Exploration of the association between inflammatory cytokines and development of new-onset atrial fibrillation in critically ill patients: a retrospective cohort study

doi:10.21203/rs.3.rs-3782924/v1

Background

New-onset atrial fibrillation (new AF) in critically ill patients is associated with increased morbidity and mortality. There has been evidence linking atrial fibrillation with inflammation in both the setting of chronic atrial fibrillation and critical illness. In this study we compare serum inflammatory marker levels in patients admitted to the intensive care unit (ICU) with no atrial fibrillation (AF), chronic AF, and new AF.

Methods

A retrospective chart review was performed on 129 mechanically ventilated, critically ill patients from the PREVAIL trial. History of cardiovascular disease, previous AF, and development of new AF were documented. Inflammatory cytokines TNFα, IL-1b, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, granulocyte-colony stimulating factor, granulocyte-macrophage colony-stimulating factor, interferon-γ, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1b had been collected as part of the PREVAIL trial and were compared between three patient groups, those with no AF, chronic AF, and new AF.

Results

Higher APACHE II scores were found in patients with chronic AF (28.0±8.7) and new AF (27.1±6.2) compared to patients with no AF (23.0±7.2). No significant differences were found between groups in any inflammatory markers at baseline or on admission days 4 or 7.

Conclusion

We found no clear association between the studied inflammatory markers and the development of new AF, although this may be related to the timing of sampling. Further study is required to better elucidate the relationship between inflammatory cytokines and the development of new AF in critically ill patients.

critical illness

atrial fibrillation

inflammatory cytokines

Atrial fibrillation is a common arrythmia in the Intensive Care Unit (ICU), and 14–20% of patients will experience new-onset atrial fibrillation (new AF) during their critical illness^1,2. Patients who develop new AF are at increased risk of hemodynamic instability³, stroke^4,5, congestive heart failure⁶, and death⁷. New AF in critical illness is associated with prolonged mechanical ventilation, length of ICU stay, and increased health care costs^1,8,9.

The pathophysiology of new AF in critical illness is poorly understood and likely multifactorial. Respiratory failure^10,11, oxidative stress¹², use of vasoactive medications¹³, anemia¹⁴, and electrolyte abnormalities¹⁵ are common in critically ill patients and have been linked to the development of new AF. Critically ill patients often suffer an aggressive pro-inflammatory response in combination with an insufficient anti-inflammatory response, resulting in multisystem organ dysfunction¹⁶. This heightened inflammatory state has been proposed as an important driver of new AF through atrial structural remodelling and electrical remodelling^17,18. Several cytokines have been implicated in this process, including tumor necrosis factor (TNF), IL-1¹⁹, IL-8²⁰, and IL-6, which can rapidly induce reversible atrial electrical remodeling²¹.

Despite the biologic plausibility of inflammatory causes of new AF, there is limited evidence showing causal relationships between inflammation and new AF in critically ill patients. The purpose of this study was to evaluate the relationship between serum inflammatory markers and the development of new AF in patients admitted to the ICU.

We performed a retrospective analysis of patients enrolled in the Prevention of Nosocomial Infections in Critically Ill Patients With Lactoferrin: The PREVAIL Study (PREVAIL), a phase II randomized, multicenter, double-blinded trial in five Canadian tertiary ICUs, examining the efficacy of lactoferrin in the prevention of nosocomial infections²². Patients from the Kingston Health Sciences Centre site were included in this analysis. The Queen’s University Health Sciences Research Ethics Board approved this study and procedures were followed in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1975 (HSREB #6037462, CCM-041-22: Association of Inflammatory markers with the development of new onset atrial fibrillation in critically ill patients, approved November 2, 2022).

The inclusion criteria for the PREVAIL trial were adult patients (≥ 18 years old) who had received invasive mechanical ventilation for less than or equal to 48 hours and who were expected to require invasive mechanical ventilation for greater than 72 hours. All patients received standard ICU care for critically ill mechanically ventilated patients.

