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Clinical Chemistry 53: 2112-2118, 2007. First published October 11, 2007; 10.1373/clinchem.2007.090613
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Right arrow Proteomics and Protein Markers
(Clinical Chemistry. 2007;53:2112-2118.)
© 2007 American Association for Clinical Chemistry, Inc.

Proteomics and Protein Markers

Risk Stratification for Heart Failure and Death in an Acute Coronary Syndrome Population Using Inflammatory Cytokines and N-Terminal Pro-Brain Natriuretic Peptide

Peter A. Kavsak1,a, Dennis T. Ko2, Alice M. Newman2, Glenn E. Palomaki3, Viliam Lustig4, Andrew R. MacRae4,5 and Allan S. Jaffe6

1 Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
2 Institute for Clinical Evaluative Sciences, University of Toronto, Toronto, Ontario, Canada.
3 Department of Pathology, Women and Infants Hospital, Providence, RI.
4 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
5 Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.
6 Cardiovascular Division and Division of Laboratory Medicine, Mayo Clinic, Rochester, MN.

aAddress correspondence to this author at: Hamilton Regional Laboratory Medicine Program, Henderson General Hospital (Core Laboratory Section), 711 Concession St. Hamilton, Ontario, Canada L8V 1C3. Fax 905-575-2581; e-mail kavsakp{at}mcmaster.ca.


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Inflammation in acute coronary syndrome (ACS) can identify those at greater long-term risks for heart failure (HF) and death. The present study assessed the performance of interleukin (IL)-6, IL-8, and monocyte chemoattractant protein-1 (MCP-1) (cytokines involved in the activation and recruitment of leukocytes) in addition to known biomarkers [e.g., N-terminal pro-brain natriuretic peptide (NT-proBNP)] for predicting HF and death in an ACS population.

Methods: In a cohort of 216 ACS patients, NT-proBNP (Elecsys®; Roche) and IL-6, IL-8, and MCP-1 (evidence investigatorTM; Randox) were measured in serial specimens collected early after symptom onset (n = 723). We collected at least 2 specimens from each participant: an early specimen (median 2 h; interquartile range 2–4 h) and a later specimen (9 h; 9–9 h), and used the later specimens’ biomarker concentrations for risk stratification.

Results: An increase in both IL-6 and NT-proBNP was observed but not for IL-8 or MCP-1 early after pain onset. Kaplan–Meier analysis demonstrated that individuals with increased NT-proBNP (>183 ng/L) or cytokines (IL-6 > 6.4 ng/L; above upper limit of normal for IL-8 or MCP-1) had a greater probability of death or HF in the following 8 years (P <0.05). In a Cox proportional hazard model adjusted for both CRP and troponin I, increased IL-6, MCP-1, and NT-proBNP remained significant risk factors. Combining all 3 biomarkers resulted in a higher likelihood ratio for death or HF than models restricted to any 2 of these biomarkers.

Conclusion: IL-6, MCP-1, and NT-proBNP are independent predictors of long-term risk of death or HF, highlighting the importance of identifying leukocyte activation and recruitment in ACS patients.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Even modestly increased concentrations of C-reactive protein (CRP),1 a marker of inflammation, have been shown to be predictive for both short- and long-term risk of heart failure (HF) and death, but not acute myocardial infarction, in patients with acute coronary syndrome (ACS)(1)(2)(3)(4). A recent report also indicated that increased CRP concentrations are associated with new HF in non-ACS patients with stable coronary artery disease(5). CRP is an acute-phase reactant, but its concentration takes time to increase during an acute event(6). Furthermore, increases are not specific for vascular inflammation(7). Interleukin (IL)-6 is a proinflammatory cytokine thought to be the most important proximate stimulator for CRP; it also stimulates activation of leukocytes(7)(8). IL-8 and monocyte chemoattractant protein-1 (MCP-1) are both chemokines that recruit neutrophils and monocytes, respectively, to the inflammatory process(9). We have reported that increased baseline concentrations of CRP are predictive of long-term risk for HF and death in an ACS population(4). In the present study, we sought to determine if these more specific and earlier mediators of leukocyte activation and recruitment, coupled with assessment of heart dysfunction based on N-terminal pro-brain natriuretic peptide (NT-proBNP) concentrations, could provide prognostic information beyond that of CRP and troponin in a cohort of chest pain patients presenting to the emergency department. Moreover, because the optimal timing for measuring cytokines is unknown in this setting, we wanted to document the cytokine profile early after chest pain onset.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
study population
The study population and its characteristics have been reported(4)(10)(11)(12). At the time of study enrollment in 1996, 448 consecutive unique patients presenting with symptoms suggestive of cardiac ischemia to the emergency department in a community hospital were recruited for a retrospective cardiac marker study. Time of symptom onset was solicited, and blood samples (both EDTA and heparin anticoagulated blood from all patients) were collected at specified intervals (from time of symptom onset hourly until 6 h, and then at 9, 12, 24, and 48 h) until the patient was discharged, declined further participation, or was removed from the study by those responsible for his or her care. All specimens from 1996 were frozen, predominantly at –70 °C, until 2003 when the heparin specimens were thawed and cardiac troponin I (cTnI) and CRP measurements were performed on the Access® (AccuTnI assay) and Immage® (high-sensitivity CRP assay) instruments, respectively, from Beckman Coulter(4)(10)(11)(12). We have confirmed the stability of troponin I and CRP over time in our cohort(4). For the present study, we selected only those individuals (n = 216) who had at least 2 EDTA specimens available in storage. The median number of specimens per participant was 3 [interquartile range (IQR) 2–5], and all specimens (n = 723) were measured with the cytokine array and NT-proBNP to provide a serial and temporal profile of the biomarkers. For the outcome analysis, we selected only 2 specimens per participant based on the following criteria: the earliest available (1st specimen) and the closest to 9 h after onset (2nd specimen). In the event that the 1st specimen obtained was >6 h after onset, then the next specimen at least 3 h later was selected as the 2nd specimen. Thus the minimum interval between specimen pairs was 3 h [median 6.5 h (IQR 5–8)].

