Chemokines CCL3/MIP1α, CCL5/RANTES and CCL18/PARC are Independent Risk Predictors of Short-Term Mortality in Patients with Acute Coronary Syndromes

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Abstract

Cytokines play an important role in ischemic injury and repair. However, little is known about their prognostic value in cardiovascular disease. The aim of this study was to investigate the prognostic importance of chemokines CCL3/MIP-1α, CCL5/RANTES and CCL18/PARC for the risk of future cardiovascular events in patients with acute coronary syndromes (ACS). Baseline levels of CCL3/MIP-1α, CCL5/RANTES and CCL18/PARC were determined in ACS patients from the Bad Nauheim ACS II registry (n = 609). During the following 200 days, patients were monitored for the occurrence of fatal and non-fatal cardiovascular events. Patients with CCL3/MIP1α, CCL5/RANTES and CCL18/PARC concentrations in the highest tertile were associated with an increased risk of a fatal event during follow-up (HR: 2.19, 95%CI: 1.04–4.61 for CCL3/MIP1α, HR: 3.45, 95%CI: 1.54–7.72 for CCL5/RANTES and HR: 3.14, 95%CI: 1.33–7.46 for CCL18/PARC). This risk was highest for patients with all three biomarkers concentrations in the upper tertile (HR: 2.52, 95%CI: 1.11–5.65). Together with known risk predictors of cardiovascular events, CCL3/MIP-1α, CCL5/RANTES and CCL18/PARC combined improved the c-statistics from 0.74 to 0.81 (p = 0.007). In conclusion, CCL3/MIP-1α, CCL5/RANTES and CCL18/PARC are independently associated with the risk of short-term mortality in ACS patients. Combining all three biomarkers further increased their prognostic value.

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Most cited references 37

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A validated prediction model for all forms of acute coronary syndrome: estimating the risk of 6-month postdischarge death in an international registry.

Kim Eagle, Michael Lim, Omar Dabbous … (2004)

Accurate estimation of risk for untoward outcomes after patients have been hospitalized for an acute coronary syndrome (ACS) may help clinicians guide the type and intensity of therapy. To develop a simple decision tool for bedside risk estimation of 6-month mortality in patients surviving admission for an ACS. A multinational registry, involving 94 hospitals in 14 countries, that used data from the Global Registry of Acute Coronary Events (GRACE) to develop and validate a multivariable stepwise regression model for death during 6 months postdischarge. From 17,142 patients presenting with an ACS from April 1, 1999, to March 31, 2002, and discharged alive, 15,007 (87.5%) had complete 6-month follow-up and represented the development cohort for a model that was subsequently tested on a validation cohort of 7638 patients admitted from April 1, 2002, to December 31, 2003. All-cause mortality during 6 months postdischarge after admission for an ACS. The 6-month mortality rates were similar in the development (n = 717; 4.8%) and validation cohorts (n = 331; 4.7%). The risk-prediction tool for all forms of ACS identified 9 variables predictive of 6-month mortality: older age, history of myocardial infarction, history of heart failure, increased pulse rate at presentation, lower systolic blood pressure at presentation, elevated initial serum creatinine level, elevated initial serum cardiac biomarker levels, ST-segment depression on presenting electrocardiogram, and not having a percutaneous coronary intervention performed in hospital. The c statistics for the development and validation cohorts were 0.81 and 0.75, respectively. The GRACE 6-month postdischarge prediction model is a simple, robust tool for predicting mortality in patients with ACS. Clinicians may find it simple to use and applicable to clinical practice.

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C-Reactive Protein, the Metabolic Syndrome, and Risk of Incident Cardiovascular Events: An 8-Year Follow-Up of 14 719 Initially Healthy American Women

Paul Ridker, Julie Buring, Nancy Cook … (2003)

The metabolic syndrome describes a high-risk population having 3 or more of the following clinical characteristics: upper-body obesity, hypertriglyceridemia, low HDL, hypertension, and abnormal glucose. All of these attributes, however, are associated with increased levels of C-reactive protein (CRP). We evaluated interrelationships between CRP, the metabolic syndrome, and incident cardiovascular events among 14 719 apparently healthy women who were followed up for an 8-year period for myocardial infarction, stroke, coronary revascularization, or cardiovascular death; 24% of the cohort had the metabolic syndrome at study entry. At baseline, median CRP levels for those with 0, 1, 2, 3, 4, or 5 characteristics of the metabolic syndrome were 0.68, 1.09, 1.93, 3.01, 3.88, and 5.75 mg/L, respectively (P(trend) <0.0001). Over the 8-year follow-up, cardiovascular event-free survival rates based on CRP levels above or below 3.0 mg/L were similar to survival rates based on having 3 or more characteristics of the metabolic syndrome. At all levels of severity of the metabolic syndrome, however, CRP added prognostic information on subsequent risk. For example, among those with the metabolic syndrome at study entry, age-adjusted incidence rates of future cardiovascular events were 3.4 and 5.9 per 1000 person-years of exposure for those with baseline CRP levels less than or greater than 3.0 mg/L, respectively. Additive effects for CRP were also observed for those with 4 or 5 characteristics of the metabolic syndrome. The use of different definitions of the metabolic syndrome had minimal impact on these findings. These prospective data suggest that measurement of CRP adds clinically important prognostic information to the metabolic syndrome.