Patients were excluded in the PREVAIL trial based on the following criteria: 1) those expected to be in ICU for less than 72 hours from time of randomization (due to imminent death, withdrawal of life-sustaining therapies, or discharge); 2) immunocompromised patients defined as follows: post-organ transplantation, AIDS, neutropenia (< 1,000/cc absolute neutrophils), corticosteroids (> 20 mg/d of prednisone or equivalent for > 6 months); 3) fulminant liver failure or end-stage liver disease (Child Pugh Class C); ) life expectancy less than 6 months due to pre-existing conditions; 5) those pregnant or lactating; 6) enrolled in an industry-sponsored interventional trial (co-enrollment in other interventional studies was allowed if there was unlikely to be an interaction between the interventions); and 7) prior randomization in this study.

For the current study patients were excluded if they did not have any inflammatory markers measured.

A chart review was performed. Evidence of history of coronary artery disease (CAD) and atrial fibrillation was collected through review of admission notes and discharge summaries, clinic notes, previous cardiac catheterizations, pharmacy records and previous electrocardiograms (ECG). To determine if a patient had developed New AF while hospitalized ECGs taken during ICU admission were reviewed. In addition, the patient’s medication profile was reviewed for administration of rate or rhythm controlling agents including beta blockers, calcium channel blockers, amiodarone, and digoxin. If ordered, the time of administration of these medications was cross-referenced to nursing notes and rhythm strips from the chart. Finally, for patients with New AF, time from ICU admission to onset of New AF was documented.

Additional laboratory data available included sequential measurement of the following inflammatory markers at baseline (date of enrolment in PREVAIL), day 4, day 7, and then weekly until 28 days post-randomization: a2 macroglobulin, C-reactive protein (CRP) haptoglobin, serum amyloid P, serum amyloid A, ferritin, fibrinogen, procalcitonin, tissue plasminogen activator, tumor necrosis factor α, IL-1b, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, granulocyte-colony stimulating factor, granulocyte-macrophage colony-stimulating factor, interferon-γ, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1b.

Patients were stratified into “no atrial fibrillation” (No AF), “chronic atrial fibrillation” (Chronic AF), and “new atrial fibrillation” (New AF) subgroups. No AF was defined as having no previous history of AF noted in the chart and no ECGs demonstrating AF. Chronic AF was defined as previously documented AF in clinic notes or previous ECGs, even if the AF was paroxysmal. New AF was defined as AF that occurred during the ICU admission or developed prior to the ICU admission (in the emergency department, operating room, or inpatient unit) but without previous documentation or ECGs of AF.

Statistical Analysis

Baseline clinical and demographic characteristics were summarized as means and standard deviations for continuous variables and proportions for binary and categorical variables. Inflammatory cytokines were described as medians and quartiles and compared between groups by the Kruskal-Wallis test. Given there were patients who had developed New AF late in their ICU course due to a secondary insult that would not be reflected by their baseline inflammatory markers, a post-hoc sensitivity analysis was performed on baseline inflammatory markers between patients with no AF, chronic AF, and New AF that developed on ICU admission days 0, 1, 2, and 3. Raw p-values are presented, but we interpreted the 26 inflammatory marker results over 3 time points using the False Discovery Rate of Benjamini and Hochberg²³ allowing for the 78 tests. We considered a False Discovery Rate of < 0.05 as significant.

Patients were enrolled in the PREVAIL trial between November 2013 and September 2016, with the completion of 3-month follow-up in December 2017. Across all recruiting hospitals, 638 patients were screened for enrollment, and 214 patients were randomized: two did not receive any study interventions and the remaining 212 were included in the primary anlaysis. For further details please refer to the primary reporting of the PREVAIL study²². The current analysis includes the 129 patients from the Kingston Health Sciences Centre as this subgroup had their inflammatory markers collected.

