High-sensitivity C-reactive protein (hs-CRP) is a marker for the risk of cardiovascular and overall mortality. However, information about the association between hs-CRP and mortality in patients with atrial fibrillation is scarce. A total of 293 participants of the Atherosclerosis Risk In Communities study with a history of AF and hs-CRP levels available were studied. During a median follow-up of 9.4 years, 134 participants died (46%). The hazard ratio of all-cause mortality associated with the highest versus the lowest tertile of hs-CRP was 2.52 (95% confidence interval 1.49 to 4.25) after adjusting for age, gender, history of cardiovascular diseases, and cardiovascular risk factors. A similar trend was observed for cardiovascular mortality (57 events; hazard ratio 1.90, 95% confidence interval 0.81 to 4.45). The Congestive heart failure, Hypertension, Age >75 years, Diabetes, and previous Stroke or transient ischemic attack (CHADS2) score was also associated with all-cause and cardiovascular mortality, with an adjusted hazard ratio of 3.39 (95% confidence interval 1.91 to 6.01) and 8.71 (95% confidence interval 2.98 to 25.47), respectively, comparing those with a CHADS2 score >2 versus a CHADS2 score of 0. Adding hs-CRP to a predictive model including the CHADS2 score was associated with an improvement of the C-statistic for total mortality (from 0.627 to 0.677) and for cardiovascular mortality (from 0.700 to 0.718). In conclusion, high levels of hs-CRP constitute an independent marker for the risk of mortality in patients with atrial fibrillation.
We examined the association of C-reactive protein (CRP) plasma levels with the incidence of all-cause death and cardiovascular death in patients with atrial fibrillation (AF) in the Atherosclerosis Risk In Communities (ARIC) study to examine whether the addition of CRP levels to the Congestive heart failure, Hypertension, Age >75 years, Diabetes, and previous Stroke or transient ischemic attack (CHADS2) score improves the stratification of patients in terms of the risk of all-cause death and cardiovascular death.
Methods
From 1987 to 1989, the ARIC study recruited 15,792 men and women aged 45 to 64 years at the baseline examination, sampled from 4 communities: Forsyth County, North Carolina; Jackson, Mississippi; the northwest suburbs of Minneapolis, Minnesota; and Washington County, Maryland. The participants underwent additional examinations in 1990 to 1992, 1993 to 1995, and 1996 to 1998 and were followed up throughout by annual telephone interviews and hospital surveillance for the incidence of cardiovascular events. High-sensitivity CRP (hs-CRP) was measured in blood samples obtained at visit 4 (1996 to 1998). For the present analysis, we included ARIC participants who had attended visit 4 and had a history of AF at that date. Participants with missing data on hs-CRP or other covariates and race other than white or black were excluded.
AF was ascertained as previously described. In brief, AF was determined from standard 12-lead electrocardiograms conducted at each study visit and from the hospitalization discharge codes. Previous validation studies have found excellent validity of hospitalization for the diagnosis of AF. The ARIC participants with electrocardiographic-based AF at any of the 4 study examinations or an AF hospitalization before visit 4 were considered to have prevalent AF.
At visit 4, blood was drawn after an 8-hour fasting period from an antecubital vein with minimal trauma. The samples were processed using a standardized protocol and stored at −70°C until assayed. The plasma levels of hs-CRP were determined by an immunophelometric assay (Siemens Healthcare Diagnostics, Deerfield, Illinois). The reliability coefficient in 421 blinded replicates was 0.99.
At each study visit, the participants reported information on smoking and the use of medications, underwent a physical examination, and provided blood samples. For the present analysis, we used the information collected at visit 4. Prevalent diabetes mellitus was defined as a fasting glucose level of ≥126 mg/dl, nonfasting glucose level of ≥200 mg/dl, or a history of diabetes. Two blood pressure measurements were taken with a random-zero sphygmomanometer and averaged. Hypertension was defined as systolic blood pressure of ≥140 mm Hg, diastolic blood pressure of ≥90 mm Hg, or the use of antihypertensive medication. The body mass index was assessed as the weight in kilograms in a scrub suit divided by the height in meters squared.
