Assessment of Inflammatory Biomarkers and Incident Atrial Fibrillation in Older Adults

Sanyog G. Shitole; Susan R. Heckbert; Gregory M. Marcus; Sanjiv J. Shah; Nona Sotoodehnia; Jeremy D. Walston; Alexander P. Reiner; Russell P. Tracy; Bruce M. Psaty; Jorge R. Kizer

doi:10.1161/JAHA.124.035710

Assessment of Inflammatory Biomarkers and Incident Atrial Fibrillation in Older Adults

Sanyog G. Shitole^*, Susan R. Heckbert, Gregory M. Marcus, Sanjiv J. Shah, Nona Sotoodehnia, Jeremy D. Walston, Alexander P. Reiner, Russell P. Tracy, Bruce M. Psaty, Jorge R. Kizer

^*Corresponding author for this work

Medicine, Cardiology Division

Research output: Contribution to journal › Article › peer-review

Abstract

BACKGROUND: Available evidence supports the importance of inflammation in atrial fibrillation (AF) pathogenesis, yet general anti-inflammatory therapies have failed to show benefit for prevention of the arrhythmia. Better understanding of the specific inflammatory pathways involved is necessary to advance therapeutics. METHODS AND RESULTS: We evaluated 9 circulating markers of inflammation measured by immunoassays and incidence of AF in a population-based older cohort. Biomarkers included measures of general inflammation and the NLR (nucleotide-binding oligomerization domain-like receptor) family pyrin domain containing 3 inflammasome, TNF-α (tumor necrosis factor α), monocyte activation markers, and sIL-2 (soluble interleukin-2). Among 5726 participants (median age 72 years), 1836 developed AF over median follow-up of 11.5 years. After adjustment for conventional risk factors, 5 biomarkers were positively associated with incident AF: IL-6 (interleukin-6), hazard ratio (HR), 1.14 (95% CI, 1.07–1.21); hs-CRP (high-sensitivity C-reactive protein), HR, 1.05 (95% CI, 1.01–1.09); white blood cell count, HR, 1.18 (95% CI, 1.04–1.35); sTNFR1 (soluble TNF receptor 1), HR, 1.21 (95% CI, 1.05–1.39); and sIL-2Rα (sIL-2 receptor α), HR, 1.16 (95% CI, 1.05–1.29) (all per doubling of biomarker). sCD14, sCD163, IL-18, and IL-1 receptor antagonist showed no association with AF. Upon concurrent adjustment for all biomarkers, only IL-6 remained significantly associated with the arrhythmia, HR, 1.17 (95% CI, 1.07–1.26). CONCLUSIONS: Among older adults, IL-6, hs-CRP, white blood cell count, sTNFR1, and sIL-2Rα were positively associated with incident AF, but only IL-6 retained significance on concurrent adjustment. These findings newly document associations for sTNFR1 and sIL-2Rα and lend support to a preeminent role for IL-6 in development of this arrhythmia. The efficacy of IL-6 blockade for AF prevention awaits completion of appropriate clinical trials.

Original language	English (US)
Article number	e035710
Journal	Journal of the American Heart Association
Volume	13
Issue number	24
DOIs	https://doi.org/10.1161/JAHA.124.035710
State	Published - Dec 17 2024

Funding

This research was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, 75N92021D00006, and grants U01HL080295 and U01HL130114 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided by R01AG023629 and R01HL158825 from the National Institutes of Health. The work also received support from award K24HL135413 from the National Heart, Lung, and Blood Institute to Jorge R. Kizer.

Keywords

atrial fibrillation
inflammation
older adults

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

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10.1161/JAHA.124.035710

Cite this

@article{9b785e15d1ce444f85ac99854d18a0d5,

title = "Assessment of Inflammatory Biomarkers and Incident Atrial Fibrillation in Older Adults",

abstract = "BACKGROUND: Available evidence supports the importance of inflammation in atrial fibrillation (AF) pathogenesis, yet general anti-inflammatory therapies have failed to show benefit for prevention of the arrhythmia. Better understanding of the specific inflammatory pathways involved is necessary to advance therapeutics. METHODS AND RESULTS: We evaluated 9 circulating markers of inflammation measured by immunoassays and incidence of AF in a population-based older cohort. Biomarkers included measures of general inflammation and the NLR (nucleotide-binding oligomerization domain-like receptor) family pyrin domain containing 3 inflammasome, TNF-α (tumor necrosis factor α), monocyte activation markers, and sIL-2 (soluble interleukin-2). Among 5726 participants (median age 72 years), 1836 developed AF over median follow-up of 11.5 years. After adjustment for conventional risk factors, 5 biomarkers were positively associated with incident AF: IL-6 (interleukin-6), hazard ratio (HR), 1.14 (95% CI, 1.07–1.21); hs-CRP (high-sensitivity C-reactive protein), HR, 1.05 (95% CI, 1.01–1.09); white blood cell count, HR, 1.18 (95% CI, 1.04–1.35); sTNFR1 (soluble TNF receptor 1), HR, 1.21 (95% CI, 1.05–1.39); and sIL-2Rα (sIL-2 receptor α), HR, 1.16 (95% CI, 1.05–1.29) (all per doubling of biomarker). sCD14, sCD163, IL-18, and IL-1 receptor antagonist showed no association with AF. Upon concurrent adjustment for all biomarkers, only IL-6 remained significantly associated with the arrhythmia, HR, 1.17 (95% CI, 1.07–1.26). CONCLUSIONS: Among older adults, IL-6, hs-CRP, white blood cell count, sTNFR1, and sIL-2Rα were positively associated with incident AF, but only IL-6 retained significance on concurrent adjustment. These findings newly document associations for sTNFR1 and sIL-2Rα and lend support to a preeminent role for IL-6 in development of this arrhythmia. The efficacy of IL-6 blockade for AF prevention awaits completion of appropriate clinical trials.",