The baseline characteristics of patients in this study are shown in Table 1. Twenty-four (19%) patients were identified from this cohort as having New AF, and twenty patients (16%) had Chronic AF. Patients in the No AF category were younger and had lower mean APACHE II than those with New AF or Chronic AF (both p<0.001). Patients in the Chronic AF group had a greater prevalence of CAD than the other groups. (p=0.03)

Table 1 – Baseline Patient Demographics

Characteristics	No AF (n = 85)	Chronic AF (n = 20)	New AF (n = 24)	All (n = 129)
Mean age (SD)	59.2±16.2	73.8±12.3	71.0±11.0	63.7±16.0
Male Sex (%)	35 (41)	7 (35)	14 (58)	56 (43)
Primary Diagnosis (%) Cardiovascular Respiratory Gastrointestinal Neurologic Sepsis Trauma Metabolic Renal Disease Other	10 (12) 21 (25) 2 (2) 15 (18) 20 (24) 7 (8) 2 (2) 2 (2) 6 (7)	4 (20) 4 (20) 0 (0) 4 (20) 4 (20) 0 (0) 0 (0) 1 (5) 3 (15)	4 (17) 7 (29) 2 (8) 1 (4) 6 (25) 1 (4) 0 (0) 1 (4) 2 (8)	18 (14) 32 (25) 4 (3) 20 (16) 30 (23) 8 (6) 2 (2) 4 (3) 11 (9)
Mean APACHE II score (SD)	23.0±7.2	28.0±8.7	27.1±6.2	24.5±7.5
Vasopressors at baseline (%)	58 (68)	15 (75)	19 (79)	92 (71)
History of CAD (%)	21 (25)	11 (55)	7 (29)	39 (30)

The median length of hospital stay prior to development of new AF was 2 days (IQR 1-6 days). Four patients had New AF at admission to the ICU, and five patients developed New AF at admission day 7 or later. Nineteen patients (79%) with New AF were treated with intravenous amiodarone during their ICU stay.

There were no statistically significant differences in serum levels of any of the measured inflammatory cytokines after adjustments for multiple testing (Table 2). (Full cytokine results available in Supplementary Appendix – eTable 1). In the post-hoc sensitivity analysis of patients who developed AF early in their ICU course (day 0, 1, 2, and 3) there were no significant differences between groups at baseline (Figure 1).

Figure 1 - Baseline inflammatory markers of critically ill patients with no AF, chronic AF, or New AF on day 0, 1, 2, or 3 of ICU admission. Inflammatory markers are measured in picograms/mL. Plots are on a logarithmic scale with values of 0 set to 0.5.

Table 2 – Median baseline inflammatory cytokines (picograms/mL) of critically ill patients enrolled in the PREVAIL study.

Inflammatory cytokines Median (IQR)	No AF (n=85)	Chronic AF (n=20)	New AF (n=24)	All (n=129)	Raw p-value
TNF-	16.8 (5.4-65.8)	40.9 (12.2-81.5)	30.3 (7.5-89.2)	22.5 (7.1-73.8)	0.10
IL-1b	3.0 (1.4-5.5)	3.7 (1.9-7.8)	4.2 (1.1-10.0)	3.3 (1.5-7.4)	0.35
IL-2	0.0 (0.0-5.0)	0.0 (0.0-4.9)	4.6 (0.0-13.3)	0.0 (0.0-7.7)	0.10
IL-4	2.9 (0.9-5.1)	3.5 (1.4-5.9)	3.0 (1.3-8.3)	2.9 (1.1-5.7)	0.28
IL-6	74.0 (41.4-178.5)	80.4 (32.0-185.9)	205.9 (54.2-641.0)	79.8 (46.1-219.9)	0.06
IL-8	34.9 (18.9-73.1)	38.1 (20.2-106.4)	64.5 (26.9-105.3)	39.8 (19.7-80.3)	0.15
IL-10	24.8 (9.7-47.8)	24.3 (13.4-50.8)	41.6 (11.5-109.5)	25.3 (10.1-50.8)	0.33

All patients who developed New AF later than seven days had a secondary insult prior to their AF episode. These insults were new infections or hypoxia (Table 3).

