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Neutrophilia Predicts Death and Heart Failure After Myocardial Infarction

A Community-Based Study
Adelaide M. Arruda-Olson, MD, PhD, Guy S. Reeder, MD, Malcolm R. Bell, MD, Susan A. Weston, MS and Vronique L. Roger, MD, MPH From the Division of Cardiovascular Diseases and Internal Medicine (A.M.A.-O., G.S.R., M.R.B., V.L.R.) and the Department of Health Sciences Research (A.M.A.-O., S.A.W., V.L.R.), Mayo Clinic and Mayo Foundation, Rochester, Minn. Correspondence to Vronique L. Roger, MD, MPH, Cardiovascular Diseases, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail roger.veronique@mayo.edu

Abstract
Background The relationship between neutrophils and outcomes postmyocardial infarction (MI) is not completely characterized. We examined the associations of neutrophil count with mortality and post-MI heart failure (HF) and their incremental value for risk discrimination in the community. Methods and Results MI was diagnosed with cardiac pain, biomarkers, and Minnesota coding of the ECG. Neutrophil count at

presentation, reported as counts 109/L, was categorized by tertiles (lower tertile, <5.7; middle tertile, 5.7 to 8.5; upper tertile, >8.5). From 1979 to 2002, 2047 incident MIs occurred in Olmsted County, Minn (mean age, 6814 years; 44% women). Median (25th to 75th percentile) neutrophil count was 7.0 (5.1 to 9.5). Within 3 years post-MI, 577 patients died, and 770 developed HF. Overall survival and survival free of HF decreased with increased neutrophil tertile (P<0.001). Compared with the lower tertile, the age and sex adjusted hazard ratio for death was 1.44 (95% CI, 1.14 to 1.81) for the middle tertile and 2.60 (95% CI, 2.10 to 3.22) for the upper tertile (P<0.001). Similarly, for HF, the hazard ratio was 1.32 (95% CI, 1.09 to 1.59) for the middle and 2.12 (95% CI, 1.77 to 2.53) for the upper tertile (P<0.001). These associations persisted after adjustment for risk factors, comorbidities, Killip class, revascularization, and ejection fraction. Neutrophil count improved risk discrimination as indicated by increases in the area under the receiver operating characteristic curves (all P<0.05) and by the integrated discrimination improvement analysis (all P<0.001). Conclusions In the community, the neutrophil count was strongly and independently associated with death and HF post-MI and improved risk discrimination over traditional predictors. Key Words: failure myocardial infarction blood cells mortality heart

Received October 23, 2008; accepted July 27, 2009.

Introduction
Inammatory biomarkers have been identied as an important tool for risk stratication postmyocardial infarction (MI). peripheral leukocyte count provides an assessment of the
1,2

The
35

inammatory status, and is inexpensive and readily available. Myocardial infarction promotes inammation which is frequently
6 characterized by peripheral leukocytosis, and in previous studies this has been associated with increased early post-MI

mortality (HF).
11

710

and greater frequency of post-MI heart failure

A major component of the post-MI peripheral leukocytosis is attributable to elevation of the peripheral neutrophil count. However, secondary analyses of clinical trials of ST-elevation MI have shown conicting associations between peripheral neutrophil count and 30-day post-MI outcomes.
12,13

Furthermore, little is known about the association between peripheral neutrophil count with late post-MI outcomes in community-based patients who typically have a wider spectrum of the disease which includes both ST-elevation MI and nonSTelevation MI. Accordingly, this study was undertaken to address these gaps in knowledge using the strengths of a rigorously ascertained geographically dened MI incidence cohort. The goals of this study were to examine the associations of neutrophil count with mortality and with the development of post-MI HF, and the incremental value of neutrophil count for risk discrimination over traditional predictors.

