Usefulness of High-Sensitivity C-Reactive Protein to Predict Mortality in Patients With Atrial Fibrillation (from the Atherosclerosis Risk In Communities [ARIC] Study)

doi:10.1016/j.amjcard.2011.08.010

The American Journal of Cardiology

Volume 109, Issue 1, 1 January 2012, Pages 95-99

https://doi.org/10.1016/j.amjcard.2011.08.010 Get rights and content

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.

Section snippets

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.¹ 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

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

Discussion

In the present analysis of a prospective cohort followed up for a median of 9.4 years, we found that higher hs-CRP levels were associated with increased all-cause and cardiovascular mortality in patients with AF, independent of other risk factors. Specifically, participants with hs-CRP levels in the highest tertile exhibited an incidence of all-cause or cardiovascular death approximately twice that of those in the lowest tertile. The CHADS2 score was also associated with all-cause and

References (20)

A. Alonso et al.
Incidence of atrial fibrillation in whites and African-Americans: the Atherosclerosis Risk in Communities (ARIC) study
Am Heart J
(2009)
A.M. Chamberlain et al.
Metabolic syndrome and incidence of atrial fibrillation among blacks and whites in the Atherosclerosis Risk in Communities (ARIC) Study
Am Heart J
(2010)
L.R. Loehr et al.
Heart failure incidence and survival (from the Atherosclerosis Risk In Communities study)
Am J Cardiol
(2008)
A.D. White et al.
Community surveillance of coronary heart disease in the Atherosclerosis Risk In Communities (ARIC) study: methods and initial two years' experience
J Clin Epidemiol
(1996)
D.S. Conway et al.
Prognostic significance of raised plasma levels of interleukin-6 and C-reactive protein in atrial fibrillation
Am Heart J
(2004)
T.M. Khumri et al.
Clinical and echocardiographic markers of mortality risk in patients with atrial fibrillation
Am J Cardiol
(2007)
The Atherosclerosis Risk in Communities (ARIC) Study: design and objectivesThe ARIC investigators
Am J Epidemiol
(1989)
B.M. Psaty et al.
Incidence of and risk factors for atrial fibrillation in older adults
Circulation
(1997)
A.R. Folsom et al.
C-reactive protein and venous thromboembolism: a prospective investigation in the ARIC cohort
Thromb Haemost
(2009)
W.D. Rosamond et al.
Stroke incidence and survival among middle-aged adults: 9-year follow-up of the Atherosclerosis Risk In Communities (ARIC) cohort
Stroke
(1999)

There are more references available in the full text version of this article.