biomarker measurements
In 2006, the EDTA specimens were thawed for the 1st time, and a cytokine array was measured using the evidence investigatorTM (Randox) biochip platform(9)(13). The biochip can assay 12 cytokines; however, a priori the decision was made to evaluate only IL-6, IL-8, and MCP-1 for the present study assessing HF and death in an ACS population. The interassay (n = 20 assays) imprecision (CV), determined by measuring 3 levels of quality control material, ranged from 10.9% to 16.2% for IL-6, 8.3% to 16.1% for IL-8, and 7.6% to 13.0% for MCP-1. We measured NT-proBNP by use of the Elecsys® 1010 (Roche), with interassay impression <7%. There is evidence to support the stability of the cytokines measured in the present study after 10 years’ storage, in that the reference ranges for IL-8 and MCP-1 published in 2006 for this method were derived from samples collected as early as 1994(9)(14). IL-6 and NT-proBNP also appear to be stable during long-term storage(15)(16)(17).

health outcomes and statistical analysis
Research ethics board approval was obtained to measure biomarkers in the stored samples and to make health outcome linkages to the Registered Persons Data Base for mortality outcomes and the Canadian Institute for Health Information Discharge Abstract Database for hospital discharges associated with HF(11). Both the Registered Persons Data Base and Canadian Institute for Health Information Discharge Abstract Database (i.e., administrative databases) have been reported to be highly accurate in obtaining these endpoints(18)(19)(20)(21). Based on the death date and earliest subsequent readmission for HF, indicators were created to reflect whether an event (death or HF readmission) occurred within 8 years postpresentation (in patients who died without previous HF readmission, follow-ups were censored at the date of death). We used biomarker concentrations (e.g., NT-proBNP, IL-6, IL-8, MCP-1) in the later (2nd) specimen to determine risk based on the hypothesis that this specimen would reflect the severity of cardiac dysfunction and the inflammatory response of the patient better than the earlier specimen. Of note, exploratory analyses using logistic regression models with the cytokines for the combined endpoint death/HF suggested no difference in long-term outcomes (e.g., at 8 years) between the 1st and 2nd specimen; however, the 2nd specimen tended to be more predictive for early outcomes (e.g., 30 days and 1 year) than the 1st specimen. The analyses were based on the following classifications. For both IL-6 and NT-proBNP, we used the median concentrations at the 2nd time point (IL-6 > 6.4 ng/L and NT-proBNP >183 ng/L). We used the upper limit of normal (97.5th percentile) for IL-8 (>7.5 ng/L) and MCP-1 (>156 ng/L). For our study population (n = 216), the combined endpoint (death/HF) was used for all analyses to maximize the number of events.