Methods
MI Ascertainment

The parent study, which enabled the present investigation, consists of a retrospective observational cohort of subjects with MI within the geographically dened population of Olmsted County, Minn, where the Mayo Clinic and Olmsted Medical Center provide medical care for all county residents. These facilities use a unied record linkage system that accumulates comprehensive clinical records. The Rochester Epidemiology Project enables these records to be easily retrieved.
14

WHAT IS KNOWN
Clinical studies have consistently demonstrated intense systemic activation of neutrophils in patients with acute coronary syndromes. Studies reporting data from secondary analyses of clinical trials demonstrated conicting ndings regarding the association between peripheral neutrophil count and postmyocardial infarction outcomes.

WHAT THE STUDY ADDS

In this population-based incidence cohort, the absolute

neutrophil count on presentation was strongly and independently associated with death and heart failure post-myocardial infarction in a dose-response relationship. The peripheral neutrophil count on presentation provided incremental value in risk discrimination over traditional predictors.

The methodology used to assemble the retrospective cohort has been previously reported. 15 Briey, subjects discharged from Olmsted County hospitals with diagnoses compatible with an MI were obtained from 2 separate data sources: the Rochester Epidemiology Project Index of

16 Trained nurse abstractors reviewed cases meeting studies. criteria for residency and collected information to classify the MI. Standard criteria were applied to assign a MI diagnosis based on cardiac pain, cardiac biomarkers, and Minnesota coding of the ECG. Information on the reliability of these criteria have been

14 and the Hospital Utilization Review Database, 15 an Diagnoses administrative database of hospitalizations maintained by Mayo Clinic. The target International Classication of Diseases, Ninth Revision, codes included 410 (acute MI), 411 (other acute and subacute forms of ischemic heart disease), 412 (old MI), 413 (angina pectoris), and 414 (other forms of ischemic heart disease). All events coded as 410, a 50% random sample of codes 411, and a 10% random sample of codes 412, 413, and 414 were reviewed. The sampling fractions were similar to those used in other

published before.
Data Collection

15

Clinical data obtained included comorbidities measured by the

17 and Killip class. Clinical diagnoses were used to Charlson index ascertain hypertension, diabetes mellitus, hyperlipidemia, family history of coronary disease (dened as coronary disease in rst line male descendants less than 55 years of age and in rst line female descendants less than 65 years of age), and smoking status. Body mass index (BMI) was calculated using the presentation height and weight and analyzed as a continuous variable. Clinical diagnosis was used to ascertain metastatic cancer, leukemia, lymphoma, polycythemia vera, chronic pancytopenia, thrombocytopenia, myeloproliferative disorder, and treatment with chemotherapy during the year before the diagnosis of MI. We also abstracted clinical diagnosis infections within 2 weeks before the acute event and results of anti-HIV

serology. Reperfusion or revascularization therapy was dened as the use of thrombolytic therapy, percutaneous coronary intervention, or coronary artery bypass surgery within the same hospitalization. All decisions regarding patient management were left to the discretion of the attending cardiologists, the majority of whom were not involved in this study. Blood samples were obtained at presentation for the MI. Blood draws were also obtained during ambulatory outpatient visits for unrelated problems or for general medical examinations before the MI diagnosis. Peripheral blood leukocyte count was estimated with an automated hematology analyzer. This instrument uses approximately 100 000 cells per dierential to produce a dierential count.
18

Left Ventricular Ejection Fraction

Left ventricular ejection fraction (EF) was measured during the hospitalization for the acute MI by previously validated methods, including M-mode or bidimensional echocardiography using the
19 by the Quinones formula from the parasternal views, quantitative bidimensional biplane volumetric Simpson method

21 EF values were method from multiple echocardiographic views. averaged when multiple measurements were performed.

from 4 and 2 chambers views,

20

and bidimensional estimate

Outcome Denitions and Ascertainment

22 The diagnosis of HF post-MI using Framingham criteria. reliability of ascertaining Framingham HF in our experience is

Inpatient and outpatient records of all subjects were reviewed by nurse abstractors who collected clinical data and validated the

excellent.