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Association of C-reactive protein level with adverse outcomes in patients with atrial fibrillation: A meta-analysis
2024, American Journal of the Medical Sciences
Studies on the association between C-reactive protein (CRP) level and poor outcomes have been yielded controversial results in patients with atrial fibrillation (AF). This meta-analysis sought to investigate the utility of elevated CRP level in predicting adverse outcomes in AF patients.
Two authors systematically searched PubMed and Embase databases (until December 10, 2022) for studies evaluating the value of elevated CRP level in predicting all-cause mortality, cardiovascular death, stroke, or major adverse cardiovascular events (MACEs) in AF patients. The predictive value of CRP was expressed by pooling adjusted hazard ratio (HR) with 95% confidence intervals (CI) for the highest versus the lowest level or per unit of log-transformed increase.
Ten studies including 30,345 AF patients satisfied our inclusion criteria. For the highest versus the lowest CRP level, the pooled adjusted HR was 1.57 (95% CI 1.34-1.85) for all-cause mortality, 1.18 (95% CI 0.92-1.50) for cardiovascular death, and 1.57 (95% CI 1.10-2.24) for stroke, respectively. When analyzed the CRP level as continuous data, per unit of log-transformed increase was associated with a 27% higher risk of all-cause mortality (HR 1.27; 95% CI 1.23-1.32) and 16% higher risk of MACEs (HR 1.16; 95% CI 1.05-1.28).
Elevated CRP level may be an independent predictor of all-cause mortality, stroke, and MACEs in patients with AF. CRP level at baseline can provide important prognostic information in risk classification of AF patients.
Polygenic risk score in comparison with C-reactive protein for predicting incident coronary heart disease
2023, Atherosclerosis
Despite interest in the use of polygenic risk scores (PRS) for predicting coronary heart disease (CHD) risk, the clinical utility of PRS compared to conventional risk factors has not been demonstrated. We compared the performance of PRS with that of high-sensitivity C-reactive protein (hsCRP) in two well-established cohorts.
The study population included individuals of European ancestry free of baseline CHD from ARIC (N = 13,113) and the Framingham Offspring Study (FHS) (N = 2,696). The primary predictors included a validated PRS consisting of >6.6 million single nucleotide polymorphisms and hsCRP. The outcome was incident CHD, defined as non-fatal or fatal myocardial infarction. We compared the performance of both predictors after adjusting for the Pooled Cohort Equations in multivariable-adjusted Cox regression models. We assessed discrimination and reclassification using c-statistics and net reclassification improvement.
Incident CHD occurred in 565 ARIC and 153 FHS participants. In multivariable-adjusted models, both PRS and hsCRP were associated with incident CHD (p < 0.05 in both cohorts). In models incorporating both predictors, strengths of association were similar. For instance, in ARIC, the hazard ratio per SD increment was 1.38 (95% CI, 1.27–1.50, p = 2.94 × 10⁻¹⁴) for PRS and 1.41 (1.30–1.55, p = 3.10 × 10⁻¹⁵) for hsCRP. Neither predictor significantly increased model discrimination or net reclassification when compared with models containing the Pooled Cohort Equations alone.
In two independent cohorts, PRS performed similarly to hsCRP for the prediction of CHD risk. These findings suggest PRS does not have unique clinical utility beyond this widely-available, inexpensive measure of risk in unselected middle-aged populations.
Cohort Study and Bias Analysis of the Obesity Paradox Across Stages of Chronic Kidney Disease
2022, Journal of Renal Nutrition
In advanced chronic kidney disease (CKD), patients with obesity often have better outcomes than patients without obesity, often called the ‘obesity paradox’. Yet, in CKD, the prevalence of inflammation increases as CKD progresses. Although a potential confounder, inflammation may be left unaccounted in obesity–mortality studies. We examined the associations of body mass index (BMI) with all-cause and cause-specific mortality across CKD stages, with consideration for uncontrolled confounding due to unmeasured inflammation.
We investigated 2,703,512 patients with BMI data between 2004 and 2006. We used Cox models to examine the associations of BMI with all-cause, cardiovascular, and cancer mortality, (ref: BMI 25-<30 kg/m²), adjusted for clinical characteristics and stratified by CKD stages. To address uncontrolled confounding, we performed bias analysis using a weighted probabilistic model of inflammation given the observed data applied to weighted Cox models.
The cohort included 5% females and 14% African Americans. In adjusted analyses, the associations of the BMI with all-cause and cardiovascular mortality showed a reverse J-shape, where a higher BMI (>40 kg/m²) was associated with a higher risk. Conversely, a lower mortality risk was observed with a BMI 30-<35 kg/m² across all CKD stages and for BMI >40 kg/m² in CKD stage 4/5. Cancer mortality analyses showed an inverse relationship. Bias analysis for uncontrolled confounding suggested that independent of inflammation, the obesity paradox was present.
We observed the presence of the obesity paradox in this study. This association was consistent in advanced CKD and in our bias analysis, suggesting that inflammation may not fully explain the observed BMI-mortality associations including in patients with CKD.
Correlation between genetic polymorphisms in apolipoprotein E and atrial fibrillation
2022, Revista Portuguesa de Cardiologia