Prevalent heart failure was defined as the self-reported use of heart failure medications or the presence of heart failure according to the Gothenburg criteria at visit 1 (baseline) or a hospitalization for heart failure ( International Classification of Disease, 9th Revision, Clinical Modification code 428) before visit 4. Prevalent coronary heart disease was defined according to previously published criteria using self-reported information, electrocardiographic data, and hospitalization records.
Cohort participants, or their next of kin if the participant had died, were interviewed by telephone annually and queried regarding hospitalizations in the previous year. Information on each hospitalization involving cardiovascular disease, including stroke, was collected by trained abstractors. Mortality was ascertained through the annual telephone interviews, ongoing surveillance of state health department death certificate files, a search of the hospital records, and linkage with the National Death Index. Cardiovascular mortality was determined according to published criteria by a combination of a computer algorithm and physician’s review using information on clinical signs and symptoms from the hospital records, history of cardiovascular disease, data from the death certificates, and interviews with the next of kin and the participant’s physicians.
We estimated the association of hs-CRP tertiles with all-cause death or cardiovascular death using Cox proportional hazard models. Follow-up was defined as the period from the visit 4 examination to death, the end of follow-up, or December 31, 2007, whichever came first. The linear trend in hazard ratios (HRs) across categories was tested by including hs-CRP as a continuous variable in the models. In an initial analysis, we adjusted for the CHADS2 score (as a continuous variable). A subsequent analysis also adjusted for gender, race (white, black), ARIC center, prevalent coronary heart disease (yes/no), body mass index (continuous), smoking status (never, former, current), education (less than high school, completed high school with some college, college or more, graduate school), antiplatelet medications (yes/no), anticoagulants (yes/no), statins (yes/no), and electrocardiographically defined left ventricular hypertrophy (yes/no). In a final analysis, we included the previous variables plus the individual components of the CHADS2 score: age (continuous), prevalent heart failure, diabetes (yes/no), systolic blood pressure (continuous), use of antihypertensive medications (yes/no), and prevalent stroke (yes/no).
In additional analyses, we classified participants as having high (≥2 mg/L) and low (<2 mg/L) hs-CRP levels. Tests of 2-way multiplicative interactions were performed in regression models using cross-product terms for hs-CRP, as a continuous variable, and gender, age, race, and CHADS2 score.
The added value of hs-CRP in the prediction of mortality and other outcomes was assessed by calculating the c-statistics and the net reclassification improvement in the models with the CHADS2 score only and the CHADS2 score plus hs-CRP.
Results
Of the 11,656 ARIC participants attending visit 4, 293 (2.5%) had a history of AF and met the other inclusion criteria. Of these, 114 had AF diagnosed on any study electrocardiogram and 48 on the visit 4 electrocardiogram. The median period between AF ascertainment and visit 4 was 2.9 years. The participants’ characteristics by hs-CRP tertiles are listed in Table 1 . Higher hs-CRP was associated with female gender, black race, higher body mass index, a greater prevalence of cardiovascular disease, hypertension, diabetes, and smoking, and a greater CHADS2 score.
