106 patients with chronic AF and 41 healthy controls
Median comparison between groups
At baseline of the study
Patients with AF had significantly higher levels of IL-6 (median 24 versus 3 pg/mL, ) and CRP (median 0.27 versus 0.13 mg/dL, ), compared with controls. Plasma IL-6 levels were higher among AF patients at “high” risk of stroke using risk scores ()
Patients with identified thromboembolic risk factors on TEE had greater CRP levels than those without (1.00 versus 0.302 mg/dL). CRP also correlated with clinical stroke risk factors
90 patients with AF (70 with persistent AF who underwent PCV and 20 with permanent AF) and 46 controls
Mean comparison between groups
6 hours after CV or in the morning hours after fasting
Compared with controls patients with AF had increased CRP (mean 5.7 versus 2.3 mg/L, ) and IL-6 (mean 8.3 versus 2.9 pg/mL, ). There was positive relation between LAD and inflammatory markers (CRP [, ] and IL-6 [, ])
≤0.12 mg/dL for CV success and ≥0.06 mg/dL for recurrence
Immediately prior to ECV
A lower hs-CRP (≤0.12 mg/dL) was an independent predictor of successful ECV (OR 0.33, 95% CI 0.21–0.51). In turn, a high hs-CRP was the only independent predictor of AF recurrence (OR 5.30, 95% CI 2.46–11.5) using a cut-off value of hs-CRP ≥ 0.06 mg/dL, and after adjustment for coexisting cardiovascular risks
Within 30 days of enrollment or after 3 months in the study
Patients with moderate to high stroke risk (measured by CHADS2 score and NICE criteria) had the highest levels of CRP (Kruskal Wallis test, ). All-cause mortality (log rank test, ) and vascular events (), but not stroke, were more common in patients with high CRP levels during a mean follow-up of 453 (±229) days. Soluble CD40 ligand was not related to prognosis
A meta-analysis of 7 studies with 420 AF patients who underwent successful ECV
Mean difference between groups
At baseline of primary studies
Atrial fibrillation relapsed in 229 patients. Baseline CRP levels were greater in patients with AF recurrence than in those without (SMD 0.35 units, 95% CI 0.01–0.69)
During the 1-year follow-up period, 15 patients presented recurrence of AF. Patients with AF recurrence had significantly higher plasma levels of both IL-6 (mean 1.84 ± 0.66 versus 1.19 ± 0.51 ng/L, ) and CRP (1.24 ± 0.79 mg/L versus 0.59 ± 0.40, ) than those without. There was a significant positive correlation between levels of IL-6 and CRP
56 patients with persistent AF who underwent successful ECV
2.8 pg/mL for IL-6 and 3.0 mg/L for hs-CRP (analysis included median comparison)
Before CV and after 1, 30, and 180 days
After 180 days of follow-up, the recurrence rate was 68%. Patients with recurrence of AF had significantly higher hs-CRP (2.0 versus 1.25 mg/L, ) and IL-6 (2.75 versus 1.96 pg/mL, ) than those who maintained SR. Baseline IL-6 was the only independent predictor of recurrent AF () in a multivariate Cox analysis
46 patients with paroxysmal or persistent AF who underwent RFCA
Median comparison between groups
Before the first ablation procedure and at follow-up visits
After 12 months of follow-up, the recurrence rate was 59%. Patients with recurrence of AF had significantly higher IL-6 (1.4 versus 0.9 pg/mL, ) and hs-CRP (2.2 versus 0.7 mg/L, ) at baseline than those who maintained SR. IL-6 concentration prior to ablation was an independent predictor of recurrent AF ()
137 patients with AF who underwent mapping and catheter ablation
2.92 mg/L
Before the first ablation procedure
Higher hs-CRP was associated with an increased frequency of nonpulmonary vein ectopies (34.4% versus 17%, ) and was an independent predictor of recurrence () in a multivariable regression model after adjusting for other potential covariates
Patients in the high-risk group according to CHADS2 score had significantly greater CRP levels than those in the intermediate- and low-risk groups (0.80 mg/dL versus 0.16 mg/dL versus 0.08 mg/dL, , resp.). And the incidence of LA SEC and LA thrombus on TEE increased with an increasing CHADS2 score
46,876 individuals from 2 large studies (including 2,111 with AF)
Multiple cut-offs (quintiles)
NA
The highest CRP quintile was associated with increased risk of atrial fibrillation compared with the lower quintile (OR 2.19, 95% CI 1.54–3.10). However, CRP did not fulfill the causality criterion, whereas its elevation by genetically CRP did not increase atrial fibrillation risk