Table 3 – Secondary insults leading to late New AF.

Patient #	ICU admission day New AF developed	Secondary Insult
44	9	Hypoxia after extubation
70	10	Staphylococcus epidermidis bacteremia
75	14	Ventilator associated pneumonia
91	18	Ventilator associated pneumonia
97	7	Fluid overload with initiation of dialysis

In this study, we analyzed plasma levels of inflammatory cytokines collected from critically ill adults undergoing mechanical ventilation to investigate the hypothesis that ICU-associated New AF is related to inflammation. Our analysis did not demonstrate an association between any of the cytokines tested and the development of New AF.

A heightened inflammatory state has been proposed as an important driver of New AF^17,18,24. This may be due to direct cardiac effects, which are noted early after exposure to inflammatory cytokines. In post-cardiac surgery patients IL-1b has been shown to increase fibroblast proliferation and collagen production in atrial tissue that may contribute to atrial remodeling and sustained AF^25,26. IL-1b also promotes the induction of IL-6²⁷, and Lazzerini et al demonstrated a relationship between elevated IL-6 and down-regulation of cardiac connexin leading to dysfunction in gap junctions and rapid atrial electrical remodeling²². Local inflammatory conditions, such as myopericarditis and pericarditis, have been associated with increased incidence of atrial fibrillation.^28,29 and similar changes in connexin expression are seen³⁰. Inflammatory alterations in calcium^31,32 and sodium handling³³ have also been proposed as mechanisms that may exacerbate electrical remodeling leading to New AF. Structural changes due to atrial fibrosis may also play a role in the development of New AF in critical illness. IL-6 and TNF-\(a\) promote fibroblast differentiation, proliferation and migration, and animal models demonstrate rapid cardiac fibrosis and dysfunction in the setting of sepsis^33,34. Lastly, two observational studies in ICU patients suggested that hydrocortisone use was associated with a decreased risk of developing New AF in the acute phase of critical illness ^35,36. Similarly, corticosteroids were effective in reducing post-operative AF after cardiac surgery³⁷ and catheter ablation³⁸. Colchicine reduces IL-6 and CRP and has been associated with reduced incidence of post-operative AF³⁹.

There are several potential reasons why our data do not clearly support an inflammatory etiology for New AF in critically ill patients. First, the data on which the inflammatory hypothesis is based are derived primarily from in vitro studies, animal models, and human studies of patients undergoing cardiac surgery. Our findings are the first to look at inflammatory cytokines in a cohort of critically ill patients undergoing mechanical ventilation, who may present with a greater heterogeneity of biologic states, including states of inflammation.

Second, inflammatory states in critical illness are likely dynamic and variable, while the blood sampling strategy used here was fixed, with samples taken days apart, and not necessarily at the time of New AF onset. TNF-\(a\) is generated early in an inflammatory response and peaks as early as eight hours after an inflammatory insult⁴⁰, and may have been missed in the 48-hour enrolment window of the PREVAIL study. IL-1B is also considered a marker of the early phase of inflammation, with peaks found 24 to 48-hours after an inflammatory insult⁴¹. IL-6 is a late-phase inflammatory cytokine whose production is stimulated by IL-1B²⁷, peaking after 72 hours and not captured by the baseline sampling. Patients in the PREVAIL study could be enrolled for 48 hours after the start of mechanical ventilation, so even the baseline measurements could represent various timepoints in the course of the illness. Future studies should consider more targeted sampling of cytokine levels, with samples drawn as near as possible to baseline, onset of AF, and resolution.

Third, though most critically ill patients have some degree of inflammation, not all develop New AF. If we consider IL-6 in this study, we can see that most patients had levels above those of healthy volunteers⁴², yet only 19% developed New AF. This suggests a more complex etiology of New AF, which may include contributions from regional ischemia, electrolyte imbalances, sympathetic tone, atrial volume, and other factors. The effect of such contributors is evidenced by underlying risk factors for New AF such as age, comorbidities, hypoxia, and vasopressor use⁴³. Genetic susceptibility for the development of New AF in critical illness may also contribute, with a recent study demonstrating New AF is associated with genes that influence expression of antioxidant proteins. These variations could affect myocardial capacity to maintain homeostasis during times of oxidative stress and increase susceptibility for development of New AF⁴⁴.