| Variable | Tertiles of hs-CRP (mg/L) | ||
|---|---|---|---|
| <2.00 (n = 96) | 2.00–5.99 (n = 96) | ≥6.00 (n = 101) | |
| Age (years) | 67 ± 5 | 67 ± 5 | 65 ± 5 |
| Women | 28% | 27% | 44% |
| Black | 4% | 5% | 13% |
| Education | |||
| Less than high school | 17% | 22% | 24% |
| High school–college | 42% | 45% | 48% |
| Graduate school | 42% | 33% | 28% |
| Body mass index (kg/m 2 ) | 27 ± 4 | 29 ± 6 | 31 ± 7 |
| Cigarette smoker | |||
| Current | 7% | 11% | 19% |
| Former | 60% | 55% | 54% |
| Never | 32% | 33% | 27% |
| Diabetes mellitus | 19% | 31% | 37% |
| Systolic blood pressure (mm Hg) | 130 ± 20 | 133 ± 20 | 128 ± 20 |
| Diastolic blood pressure (mm Hg) | 70 ± 11 | 72 ± 11 | 68 ± 12 |
| Prevalent coronary heart disease | 27% | 34% | 33% |
| Prevalent heart failure | 19% | 37% | 46% |
| Prevalent stroke | 6% | 7% | 10% |
| Left ventricular hypertrophy on electrocardiogram | 3% | 7% | 4% |
| Hypertension medication | 69% | 80% | 89% |
| Antiplatelet medication | 61% | 72% | 71% |
| Anticoagulant medication | 26% | 31% | 39% |
| Statin medication | 16% | 13% | 15% |
| Interval to death or end of follow-up (days) | 3,296 ± 992 | 3,083 ± 1,093 | 2,565 ± 1,318 |
| Congestive heart failure, Hypertension, Age ≥75 years, Diabetes, previous Stroke/transient ischemic attack | 1.07 ± 0.97 | 1.55 ± 1.01 | 1.78 ± 1.15 |
During a median of 9.4 years of follow-up, 134 participants died (46%). The hs-CRP levels were positively associated with mortality in a dose–response manner ( Table 2 ). The fully adjusted HR for the highest tertile versus the lowest tertile was 2.52 (95% confidence interval [CI] 1.49 to 4.25; p for trend <0.0001). hs-CRP values >2.0 mg/L were associated with a HR of 1.59 (95% CI 1.03 to 2.48) in the fully adjusted model compared to lower hs-CRP values. We observed no significant multiplicative interaction between hs-CRP and age, gender, race, or CHADS2 score.
| Variable | Tertiles of hs-CRP (mg/L) | p Value for Trend | ||
|---|---|---|---|---|
| <2.00 (n = 96) | 2.00–5.99 (n = 96) | ≥6.00 (n = 101) | ||
| Deaths | 30 (31%) | 42 (44%) | 62 (61%) | — |
| Relative hazard for death | <0.0001 | |||
| Model 1 | 1 (reference) | 1.33 (0.83–2.13) | 2.13 (1.36–3.33) | |
| Model 2 | 1 (reference) | 1.26 (0.77–2.06) | 2.04 (1.24–3.36) | |
| Model 3 | 1 (reference) | 1.24 (0.75–2.03) | 2.52 (1.49–4.25) | |
In the analysis restricted to cardiovascular mortality (57 events), the results followed the same trend ( Table 3 ), with the hs-CRP in the highest tertile associated with greater risk compared to the lowest tertile (HR 2.23, 95% CI 1.09 to 4.57) after adjustment for the CHADS2 score. Additional adjustment attenuated the associations ( Table 3 , models 2 and 3). The relation between hs-CRP and ischemic stroke could not be properly studied owing to the small number of patients with AF and not taking anticoagulants who developed an ischemic stroke during follow-up (n = 21).
| Variable | Tertiles of hs-CRP (mg/L) | p Value for Trend | ||
|---|---|---|---|---|
| <2.00 (n = 96) | 2.00–5.99 (n = 96) | ≥6.00 (n = 101) | ||
| Cardiovascular deaths | 11 (11.46%) | 17 (17.71%) | 29 (28.71%) | |
| Relative hazard for cardiovascular death | ||||
| Model 1 | 1 (reference) | 1.32 (0.62–2.84) | 2.23 (1.09–4.57) | 0.10 |
| Model 2 | 1 (reference) | 1.19 (0.54–2.64) | 1.81 (0.81–4.03) | 0.14 |
| Model 3 | 1 (reference) | 1.05 (0.47–2.34) | 1.90 (0.81–4.45) | 0.12 |
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