We constructed Kaplan–Meier curves to display time to an event (death/HF) and assessed differences between groups by use of the log-rank test. We used the Cox proportional hazard model to compare time to an event for the increased biomarkers. In keeping with our previous analyses in this cohort(4)(11), we used different models to assess the risk associated with increased cytokines: model 1 adjusts for age (continuous variable), sex, history of HF, and STEMI (Q wave) at presentation; model 2 adjusts for age (continuous variable), sex, history of HF, STEMI (Q wave), presentation CRP concentration >7.44 mg/L (the concentration that optimized performance of the model), and cTnI peak categories. The cTnI peak concentrations were categorized into 4 groups with values defined as ≤0.01 µg/L, 0.02–0.03 µg/L, 0.04–0.10 µg/L, and >0.10 µg/L. We designated values of 0.00–0.01 µg/L as the reference group based on previous analyses showing that increases in risk occur at values ≥0.02 µg/L(11)(22). We used the highest cTnI concentration in the model to assess the possibility that the inflammatory markers measured increased in proportion to the extent of necrosis and thus reflected infarct size, a known determinant of prognosis. Significance of the association was based on the Wald {chi}2 statistic, with significance set at P <0.05. We used Cox proportional hazard models to assess the ability of combinations of IL-6, NT-proBNP, and MCP-1 and their interactions to predict death/HF. Models were constructed for IL-6 alone, IL-6 and MCP-1 (with and without interaction), IL-6 and NT-proBNP (with and without interaction), and IL-6, MCP-1, and NT-proBNP (with and without interactions), with the likelihood ratio as well as the significance of the association based on the Wald {chi}2 statistic (P <0.05). We based between-group comparisons of central tendency on the Wilcoxon and Kruskal–Wallis tests. Analyses were performed using SAS version 9.1.3 and GraphPad Prism version 5.00.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
For the 216 participants (61% male), the median age (25th–75th percentile) was 66 years (53–76) (Table 1 ). At the time of study enrollment in 1996, 19.4% of the participants were diagnosed with acute myocardial infarction based on WHO Monitoring Cardiovascular Disease (MONICA) criteria(10)(23). Applying the European Society of Cardiology/American College of Cardiology criteria retrospectively based on the peak cTnI concentrations resulted in 44.4% of participants having a cTnI concentration >99th percentile (>0.04 µg/L)(10)(24)(25). There were increases in both NT-proBNP and IL-6 concentrations, but not IL-8 or MCP-1, early after the onset of chest pain (Fig. 1 ). This result was also evident by the increased concentrations in the 2nd specimen (median 9 h after onset) vs the 1st specimen (median 2 h after onset) (Table 2 ).


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  		Table 1. Study cohort characteristics.


Figure 1
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  		Figure 1. Time-concentration profile for IL-6, IL-8, MCP-1, and NT-proBNP after symptom onset.

Each point with error bars represents the median and IQR for each of the biomarkers, respectively.


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  		Table 2. Biochemical characteristics for specimen set.1

Kaplan–Meier analysis using the concentrations from the later (2nd) specimen demonstrated that increased concentrations of each of the cytokines and NT-proBNP resulted in a greater probability for death/HF over the 8 years after emergency department presentation (Fig. 2 ). Cox proportional hazard models adjusting for age, sex, history of HF, and STEMI at presentation yielded significant hazard ratios (HRs) for IL-6, MCP-1, and NT-proBNP, but not for IL-8, at all 3 time points. After adjusting for high CRP and peak cTnI concentrations, only the increased IL-6 and MCP-1 groups were significantly associated with an increased risk for death/HF at 6 months; however, at 2 and 8 years, increased IL-6, MCP-1, and NT-proBNP all had significant HRs (Table 3 ). To assess whether there was a synergistic relationship between IL-6, NT-proBNP, and MCP-1 for predicting long-term death/HF in our population, a time-to-event analysis (Cox proportional model) was performed with IL-6 alone and with MCP-1 and NT-proBNP alone and together to assess their combinations and interactions (Table 4 ). Including IL-6, MCP-1, and NT-proBNP in the model resulted in a significantly higher likelihood ratio for death/HF compared with IL-6 alone and the combination of IL-6 with either MCP-1 or NT-proBNP.


Figure 2
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Figure 2
Figure 2
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  		Figure 2. Kaplan–Meier survival curves for IL-6, NT-proBNP, IL-8, and MCP-1.

IL-6 (A) and NT-proBNP (B) group assignments based on median values; IL-8 (C) and MCP-1 (D) group assignments based on published reference ranges(9).


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  		Table 3. HRs for death/HF as determined by IL-6, MCP-1, and NT-proBNP.1


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  		Table 4. Cox proportional hazard models for assessing combinations of IL-6, MCP-1, and NT-proBNP for death/HF at 8 years.