Strengths of this study include a sample size that is relatively large within the context of New AF research, the use of a state-of-the-art multiplex assay to determine the concentrations of numerous cytokines, the use of chart reviews to determine the exact timing of New AF, and a relatively high event rate. Limitations include its single-center, retrospective nature, and a sample size that might have lacked sufficient power to detect small differences in cytokine levels. Finally, brief episodes of New AF that were not captured by ECG or not treated due to quick resolution would not be documented from our chart review, which may have resulted in missed episodes of New AF.

In this study we found no association of inflammatory cytokines with the development of new-onset atrial fibrillation. Given the biologic plausibility of an inflammatory component to the pathogenesis of new-onset atrial fibrillation, better sampling strategies are needed to better clarify this hypothesis. These studies will improve our understanding of the complex pathophysiology of this common arrythmia and may improve our ability to predict, prevent, and treat new AF in critically ill patients. Further, the pathogenesis of new-onset atrial fibrillation is likely multi-factorial and requires the consideration of non-inflammatory hypotheses as well.

AF – atrial fibrillation

ICU – intensive care unit

TNF – tumor necrosis factor

CAD – coronary artery disease

ECG – electrocardiogram

CRP – C-reactive protein

The Queen’s University Health Sciences Research Ethics Board approved this study and procedures were followed in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1975 (HSREB #6037462, CCM-041-22: Association of Inflammatory markers with the development of new onset atrial fibrillation in critically ill patients, approved November 2, 2022).
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
No financial support was obtained for this study.
The authors have no financial disclosures or conflicts of interest to declare.

Author’s contributions:
HD performed the retrospective chart review and wrote and revised the manuscript.
JM is the PI of the PREVAIL study, curated and analyzed the data, and revised the manuscript.
DM reviewed and revised the manuscript.
GB reviewed and revised the manuscript.
AD performed the statistical analysis and reviewed and revised the manuscript.
SS conceptualized the study, performed the retrospective chart review, curated and analyzed the data, and wrote and revised the manuscript.