This work explores correlations between genetic polymorphisms in apolipoprotein E (ApoE) and atrial fibrillation (AF). We detected polymorphisms in the APOE gene in 64 patients with AF and 49 non-AF volunteers at the Department of Cardiology of Lianyungang Second People's Hospital between July 2017 and July 2019. We found significant differences in age, body mass index, left atrial diameter, and left ventricular ejection fraction between the two groups. Six APOE genotypes were observed: ɛ2/ɛ2; ɛ2/ɛ3; ɛ2/ɛ4; ɛ3/ɛ3; ɛ3/ɛ4; and ɛ4/ɛ4. The ɛ3/ɛ3 genotype was significantly less frequent in the AF group than in the control group, while the ɛ3/ɛ4 and ɛ4/ɛ4 genotypes were significantly more frequent in the AF group than in the control group (p<0.05). ApoE3 penetrance was significantly lower in the AF group than in the control group (p<0.05), while ApoE4 penetrance was significantly higher in the AF group than in the control group (p<0.05). ApoE3 penetrance was significantly lower in the AF group than in the control group (p<0.05). Binary logistic regression analysis showed that age, body mass index, left atrial diameter, left ventricular ejection fraction, and ApoE4 were risk factors for AF. Finally, we found that ApoE polymorphisms impacted the occurrence of AF and that ApoE4 is an AF-sensitive phenotype.
Este trabalho estudou as correlações entre os polimorfismos genéticos da apolipoproteína E (ApoE) e fibrilhação auricular (FA). Entre julho de 2017 e julho de 2019 detetámos polimorfismos no gene da ApoE em 64 doentes com FA e em 49 voluntários sem FA (Serviço de Cardiologia do Lianyungang Second People's Hospital). Observaram-se diferenças significativas na idade, no índice de massa corporal, no diâmetro auricular esquerdo e na fração de ejeção ventricular esquerda entre os dois grupos. Seis genotipos da ApoE foram observados: ɛ2/ɛ2; ɛ2/ɛ3; ɛ2/ɛ4; ɛ3/ɛ3; ɛ3/ɛ4; e ɛ4/ɛ4. O genotipo ɛ3/ɛ3 foi significativamente menos frequente no grupo da FA do que no grupo controlo, enquanto os genotipos ɛ3/ɛ4 and ɛ4/ɛ4 foram significativamente mais frequentes no grupo da FA em relação ao grupo controlo (p<0,05). A penetração de ApoE3 foi significativamente inferior no grupo FA do que no grupo controlo (p<0,05). A penetração de ApoE4 foi significativamente superior no grupo FA em relação ao grupo controlo (p<0,05). A penetração da ApoE3 foi significativamente menor no grupo FA do que no grupo controlo (p<0,05). A análise da regressão logística binária revelou que a idade, o índice da massa corporal, o diâmetro auricular esquerdo, a fração de ejeção ventricular esquerda e a ApoE4 constituíram fatores de risco para FA. Finalmente, considerámos que os polimorfismos ApoE tiveram impacto na ocorrência da FA e que a ApoE4 é um fenotipo sensível à FA.
BARI 2D: A Reanalysis Focusing on Cardiovascular Events
2019, Mayo Clinic Proceedings
Citation Excerpt :
The beneficial CVD effect of IS therapy compared with IP therapy was mostly accounted for by a lower level of glycemia and by a reduction in markers of inflammation (CRP) and thrombogenesis (fibrinogen) in the IS group in a multivariate analysis. Previous studies have found both CRP level32-34 and fibrinogen level35-37 to be risk factors for CVD, as is HbA1c level.38-40 It is noteworthy that the beneficial effects of IS treatment compared with IP treatment and those of REV compared with MED treatment became visible at 1 year after their initiation (Figure 2).
To reanalyze the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial using a new composite cardiovascular disease (CVD) outcome to determine how best to treat patients with type 2 diabetes mellitus and stable coronary artery disease.
From January 1, 2001, to November 30, 2008, 2368 patients with type 2 diabetes mellitus and angiographically proven coronary artery disease were randomly assigned to insulin-sensitizing (IS) or insulin-providing (IP) therapy and simultaneously to coronary revascularization (REV) or no or delayed REV (intensive medical therapy [MED]), with all patients receiving intensive medical treatment. The outcome of this analysis was a composite of 8 CVD events.
Four-year Kaplan-Meier rates for the composite CVD outcome were 35.8% (95% CI, 33.1%-38.5%) with IS therapy and 41.6% (95% CI, 38.7%-44.5%) with IP therapy (P=.004). Much of this difference was associated with lower in-trial levels of fibrinogen, C-reactive protein, and hemoglobin A_1c with IS therapy. Four-year composite CVD rates were 32.7% (95% CI, 30.0%-35.4%) with REV and 44.7% (95% CI, 41.8%-47.6%) with MED (P<.001). A beneficial effect of IS vs IP therapy was present with REV (27.7%; 95% CI, 24.0%-31.4% vs 37.5%; 95% CI, 33.6%-41.4%; P<.001), but not with MED (43.6%; 95% CI, 39.5%-47.7% vs 45.7%; 95% CI, 41.6%-49.8%; P=.37) (homogeneity, P=.05). This interaction between IS therapy and REV was limited to participants preselected for coronary artery bypass grafting (CABG). The lowest composite CVD rates occurred in patients preselected for CABG and assigned to IS therapy and REV (17.3%; 95% CI, 11.8%-22.8%).
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North American Thrombosis Forum, AF Action Initiative Consensus Document
2016, American Journal of Medicine
The North American Thrombosis Forum Atrial Fibrillation Action Initiative consensus document is a comprehensive yet practical briefing document focusing on stroke and bleeding risk assessment in patients with atrial fibrillation, as well as recommendations regarding anticoagulation options and management. Despite the breadth of clinical trial data and guideline recommendation updates, many clinicians continue to struggle to synthesize the disparate information available. This problem slows the uptake and utilization of updated risk prediction tools and adoption of new oral anticoagulants. This document serves as a practical and educational reference for the entire medical community involved in the care of patients with atrial fibrillation.