103 AF patients (28 with AF complicated by ischemic stroke) and 112 controls
Median comparison between groups
At baseline
AF patients had higher levels of hs-CRP (), IL-6 (), and cystatin C () than control subjects. Plasma hs-CRP level was also higher in patients with AF complicated by ischemic stroke compared with those with simple AF ()
IL-18 was significantly higher in patients with AF than in controls (471.50 ± 144.91 versus 232.20 ± 55.33 pg/mL; ). MMP-9 (OR = 1.02, 95% CI: 1.00–1.03, ) and IL-18 were independently associated with AF (OR = 1.02, 95% CI: 1.01–1.03, ). Interleukin-18 levels were also higher in persistent AF patients than in those with paroxysmal AF ()
1.85 mg/dL (the analysis included mean comparison between groups)
Prior to and 1, 2, 7, and 30 days after CV
The basal hs-CRP levels were higher in patients with an AF relapse than in those without (1.68 ± 0.57 versus 1.12 ± 0.53 mg/dL; ). By multivariate Cox analysis, the independent predictors of AF relapse time points were the basal and day-2 hs-CRP levels
121 patients with AF (paroxysmal/persistent AF: 77/44) who underwent CPVI
1.41 mg/L (the analysis included median comparison between groups)
On the morning of admission, before the procedure
The plasma hs-CRP concentration was significantly higher in the group with AF recurrence than in the nonrecurrent one (median 2.22 mg/L versus 0.89 mg/L, ). A higher hsCRP was a significant predictor of AF recurrence in overall (OR 5.10, 95% CI 2.14–12.11, ) and in subgroups of paroxysmal (OR 4.12, 95% CI 1.36–12.47, ) and persistent AF (OR 16.37, 95% CI 2.52–56.42, )
242 patients with AF (155 paroxysmal AF, 87 persistent AF) who underwent CA
10.0 ng/mL for TGF-β and 1.1 ng/mL for TIMP-1
Biomarker measurement, LA voltage map, and 3D-CT before CA
Patients with higher TGF-β (≥10.0 ng/mL) had lower mean LA voltage () and greater LA volume () than those with lower levels. Similarly, patients with higher TIMP-1 (≥1.1 ng/mL) had lower mean LA voltage () than those with lower levels. This reflects that higher plasma concentrations of this markers are closely related with LA electroanatomical (voltage and structural) remodeling
552 patients who underwent coronary bypass surgery, analyzed retrospectively
Multiple cut-offs (the analysis included median comparison between groups)
Preoperative
AF occurred in 21.9% of patients after surgery. The median value of CRP was higher in patients who developed AF than in those who did not (2.2 versus 1.3, ). This association persisted after adjustment for confounders (HR 1.43, 95% CI 1.22–1.97 per 1 SD increase in CRP, and HR 2.88, 95% CI 1.67–4.97 for CRP within 3.0–10.0 versus <1.0 mg/dL)
During a median follow-up of 9.4 years, hs-CRP was associated with increased risk for all-cause mortality comparing the highest versus the lowest tertiles (HR 2.52, 95% CI 1.49–4.25, ) after adjusting for potential confounders
17,120 participants without prior history of arrhythmia
Multiple cut-offs (<3.2, 3.2–5.8, and ≥5.8 mg/L)
At study baseline
Each increase in hs-CRP tertile from the lowest was associated with a 36% increase in the risk of developing AF (HR 1.37, 95% CI: 1.16–1.60, ), with an HR of 1.96 (95% CI: 1.40–2.75, ) when comparing the highest hs-CRP tertile with the lowest
930 patients with permanent/paroxysmal AF in chronic anticoagulation
Multiples (3.35 pg mL−1 for CVE, 4.16 pg mL−1 for mortality)
At baseline
During a median follow-up of 957 (784–1087) days, 107 adverse cardiovascular events occurred (3.14%/year), which included 37 stroke/TIA events (1.5%/year). On multivariate analysis, a high IL-6 was associated with adverse cardiovascular events (OR 1.97, 95% CI 1.29–3.02, ) and all-cause mortality (HR 2.48, 9% CI 1.60–3.85, )
92 patients with AF and hypertension who underwent ECV
0.30 mg/dL
Before CV
A higher hs-CRP (>0.30 mg/dL) was associated with -wave alterations such as maximum above 120 ms () and dispersion above 40 ms () that are useful predictors of AF recurrence
2,370 patients with AMI, but without AF from TRIUMPH study
Median comparison between groups
At study baseline
There was a 15% increase in the rate of AF (OR 1.15, 95% CI 1.02–1.30, ), for each 2-fold increase in CRP. Similarly, for every 2-fold increase in NT-proBNP, there was an 18% increase in the rate of AF (OR 1.18, 95% CI 1.03–1.3, )