23

Follow-up was completed by passive surveillance of the community medical records. The ascertainment of death incorporated death certicates led in Olmsted County, autopsy reports, obituary notices, and electronic les of death certicates obtained from the State of Minnesota Department of Vital and Health Statistics. All aspects of the study were approved by the Mayo Clinic and Olmsted Medical Center institutional review boards.
Statistical Analyses

Cell counts were reported as values 109/L. Patients were classied into tertiles according to neutrophil count at presentation. Data are presented as frequencies for categorical variables, meanSD for continuous variables, or median (25th to 75th percentile) for skewed variables. Trends in baseline

characteristics across tertiles were tested with 2 tests for categorical variables, t tests for continuous variables, and Kruskal Wallis tests for skewed variables. Survival analysis of time to post-MI events, including death or HF, was conducted with the KaplanMeier method. Proportionalhazards regression was used to examine the association between baseline characteristics and death or HF post-MI. To allow for detection of a dose-response eect, tertiles of the distribution for neutrophil count were modeled as 2 indicator variables with

9 neutrophil <5.710 /L as the reference level. Univariate associations between neutrophil count and death or HF post-MI were examined. Demographics (age and sex), cardiovascular risk factors (current smoker, hypertension, body mass index, hyperlipidemia, family history of coronary artery disease, and diabetes mellitus), comorbidity index, Killip class, reperfusion or revascularization, and EF were each added to the model separately. Missing values did not exceed 10% for any of the variables included in the models. The proportional hazards assumption was tested using the Schoenfeld residuals and found to be valid for the rst 3 years of follow-up, with evidence of disruption thereafter. Therefore, we restricted analyses to 3 years post-MI.

The incremental value of peripheral neutrophil count in risk discrimination for death or HF was examined by the area under the receiver operating characteristic (ROC) curve (AUC) with 3-year mortality or 3-year HF as the end points. Comparisons of the AUC before and after the addition of the peripheral neutrophil count were performed by the method of Hanley and McNeil.
24

The change in discrimination (a measure of how well a model can separate patients with an outcome at 3 years from those who did not have the outcome) was evaluated using the integrated
25 The IDI measured the discrimination improvement (IDI). change in the dierence in the mean predicted probabilities of death between those dead and alive, or the change in the dierence in the mean predicted probabilities of HF between those who experienced HF and those who did not, after the inclusion of neutrophil count in each of the models.

In ancillary analyses, we excluded patients with metastatic cancer, leukemia, lymphoma, polycythemia vera, chronic pancytopenia, thrombocytopenia, myeloproliferative disorders, infection, and those undergoing chemotherapy. We also excluded patients with positive anti-HIV serology. After exclusion of those patients, we repeated all the proportional-hazards regression models described above. In a second ancillary analysis we excluded patients with neutrophil count in the upper 5% and those in the

lower 5% of the neutrophil count distribution. After exclusion of those patients, we repeated all the proportional-hazards regression models described above. A probability value of 0.05 was used for the threshold of statistical signicance. Analyses were performed using SAS version 8.2 (SAS Institute, Inc).

Results
Baseline Characteristics

Between January 1, 1979, and December 31, 2002, 2732 patients had an incident MI in Olmsted County. Absolute neutrophil count at presentation was obtained for 2047 patients and those composed the study population. The mean age was 6814 years, and 44% were women. Echocardiograms were performed within a median interval of 2 days (25th to 75th percentile: 1 day to 3 days) after hospital admission. The median (25th to 75th percentile)
9 9 neutrophil count on presentation was 7.010 /L (5.110 /L to 9 9 9 9.510 /L). Cutos for the tertiles were 5.710 /L and 8.510 /L.