Wetterslev M, Haase N, Hassager C, et al. New-onset atrial fibrillation in adult critically ill patients: a scoping review. Intensive Care Med 2019;45:928–38.
McIntyre WF, Belley-Cote EP, Vadakken ME, et al. High-Sensitivity Estimate of the Incidence of New-Onset Atrial Fibrillation in Critically Ill Patients. Crit Care Explor 2021;3:e0311.
Kanji S, Stewart R, Fergusson DA, McIntyre L, Turgeon AF, Hebert PC. Treatment of new-onset atrial fibrillation in noncardiac intensive care unit patients: a systematic review of randomized controlled trials. Crit Care Med 2008;36:1620–4.
Walkey AJ, Wiener RS, Ghobrial JM, Curtis LH, Benjamin EJ. Incident stroke and mortality associated with new-onset atrial fibrillation in patients hospitalized with severe sepsis. JAMA 2011;306:2248–54.
Clayton B, Ball S, Read J, Waddy S. Risk of thromboembolism in patients developing critical illness-associated atrial fibrillation. Clin Med (Lond) 2018;18:282–7.
Stewart S, Hart CL, Hole DJ, McMurray JJ. A population-based study of the long-term risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/Paisley study. Am J Med 2002;113:359–64.
Qian J, Kuang L, Chen F, Liu X, Che L. Prognosis and management of new-onset atrial fibrillation in critically ill patients. BMC Cardiovasc Disord 2021;21:231.
Fernando SM, Mathew R, Hibbert B, et al. New-onset atrial fibrillation and associated outcomes and resource use among critically ill adults-a multicenter retrospective cohort study. Crit Care 2020;24:15.
Tseng YH, Ko HK, Tseng YC, Lin YH, Kou YR. Atrial Fibrillation on Intensive Care Unit Admission Independently Increases the Risk of Weaning Failure in Nonheart Failure Mechanically Ventilated Patients in a Medical Intensive Care Unit: A Retrospective Case-Control Study. Medicine (Baltimore) 2016;95:e3744.
Ambrus DB, Benjamin EJ, Bajwa EK, Hibbert KA, Walkey AJ. Risk factors and outcomes associated with new-onset atrial fibrillation during acute respiratory distress syndrome. J Crit Care 2015;30:994–7.
Terzano C, Romani S, Conti V, Paone G, Oriolo F, Vitarelli A. Atrial fibrillation in the acute, hypercapnic exacerbations of COPD. Eur Rev Med Pharmacol Sci 2014;18:2908–17.
Montaigne D, Marechal X, Lefebvre P, et al. Mitochondrial dysfunction as an arrhythmogenic substrate: a translational proof-of-concept study in patients with metabolic syndrome in whom post-operative atrial fibrillation develops. J Am Coll Cardiol 2013;62:1466–73.
Kaakeh Y, Overholser BR, Lopshire JC, Tisdale JE. Drug-induced atrial fibrillation. Drugs 2012;72:1617–30.
Sertcakacilar G, Yildiz, G.O. Association between Anemia and New-Onset Atrial Fibrillation in Critically Ill Patients in the Intensive Care Unit: A Retrospective Cohort Analysis. Clinics and Practice 2022;12:533–44.
Bosch NA, Cimini J, Walkey AJ. Atrial Fibrillation in the ICU. Chest 2018;154:1424–34.
Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR, Katze MG. Into the eye of the cytokine storm. Microbiol Mol Biol Rev 2012;76:16–32.
Hu YF, Chen YJ, Lin YJ, Chen SA. Inflammation and the pathogenesis of atrial fibrillation. Nat Rev Cardiol 2015;12:230–43.
Ihara K, Sasano T. Role of Inflammation in the Pathogenesis of Atrial Fibrillation. Front Physiol 2022;13:862164.
Lazzerini PE, Laghi-Pasini F, Boutjdir M, Capecchi PL. Inflammatory cytokines and cardiac arrhythmias: the lesson from COVID-19. Nat Rev Immunol 2022;22:270–2.
Wu ZK, Laurikka J, Vikman S, Nieminen R, Moilanen E, Tarkka MR. High postoperative interleukin-8 levels related to atrial fibrillation in patients undergoing coronary artery bypass surgery. World J Surg 2008;32:2643–9.
Lazzerini PE, Laghi-Pasini F, Acampa M, et al. Systemic Inflammation Rapidly Induces Reversible Atrial Electrical Remodeling: The Role of Interleukin-6-Mediated Changes in Connexin Expression. J Am Heart Assoc 2019;8:e011006.
Muscedere J, Maslove DM, Boyd JG, et al. Prevention of Nosocomial Infections in Critically Ill Patients With Lactoferrin: A Randomized, Double-Blind, Placebo-Controlled Study. Crit Care Med 2018;46:1450–6.
Benjamini YH, Yosef. Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing. Journal of the Royal Statistical Society 1995;57:289–300.
