer-review model: Single blind

Specialty type: Gastroenterology and hepatology

Country of origin: Sweden

Peer-review report’s classification

Scientific quality: Grade A, Grade B, Grade B, Grade B

Novelty: Grade A, Grade A, Grade A, Grade B

Creativity or innovation: Grade A, Grade A, Grade B, Grade B

Scientific significance: Grade A, Grade A, Grade B, Grade C

P-Reviewer: Augustin G, Associate Professor, MD, PhD, Croatia; Guo R, Associate Professor, China; Kostik MM, Consultant, MD, PhD, Professor, Russia S-Editor: Luo ML L-Editor: A P-Editor: Wang WB

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