Associations Between Baseline Characteristics and Neutrophils

Higher neutrophil counts were associated with older age, female sex, systemic hypertension, diabetes mellitus, smoking, higher comorbidity index, Killip class 2, 3, or 4, and lower EF (Table 1). Lower neutrophil counts were associated with higher BMI, hyperlipidemia, familial coronary disease, use of reperfusion or revascularization, use of statins, -blockers, and aspirin during hospitalization. Infection within 2 weeks before the MI was associated with neutrophil count with 9%, 13%, and 26% of the patients having recent infection in the lower, middle, and upper neutrophil tertiles, respectively (P<0.001). View this table: In this window In a new window Table 1. Characteristics Among 2047 Olmsted County Residents With Incident MI
Outcomes

The median follow-up was 4.9 years (25th to 75th percentile, 1.8 to 6.7 years). Among all patients, 89% were residents in Olmsted County within 3 years post-MI. For the remainder, 110 died and

were last seen as Olmsted County resident before their death; 112 were still alive and last seen as Olmsted County resident less than 3 years post-MI.
Overall Survival

Within 3 years post-MI, 577 patients died. There was a dramatic decrease in survival with increasing neutrophil tertile (Figure, A). The 30-day survival estimates were 0.95 (95% CI, 0.93 to 0.96), 0.91 (95% CI, 0.89 to 0.94), and 0.82 (95% CI, 0.79 to 0.85) for the lower, middle, and upper neutrophil tertiles, respectively. The 3-year survival estimates were 0.82 (95% CI, 0.79 to 0.85), 0.74 (95% CI, 0.71 to 0.78), and 0.58 (95% CI, 0.54 to 0.62), for the lower, middle, and upper neutrophil tertiles, respectively. Figure View larger version: In this window In a new window Download as PowerPoint Slide Figure. Survival (A) and survival free of HF (B) after incident MI in Olmsted County, Minn, by tertiles of the neutrophils distribution. The associations between neutrophil count and death are presented in Table 2. In the unadjusted model, there was a positive graded association between neutrophil count and death. This association persisted after adding demographics, cardiovascular risk factors, comorbidity index, Killip class, use of reperfusion or revascularization, and EF separately to the model. In the ROC analysis, the addition of neutrophil count improved each of the models (Table 3). Similarly, the IDI indicated improvement in each model after the addition of the neutrophil count (Table 3). View this table: In this window In a new window Table 2. Associations Between Neutrophil Count and Death After MI in Olmsted County View this table: In this window

In a new window Table 3. ROC and IDI Analysis for Death and HF Within 3 Years After MI
Heart Failure

Within 3 years post-MI, 770 patients developed HF. There was a dramatic reduction of survival free of HF with increasing neutrophil tertile (Figure 1B). The 30-day survival estimates were 0.80 (95% CI, 0.77 to 0.83), 0.73 (95% CI, 0.70 to 0.77), and 0.56 (95% CI, 0.53 to 0.60) for the lower, middle, and upper neutrophil tertiles, respectively. The 3-year survival estimates were 0.72 (95% CI, 0.69 to 0.76), 0.64 (95% CI, 0.60 to 0.68), and 0.47 (95% CI, 0.43 to 0.51), for the lower, middle, and upper neutrophil tertiles, respectively. The associations between HF post-MI and neutrophil count are presented in Table 4. In the unadjusted model, there was a positive graded association between tertiles of the neutrophil count and HF post-MI. This association persisted after adding demographics, cardiovascular risk factors, comorbidity index, Killip class, use of reperfusion or revascularization, and EF separately to the model. In the ROC analysis, the addition of neutrophil count improved each of the models (Table 3). Similarly, the IDI indicated improvement in each model after the addition of the neutrophil count (Table 3). View this table: In this window In a new window Table 4. Associations Between Neutrophil Count and HF Within 3 Years After MI in 2047 Incident MI Patients in Olmsted County In ancillary analysis after excluding patients with metastatic cancer, leukemia, lymphoma, polycythemia vera, chronic pancytopenia, thrombocytopenia, myeloproliferative disorder, chemotherapy, infection, and positive anti-HIV serology, the results of the proportional-hazards regression models were similar. In the second ancillary analysis, after exclusion of patients with neutrophil count in the upper 5% and those in the lower 5% of the neutrophil count distribution the results of the proportional-hazards regression models remained unchanged. In a third ancillary analysis, adjustment for infection within 2 weeks before the MI in the models predicting death and heart failure did not change the associations between the outcomes and the

neutrophil tertiles.