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Use of multiple biomarkers to improve the prediction of death from cardiovascular causes.

Johan Ärnlöv, Erik Ingelsson, Samar Basu … (2008)

The incremental usefulness of adding multiple biomarkers from different disease pathways for predicting the risk of death from cardiovascular causes has not, to our knowledge, been evaluated among the elderly. We used data from the Uppsala Longitudinal Study of Adult Men (ULSAM), a community-based cohort of elderly men, to investigate whether a combination of biomarkers that reflect myocardial cell damage, left ventricular dysfunction, renal failure, and inflammation (troponin I, N-terminal pro-brain natriuretic peptide, cystatin C, and C-reactive protein, respectively) improved the risk stratification of a person beyond an assessment that was based on the established risk factors for cardiovascular disease (age, systolic blood pressure, use or nonuse of antihypertensive treatment, total cholesterol, high-density lipoprotein cholesterol, use or nonuse of lipid-lowering treatment, presence or absence of diabetes, smoking status, and body-mass index). During follow-up (median, 10.0 years), 315 of the 1135 participants in our study (mean age, 71 years at baseline) died; 136 deaths were the result of cardiovascular disease. In Cox proportional-hazards models adjusted for established risk factors, all of the biomarkers significantly predicted the risk of death from cardiovascular causes. The C statistic increased significantly when the four biomarkers were incorporated into a model with established risk factors, both in the whole cohort (C statistic with biomarkers vs. without biomarkers, 0.766 vs. 0.664; P<0.001) and in the group of 661 participants who did not have cardiovascular disease at baseline (0.748 vs. 0.688, P=0.03). The improvement in risk assessment remained strong when it was estimated by other statistical measures of model discrimination, calibration, and global fit. Our data suggest that in elderly men with or without prevalent cardiovascular disease, the simultaneous addition of several biomarkers of cardiovascular and renal abnormalities substantially improves the risk stratification for death from cardiovascular causes beyond that of a model that is based only on established risk factors. Copyright 2008 Massachusetts Medical Society.

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: Role: Editor

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Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2012

Publication date (Electronic): 21 September 2012

Volume: 7

Issue: 9

Electronic Location Identifier: e45804

Affiliations

[1 ]Division of Biopharmaceutics, Leiden Amsterdam Centre for Drug Research, Leiden University, Leiden, The Netherlands

[2 ]Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, Maastricht, The Netherlands

[3 ]Department of Cardiology, Kerckhoff Heart Centre, Bad Nauheim, Germany

[4 ]Department of Cardiology, Leiden University Medical Centre, Leiden, The Netherlands

[5 ]Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe-University Frankfurt, Frankfurt am Main, Germany

[6 ]Department of Clinical Chemistry, Maastricht University Medical Centre, Maastricht, The Netherlands

[7 ]Department of Epidemiology, Maastricht University, Maastricht, The Netherlands

South Texas Veterans Health Care System and University Health Science Center San Antonio, United States of America

Author notes

* E-mail: Brenda.Bongaerts@ 123456mumc.nl

Competing Interests: SD is founder and advisor of t2cure GmbH. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products to declare.

Conceived and designed the experiments: EB MW SD TvB. Performed the experiments: MR SdJ. Analyzed the data: BB. Contributed reagents/materials/analysis tools: MvD MW. Wrote the paper: BB SdJ. Reviewed and edited the manuscript: AK BB EB KC MvD MR MW PN SD SdJ TvB. Contributed to data analyses: PN. Contributed to discussion: AK BB EB PN SdJ TvB.

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Publisher ID: PONE-D-12-01572

DOI: 10.1371/journal.pone.0045804

PMC ID: 3448678

PubMed ID: 23029252

SO-VID: 19878249-edf9-4336-ba2a-2f0d6eb0a92e

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This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 17 January 2012

Date accepted : 24 August 2012

Page count

Pages: 9

Funding

This work was supported by the Netherlands Heart Foundation (grant M93.001, SCAdJ, AOK, TJCvB and EALB) and the Netherlands Scientific Organization, (Health Care Efficiency program grant 170881003 BWCB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study.

Chemokines CCL3/MIP1α, CCL5/RANTES and CCL18/PARC are Independent Risk Predictors of Short-Term Mortality in Patients with Acute Coronary Syndromes

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Most cited references 37

A validated prediction model for all forms of acute coronary syndrome: estimating the risk of 6-month postdischarge death in an international registry.

C-Reactive Protein, the Metabolic Syndrome, and Risk of Incident Cardiovascular Events: An 8-Year Follow-Up of 14 719 Initially Healthy American Women

Use of multiple biomarkers to improve the prediction of death from cardiovascular causes.

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