18,556 Whites and African Americans from three primary studies (ARIC, CHS, and FHS)
Multiple cut-offs (each 1-SD increase)
At the index visit
1,186 new cases occurred in five years of follow-up. CRP was significantly associated with AF incidence (HR 1.18, 95% CI 1.11–1.25, ), per 1-SD increase of ln-transformed values, as was BNP (HR 1.66, 95% CI 1.56–1.76, )
2,768 participants without AF (43% Black) from Health ABC Study
Multiple cut-offs (depending on the biomarker)
At the baseline study visit
During a median follow-up of 10.9 years, 721 developed incident AF. Adiponectin, CRP, IL-6, TNF-, TNF- SR I, and TNF-α SR II concentrations were each higher among Whites and independently associated with a greater risk of incident AF. Together, these inflammatory cytokines mediated 42% (95% CI 15 to 119%, ) of the adjusted white race associated AF
6,187 patients with nonvalvular AF from the RE-LY study
Multiple cut-offs (quartiles)
Before start of study intervention
In patients with AF, IL-6 was independently associated with stroke or systemic embolism (), major bleeding (), vascular death (), and a composite thromboembolic outcome (ischemic stroke, systemic embolism, myocardial infarction, pulmonary embolism, and vascular death) (), after adjusting for clinical risk factors. Similarly, CRP was independently related to myocardial infarction (), vascular death (), and the composite thromboembolic outcome ()
Plasma IL-6 level was significantly associated with presence of AF at baseline (OR 1.61, 95% CI 1.21– 2.14, ) and was an independent predictor of NOAF (OR 1.25, 95% CI, 1.02–1.53, ) during a mean follow-up of 3.7 years, after adjusting for confounders
At hospital admission, 24 hours, and 28 days after SR restoration
hs-CRP concentrations were higher in patients with AF than in controls at baseline (mean 8.12 ± 0.82 versus 5.57 ± 0.21 mg/L, ), and the difference persisted 24 hours after SR restoration (8.16 ± 0.71 versus 5.57 ± 0.21 mg/L, )
14,954 patients with AF on anticoagulation from the ARISTOTLE trial
Multiple cut-offs (quartiles)
At randomisation
There was a significant association between IL-6 and CRP and all-cause mortality independent of clinical risk factors and other biomarkers (HR 1.93, 95% CI 1.57–2.37 for IL-6, and HR 1.49 95% CI 1.24–1.79 for CRP, comparing the highest with the lowest quartiles). However, there were no associations with the risk of stroke or major bleeding
3D-CT: three-dimensional computed tomography; AF: atrial fibrillation; AMI: Acute Myocardial Infarction; ARIC: Atherosclerosis Risk in Communities Study; ARISTOTLE: Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; CA: catheter ablation; CABG: coronary artery bypass grafting; CAD: coronary artery disease; CHADS2: one point for congestive heart failure, hypertension, age > 75, diabetes mellitus, and two points for prior stroke or transient ischemic attack; CHS: Cardiovascular Health Study; CI: confidence interval; CKD: chronic kidney disease; CPVI: circumferential pulmonary vein isolation; CV: cardioversion; CVE: cardiovascular events; ECV: electrical cardioversion; FHS: Framingham Heart Study; Health ABC: Health, Aging, and Body Composition; HR: hazard ratio; IL-17A: interleukin-17A; IL-6: interleukin-6; LAAWV: left atrial appendage wall velocity; LAD: left atrial diameter; MACE: major adverse cardiovascular events; MMP-9: matrix metalloproteinase-9; NA: not available; NICE: National Institute for Health and Clinical Excellence; NOAF: new-onset atrial fibrillation; NT-proBNP: NT-pro-brain natriuretic peptide; OR: Odds Ratio; PCI: percutaneous coronary intervention; PCV: pharmacological cardioversion; POAF: postoperative atrial fibrillation; RE-LY study: “Randomized Evaluation of Long-term anticoagulant therapY” study; RFCA: radiofrequency catheter ablation; SAFHIRE: Study of Atrial Fibrillation in High-Risk Elderly; SEC: spontaneous echo contrast; SMD: standardized mean difference; SPAF: Stroke Prevention in Atrial Fibrillation; sPsel: soluble P-selectin; SR: sinus rhythm; STEMI: ST-segment elevation myocardial infarction; TEE: transesophageal echocardiography; TGF-β: transforming growth factor-β; TIMP-1: tissue inhibitor of metalloproteinase-1; TNF-α: tumor necrosis factor alpha; TNF-α SR I: tumor necrosis factor alpha soluble receptor I; TNF-α SR II: tumor necrosis factor alpha soluble receptor II; vWf: von Willebrand factor.