   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present study confirms earlier work indicating that inflammation is a strong predictor of future death and/or HF in patients with ACS(1)(2)(3)(4)(26)(27)(28). This study is different from others in that the analyzed cytokines were measured early after the onset of pain, a time when they have roles in the activation and recruitment of leukocytes during the inflammatory process. In addition, they were assessed as predictors of both short-term (6 months) and long-term (8 years) outcomes after adjusting for cTnI, using a cutoff value below the 99th percentile previously shown to be of prognostic importance(11), and after adjusting for CRP values previously found to be predictive(4).

A rising pattern was observed for both IL-6 and NT-proBNP but not for the chemokines (IL-8 and MCP-1), suggesting that IL-6 and/or NT-proBNP production may be an acute response to myocardial injury. However, it did not appear to be related to the extent of cardiac injury as reflected by the Cox proportional analysis using peak cTnI concentrations to correct for this possibility. Thus, it seems that the exuberance of the acute inflammatory response is an important predictor of both intermediate and long-term prognosis independent of the extent of myocardial injury. IL-6, as a potent proinflammatory cytokine, by itself may exacerbate the damage that results from minor myocardial necrosis/injury or may itself stimulate muscle atrophy and myocardial failure during ACS(29). For immune-mediated damage, recruitment/redirection of leukocytes is required. This process may be the reason MCP-1 has been implicated in ACS(30)(31) and HF(32)(33), but to our knowledge this result is the 1st indication that increases are independent predictors for long-term death/HF in an ACS population.

Because of the small sample size, we cannot separate the risks associated for either HF or death alone or include a large number of covariates in our modeling. Moreover, our population does not represent a contemporary cohort. This approach is a strength in the sense that it provides a better natural history; however, prospective studies are necessary that take into account present medical management in patients with ACS (more medical and mechanical interventions). Also, because our aim was to evaluate and document changes in biomarkers over time, we opted to include only individuals with at least 2 specimens at least 3 h apart. The 216 individuals selected for the study were, on average, older than the 232 individuals who were excluded (64.7 vs 60.5 years; P = 0.002), they stayed in the hospital longer for their initial event, and they had higher cTnI peak concentrations (median 0.04 vs 0.01 µg/L). However, important for this analysis, there was no difference in presentation CRP concentrations, and the endpoints at 30 days and 1 year between the included and excluded patient groups were not different.

This study builds on previous work by using a validated analytical platform for cytokine measurements and reference ranges for IL-8 and MCP-1 for classifying elevations(9)(13). Moreover, the cutoffs used in this study closely resemble other reported values in the literature for risk stratification for IL-6(26) and the median value for NT-proBNP in an ACS population(34).

In conclusion, these data support the findings that inflammation and cardiac dysfunction in ACS indicate a poor prognosis, independent of the extent of myocardial necrosis, in that ACS patients with increased IL-6, MCP-1, and NT-proBNP are at greater risk for subsequent HF and death.


   Acknowledgments
 
Grant/funding support: This work was supported by a grant from the Canadian Institutes of Health Research.

Financial disclosures: None declared (P.A.K., D.T.K., A.M.N., G.E.P., A.R.M.). A.S.J. receives research support from and is a consultant for Beckman-Coulter, Dade-Behring, Ortho Diagnostics, Critical Diagnostics, Intermune, Pfizer, Bayer, and GlaxoSmithKline. He is or has been at one time or another, a consultant to most of the major diagnostic companies. V.L. has received financial support for lecturing on cardiac markers from Roche Diagnostics.

Acknowledgments: Special thanks to the staff at the Clinical Research and Clinical Trials Laboratory at the Hamilton Regional Laboratory Medicine Program and Randox Laboratories Ltd. for technical support.


   Footnotes
 
1 Nonstandard abbreviations: CRP, C-reactive protein; HF, heart failure; ACS, acute coronary syndrome; IL, interleukin; MCP-1, monocyte chemoattractant protein-1; NT-proBNP, N-terminal pro-brain natriuretic peptide; IQR, interquartile range; cTnI, cardiac troponin I; HR, hazard ratio.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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P. A. Kavsak, A. M. Newman, D. T. Ko, G. E. Palomaki, V. Lustig, A. R. MacRae, and A. S. Jaffe
Is a Pattern of Increasing Biomarker Concentrations Important for Long-Term Risk Stratification in Acute Coronary Syndrome Patients Presenting Early after the Onset of Symptoms?
Clin. Chem., April 1, 2008; 54(4): 747 - 751.
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Right arrow Proteomics and Protein Markers

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