Mahmoud Al Rifai1, Andrea L C Schneider2, Alvaro Alonso3, Nisa Maruthur2, Christina M Parrinello1, Brad C Astor4, Ron C Hoogeveen5, Elsayed Z Soliman6, Lin Y Chen7, Christie M Ballantyne5, Marc K Halushka8, Elizabeth Selvin9. 1. Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health and the Welch Center for Prevention, Epidemiology and Clinical Research. 2. Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health and the Welch Center for Prevention, Epidemiology and Clinical Research; Department of Medicine, Johns Hopkins University School of Medicine. 3. Division of Epidemiology and Community Health, School of Public Health, University of Minnesota. 4. Departments of Medicine and Population Health Sciences, University of Wisconsin School of Medicine and Public Health. 5. Department of Medicine, Section of Cardiovascular Research, Baylor College of Medicine and Houston Methodist DeBakey Heart and Vascular Center. 6. Epidemiological Cardiology Research Center (EPICARE), Department of Epidemiology and Prevention, and Department of Internal Medicine-Cardiology, Wake Forest School of Medicine. 7. Cardiovascular Division, Department of Medicine, University of Minnesota Medical School. 8. Department of Pathology, Johns Hopkins University School of Medicine. 9. Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health and the Welch Center for Prevention, Epidemiology and Clinical Research; Department of Medicine, Johns Hopkins University School of Medicine. Electronic address: eselvin@jhu.edu.
Abstract
OBJECTIVE: Advanced glycation end products (AGEs) may cause inflammation by binding to their cellular receptors (RAGE). Soluble RAGE (sRAGE) acts as a decoy receptor for AGEs and may prevent inflammation. Chronic low-grade inflammation is a risk factor for cardiovascular disease, including atrial fibrillation (AF). METHODS: We studied 1,068 participants in a subsample of the Atherosclerosis Risk in Communities (ARIC) Study who had baseline measurements of sRAGE (mean age 56, 60% female, 21% Black). Inflammation was assessed using measurements of high sensitivity C-reactive protein (hsCRP), fibrinogen, gamma-glutamyl transferase (GGT) and white blood cell (WBC) count. AF events were identified using ECG data, hospitalization discharge codes, and linkage to the National Death Index. RESULTS: Compared to the highest quartile (>1272.4 pg/mL), the lowest quartile of sRAGE (<714 pg/mL) was associated with higher baseline levels of inflammation (hsCRP ≥3 mg/L: OR=2.21 [95% CI 1.41-3.49], fibrinogen ≥400 mg/dL: OR=4.31 [95% CI 1.50-12.41], GGT ≥36 U/L in women and ≥61 U/L in men: OR=5.22 [95% CI 2.66-10.22], WBC >6.2×10⁹/L: OR=2.38 [95% CI 1.52-3.72]). sRAGE was not prospectively associated with 6-year change in inflammatory markers (hsCRP or GGT). There was no significant association of sRAGE and risk of AF (HR 1.49 [95% CI: 0.80-2.78] for the 1st vs. 4th quartile of sRAGE). CONCLUSIONS: sRAGE was strongly inversely associated with markers of inflammation at baseline, but not prospectively. sRAGE was not significantly associated with incident AF. This supports a role for sRAGE in attenuating current inflammation, but it remains unclear whether sRAGE plays a role in the development of AF.
OBJECTIVE: Advanced glycation end products (AGEs) may cause inflammation by binding to their cellular receptors (RAGE). Soluble RAGE (sRAGE) acts as a decoy receptor for AGEs and may prevent inflammation. Chronic low-grade inflammation is a risk factor for cardiovascular disease, including atrial fibrillation (AF). METHODS: We studied 1,068 participants in a subsample of the Atherosclerosis Risk in Communities (ARIC) Study who had baseline measurements of sRAGE (mean age 56, 60% female, 21% Black). Inflammation was assessed using measurements of high sensitivity C-reactive protein (hsCRP), fibrinogen, gamma-glutamyl transferase (GGT) and white blood cell (WBC) count. AF events were identified using ECG data, hospitalization discharge codes, and linkage to the National Death Index. RESULTS: Compared to the highest quartile (>1272.4 pg/mL), the lowest quartile of sRAGE (<714 pg/mL) was associated with higher baseline levels of inflammation (hsCRP ≥3 mg/L: OR=2.21 [95% CI 1.41-3.49], fibrinogen ≥400 mg/dL: OR=4.31 [95% CI 1.50-12.41], GGT ≥36 U/L in women and ≥61 U/L in men: OR=5.22 [95% CI 2.66-10.22], WBC >6.2×10⁹/L: OR=2.38 [95% CI 1.52-3.72]). sRAGE was not prospectively associated with 6-year change in inflammatory markers (hsCRP or GGT). There was no significant association of sRAGE and risk of AF (HR 1.49 [95% CI: 0.80-2.78] for the 1st vs. 4th quartile of sRAGE). CONCLUSIONS: sRAGE was strongly inversely associated with markers of inflammation at baseline, but not prospectively. sRAGE was not significantly associated with incident AF. This supports a role for sRAGE in attenuating current inflammation, but it remains unclear whether sRAGE plays a role in the development of AF.
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