Guo Y, Lip GY, Apostolakis S. Inflammation in atrial fibrillation. J Am Coll Cardiol 2012;60:2263–70.
Cabaro S, Conte M, Moschetta D, et al. Epicardial Adipose Tissue-Derived IL-1beta Triggers Postoperative Atrial Fibrillation. Front Cell Dev Biol 2022;10:893729.
Matsushita N, Ishida N, Ibi M, et al. IL-1beta Plays an Important Role in Pressure Overload-Induced Atrial Fibrillation in Mice. Biol Pharm Bull 2019;42:543–6.
Cahill CM, Rogers JT. Interleukin (IL) 1beta induction of IL-6 is mediated by a novel phosphatidylinositol 3-kinase-dependent AKT/IkappaB kinase alpha pathway targeting activator protein-1. J Biol Chem 2008;283:25900–12.
Chen MC, Chang JP, Liu WH, et al. Increased inflammatory cell infiltration in the atrial myocardium of patients with atrial fibrillation. Am J Cardiol 2008;102:861–5.
Morgera T, Di Lenarda A, Dreas L, et al. Electrocardiography of myocarditis revisited: clinical and prognostic significance of electrocardiographic changes. Am Heart J 1992;124:455–67.
Ryu K, Li L, Khrestian CM, et al. Effects of sterile pericarditis on connexins 40 and 43 in the atria: correlation with abnormal conduction and atrial arrhythmias. Am J Physiol Heart Circ Physiol 2007;293:H1231-41.
Chen G, Chelu MG, Dobrev D, Li N. Cardiomyocyte Inflammasome Signaling in Cardiomyopathies and Atrial Fibrillation: Mechanisms and Potential Therapeutic Implications. Front Physiol 2018;9:1115.
Bening C, Mazalu EA, Yaqub J, et al. Atrial contractility and fibrotic biomarkers are associated with atrial fibrillation after elective coronary artery bypass grafting. J Thorac Cardiovasc Surg 2020;159:515–23.
Friedrichs K, Klinke A, Baldus S. Inflammatory pathways underlying atrial fibrillation. Trends Mol Med 2011;17:556–63.
Tomita K, Takashina M, Mizuno N, et al. Cardiac fibroblasts: contributory role in septic cardiac dysfunction. J Surg Res 2015;193:874–87.
Launey Y, Lasocki S, Asehnoune K, et al. Impact of Low-Dose Hydrocortisone on the Incidence of Atrial Fibrillation in Patients With Septic Shock: A Propensity Score-Inverse Probability of Treatment Weighting Cohort Study. J Intensive Care Med 2019;34:238–44.
Kane S, Hanes, Scott.. 946: IMPACT OF HYDROCORTISONE ON ATRIAL FIBRILLATION IN SEPTIC SHOCK.. Crit Care Med 2014;42.
Liu L, Jing FY, Wang XW, et al. Effects of corticosteroids on new-onset atrial fibrillation after cardiac surgery: A meta-analysis of randomized controlled trials. Medicine (Baltimore) 2021;100:e25130.
Won H, Kim JY, Shim J, et al. Effect of a single bolus injection of low-dose hydrocortisone for prevention of atrial fibrillation recurrence after radiofrequency catheter ablation. Circ J 2013;77:53–9.
Verma S, Eikelboom JW, Nidorf SM, et al. Colchicine in cardiac disease: a systematic review and meta-analysis of randomized controlled trials. BMC Cardiovasc Disord 2015;15:96.
Ballou SP, Lozanski G. Induction of inflammatory cytokine release from cultured human monocytes by C-reactive protein. Cytokine 1992;4:361–8.
Csontos C, Foldi V, Palinkas L, et al. Time course of pro- and anti-inflammatory cytokine levels in patients with burns–prognostic value of interleukin-10. Burns 2010;36:483–94.
Said EA, Al-Reesi I, Al-Shizawi N, et al. Defining IL-6 levels in healthy individuals: A meta-analysis. J Med Virol 2021;93:3915–24.
Bedford JP, Harford M, Petrinic T, Young JD, Watkinson PJ. Risk factors for new-onset atrial fibrillation on the general adult ICU: A systematic review. J Crit Care 2019;53:169–75.
Kerchberger VE, Huang Y, Koyama T, et al. Clinical and Genetic Contributors to New-Onset Atrial Fibrillation in Critically Ill Adults. Crit Care Med 2020;48:22–30.

No competing interests reported.

Supplimentaryappendix.pdf

Exploration of the association between inflammatory cytokines and development of new-onset atrial fibrillation in critically ill patients: a retrospective cohort study

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Abstract

Figures

Background

Methods

Statistical Analysis

Results

Discussion

Conclusion

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

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