Discussion
In the present population-based MI incidence cohort, the absolute neutrophil count at presentation for acute MI was strongly, positively, and independently associated with both death and HF post-MI and provided incremental value in risk discrimination over traditional risk factors. Moreover, our data are also consistent with a dose-response relationship between the magnitude of neutrophilia and both death and HF at long-term follow-up. Finally, our data also demonstrated that the increased risk for adverse events in patients in the highest neutrophil tertile at presentation with acute MI began immediately after the MI and persisted over the 3-year follow-up period. These associations were independent of age, sex, cardiovascular risk factors, comorbidities, Killip class, reperfusion or revascularization therapies, and EF.
Leukocytosis and Outcomes

Several studies have reported positive associations between elevated leukocyte count and the incidence of coronary cerebrovascular diseases
32 31

2630

or

or with mortality from coronary heart

among previously healthy individuals. A prospective disease cohort study that included measurement of the dierential blood count indicated that in men the main contributor to the excess risk for ischemic heart disease events was the neutrophil count.
29

In patients with acute coronary artery disease, prior studies have reported an association of the total leukocyte count with short-term outcomes. In clinical trials of ST-elevation MI, there was an association between leukocytosis and increased short-term post-MI mortality. In the Worcester community, there was an association between leukocytosis and increased adverse outcomes during hospitalization for acute MI.
8,11,33 8 11,33

However, these

did not report on the inuence of leukocyte count studies on longer-term outcomes post-MI and did not address the incremental value of white blood cell count over the traditional clinical predictors of adverse outcomes. The present study directly addresses these gaps in knowledge.
Peripheral Neutrophils and Outcomes

Studies reporting data from secondary analyses of clinical trials which enrolled patients with ST-elevation MI have demonstrated

conicting ndings regarding the association between peripheral neutrophil count and 30-day post-MI outcomes. In a large randomized trial of clopidogrel versus placebo in ST-elevation MI patients undergoing brinolysis, the neutrophil count in the highest quartile was independently associated with the risk of
13 However, in another cardiovascular death and HF at 30 days. trial of brinolysis in ST-elevation MI, there was no signicant

12 Our association between cell counts and clinical outcomes. study examined this point in a large cohort of patients with incident MI recruited in the Olmsted County community with long-term follow-up information.

In prior studies, participants were recruited in multiple centers

34 12,13

or were recruited in an intensive coronary care

By contrast, we recruited individuals with a wide spectrum unit. of disease severity, and included patients with ST-elevation MI and those with nonST-elevation MIs, and thus extended the ndings of prior studies which included only patients with ST-elevation MI.
12,13

An elevated neutrophil to lymphocyte ratio has been previously associated with adverse outcomes in patients with suspected coronary disease,
35 37 In a study by Nunez et al 37 only patients with ST-elevation MI. ST-elevation MI admitted to a tertiary center were recruited. Conversely, we recruited patients with either ST-elevation or nonST-elevation MI in a geographically dened population, which enhances the generalizability of our ndings. Given the role of neutrophils in the inammatory response after MI, the present study focused on the ability of the absolute neutrophil count to predict outcomes and indicated that absolute neutrophil count was associated with death and HF within 3 years post-MI.

chronic coronary disease, 36 and

Potential Mechanisms

Clinical studies have consistently demonstrated intense systemic activation of neutrophils in patients with acute coronary syndromes.
3841

Neutrophils are the rst leukocytes to inltrate

42, 43

the infarcted myocardium. myeloperoxidase

40,41

Activated neutrophils release a

38

variety of proteolytic enzymes including elastase

The inammatory response fosters cytokine release, 45 which may promote demargination of intravascular neutrophils and acceleration of the release of neutrophils by the bone marrow.
46,47

with potential for tissue destruction. 44

and

In addition, there is evidence for prolongation of

48

the lifespan of neutrophils in unstable plaques.