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: This work was supported through the Unión Temporal de Empresas project CIMA and by grant PI081349 from Instituto de Salud Carlos III and grant RECAVA RD06/0014/0008 from the Red Temática de Investigación, and Health Department, Gobierno de Navarra (15/09). The Atherosclerosis Risk In Communities study was performed as a collaborative study supported by grants HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C from the National Heart, Lung, and Blood Institute (Bethesda, Maryland). This study was also supported by grants RC1-HL099452 from the National Heart, Lung, and Blood Institute (Bethesda, Maryland) and 09SDG2280087 from the American Heart Association (Rockland, Maryland). C-reactive protein assays were supported by grant R01-DK076770 from the National Institute of Diabetes and Digestive and Kidney Diseases (Bethesda, Maryland). Siemens Healthcare Diagnostics provided the reagents and loan of a BNII instrument to conduct these assays.

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Arrhythmias and conduction disturbanceUsefulness of High-Sensitivity C-Reactive Protein to Predict Mortality in Patients With Atrial Fibrillation (from the Atherosclerosis Risk In Communities [ARIC] Study)

Section snippets

Methods

Results

Discussion

Am Heart J

Am Heart J

Am J Cardiol

J Clin Epidemiol

Am Heart J

Am J Cardiol

The Atherosclerosis Risk in Communities (ARIC) Study: design and objectivesThe ARIC investigators

Am J Epidemiol

Incidence of and risk factors for atrial fibrillation in older adults

Circulation

C-reactive protein and venous thromboembolism: a prospective investigation in the ARIC cohort

Thromb Haemost

Stroke incidence and survival among middle-aged adults: 9-year follow-up of the Atherosclerosis Risk In Communities (ARIC) cohort

Stroke

Arrhythmias and conduction disturbance
Usefulness of High-Sensitivity C-Reactive Protein to Predict Mortality in Patients With Atrial Fibrillation (from the Atherosclerosis Risk In Communities [ARIC] Study)