keywords = "atrial fibrillation, inflammation, older adults",

author = "Shitole, {Sanyog G.} and Heckbert, {Susan R.} and Marcus, {Gregory M.} and Shah, {Sanjiv J.} and Nona Sotoodehnia and Walston, {Jeremy D.} and Reiner, {Alexander P.} and Tracy, {Russell P.} and Psaty, {Bruce M.} and Kizer, {Jorge R.}",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s).",

year = "2024",

month = dec,

day = "17",

doi = "10.1161/JAHA.124.035710",

language = "English (US)",

volume = "13",

journal = "Journal of the American Heart Association",

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T1 - Assessment of Inflammatory Biomarkers and Incident Atrial Fibrillation in Older Adults

AU - Shitole, Sanyog G.

AU - Heckbert, Susan R.

AU - Marcus, Gregory M.

AU - Shah, Sanjiv J.

AU - Sotoodehnia, Nona

AU - Walston, Jeremy D.

AU - Reiner, Alexander P.

AU - Tracy, Russell P.

AU - Psaty, Bruce M.

AU - Kizer, Jorge R.

PY - 2024/12/17

Y1 - 2024/12/17

N2 - BACKGROUND: Available evidence supports the importance of inflammation in atrial fibrillation (AF) pathogenesis, yet general anti-inflammatory therapies have failed to show benefit for prevention of the arrhythmia. Better understanding of the specific inflammatory pathways involved is necessary to advance therapeutics. METHODS AND RESULTS: We evaluated 9 circulating markers of inflammation measured by immunoassays and incidence of AF in a population-based older cohort. Biomarkers included measures of general inflammation and the NLR (nucleotide-binding oligomerization domain-like receptor) family pyrin domain containing 3 inflammasome, TNF-α (tumor necrosis factor α), monocyte activation markers, and sIL-2 (soluble interleukin-2). Among 5726 participants (median age 72 years), 1836 developed AF over median follow-up of 11.5 years. After adjustment for conventional risk factors, 5 biomarkers were positively associated with incident AF: IL-6 (interleukin-6), hazard ratio (HR), 1.14 (95% CI, 1.07–1.21); hs-CRP (high-sensitivity C-reactive protein), HR, 1.05 (95% CI, 1.01–1.09); white blood cell count, HR, 1.18 (95% CI, 1.04–1.35); sTNFR1 (soluble TNF receptor 1), HR, 1.21 (95% CI, 1.05–1.39); and sIL-2Rα (sIL-2 receptor α), HR, 1.16 (95% CI, 1.05–1.29) (all per doubling of biomarker). sCD14, sCD163, IL-18, and IL-1 receptor antagonist showed no association with AF. Upon concurrent adjustment for all biomarkers, only IL-6 remained significantly associated with the arrhythmia, HR, 1.17 (95% CI, 1.07–1.26). CONCLUSIONS: Among older adults, IL-6, hs-CRP, white blood cell count, sTNFR1, and sIL-2Rα were positively associated with incident AF, but only IL-6 retained significance on concurrent adjustment. These findings newly document associations for sTNFR1 and sIL-2Rα and lend support to a preeminent role for IL-6 in development of this arrhythmia. The efficacy of IL-6 blockade for AF prevention awaits completion of appropriate clinical trials.

AB - BACKGROUND: Available evidence supports the importance of inflammation in atrial fibrillation (AF) pathogenesis, yet general anti-inflammatory therapies have failed to show benefit for prevention of the arrhythmia. Better understanding of the specific inflammatory pathways involved is necessary to advance therapeutics. METHODS AND RESULTS: We evaluated 9 circulating markers of inflammation measured by immunoassays and incidence of AF in a population-based older cohort. Biomarkers included measures of general inflammation and the NLR (nucleotide-binding oligomerization domain-like receptor) family pyrin domain containing 3 inflammasome, TNF-α (tumor necrosis factor α), monocyte activation markers, and sIL-2 (soluble interleukin-2). Among 5726 participants (median age 72 years), 1836 developed AF over median follow-up of 11.5 years. After adjustment for conventional risk factors, 5 biomarkers were positively associated with incident AF: IL-6 (interleukin-6), hazard ratio (HR), 1.14 (95% CI, 1.07–1.21); hs-CRP (high-sensitivity C-reactive protein), HR, 1.05 (95% CI, 1.01–1.09); white blood cell count, HR, 1.18 (95% CI, 1.04–1.35); sTNFR1 (soluble TNF receptor 1), HR, 1.21 (95% CI, 1.05–1.39); and sIL-2Rα (sIL-2 receptor α), HR, 1.16 (95% CI, 1.05–1.29) (all per doubling of biomarker). sCD14, sCD163, IL-18, and IL-1 receptor antagonist showed no association with AF. Upon concurrent adjustment for all biomarkers, only IL-6 remained significantly associated with the arrhythmia, HR, 1.17 (95% CI, 1.07–1.26). CONCLUSIONS: Among older adults, IL-6, hs-CRP, white blood cell count, sTNFR1, and sIL-2Rα were positively associated with incident AF, but only IL-6 retained significance on concurrent adjustment. These findings newly document associations for sTNFR1 and sIL-2Rα and lend support to a preeminent role for IL-6 in development of this arrhythmia. The efficacy of IL-6 blockade for AF prevention awaits completion of appropriate clinical trials.

KW - atrial fibrillation

KW - inflammation

KW - older adults

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Assessment of Inflammatory Biomarkers and Incident Atrial Fibrillation in Older Adults

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