The absolute peripheral neutrophil count may be a marker of the severity of myocardial inammation attributable to ischemic injury
49

or of the severity of the inammation of the coronary

41

arterial tree.

Increased neutrophil count may also, in part, be

12,13 12

explained by a lower probability of successful reperfusion

or

It is conceivable that the impaired microvascular perfusion. neutrophil count may represent combinations of the aforementioned potential mechanisms.
Limitations and Strengths

Although these results provide insight into the association between neutrophilia and the outcome of acute MI, some limitations should be kept in mind. Changes in neutrophil count may be related to infections, malignancies, or blood disorders. In ancillary analysis, when patients with those conditions were excluded from the analyses, the associations between neutrophilia and post-MI outcomes were similar in both the unadjusted and adjusted models. In further analyses we excluded patients with the neutrophil count in the top or bottom 5% of the neutrophil distribution, and the association between the neutrophil count with post-MI outcomes remained unchanged. This reinforces the robustness of our ndings. The relationship of neutrophil count to the time from symptom onset or time of reperfusion could not be analyzed because data on the time of the neutrophil count was not available. As the IDI is a relatively new approach to risk prediction, there is no uniformly accepted threshold for clinically meaningful eect size.
50

The racial and ethnic composition of Olmsted County may limit the generalizability of these data to groups under-represented in the population. Although no single community can represent the nation, studies of chronic diseases in Olmsted County indicate that results from the county can be extrapolated to a large part of the
14 Nonetheless, the present study will need population. replication in other racial and ethnic groups.

Notable strengths of this study include the evaluation of the peripheral neutrophil count among a population-based cohort, which represents the comprehensive experience of a community. As all MI cases were incident cases, these results are not aected by incidence prevalence bias. In the clinical practice of most centers in the United States, neutrophil counts are routinely obtained during hospitalization for an acute coronary event. In the present study, this single measurement of neutrophil count was a strong predictor for outcomes, which highlights a potential application of this inexpensive and readily available inammatory marker for risk

stratication post-MI.
Conclusions

In this population-based incidence cohort, the absolute neutrophil count at presentation was strongly and independently associated with death and HF post-MI in a dose-response relationship. Moreover, the peripheral neutrophil count at presentation provided incremental value in risk discrimination over traditional predictors. As it is an inexpensive readily available prognostic marker, it should be incorporated in the clinical practice for risk stratication after MI.

Acknowledgments
We thank Ellen Koepsell, RN, for study management, Kay Traverse, RN, and Susan Stotz, RN, for their assistance with data collection, Ruoxiang Jiang for assistance with statistical analysis, and Kristie Shorter for secretarial support. Sources of Funding This study was supported by a Clinician Investigator Fellowship Award from the Mayo Clinic and grants from the Public Health Service and the National Institutes of Health (AR30582, R01 HL 59205, and R01 HL 72435). Dr Roger is an Established Investigator of the American Heart Association. The other authors report no disclosures. Disclosures None.

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Response to Mariusz Kruk, MD Veronique L. Roger and Adelaide M. Arruda-Olson, MD Circulation: Cardiovascular Quality and Outcomes. published online March 17, 2010 Full Text Neutrophil count does not predict short term outcomes in STEMI treated with primary angioplasty Mariusz Kruk Circulation: Cardiovascular Quality and Outcomes. published online February 2, 2010 Full Text

1. Circulation: Cardiovascular Quality and Outcomes. 2009; 2: 656-662 Published online before print September 1, 2009, doi: 10.1161/ CIRCOUTCOMES.108.831024

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