Elevated leukocyte count and adverse hospital

events in patients with acute coronary syndromes:

Findings from the Global Registry of Acute
Coronary Events (GRACE)
Mark I. Furman, MD, FACC,a Joel M. Gore, MD,a Fredrick A. Anderson, PhD,a Andrzej Budaj, MD, PhD,b
Shaun G. Goodman, MD,c Ávaro Avezum, MD,d José López-Sendón, MD,e Werner Klein, MD,f
Debabrata Mukherjee, MD,g Kim A. Eagle, MD,g Omar H. Dabbous, MD, MPH,a and Robert J. Goldberg, MD,a for
the GRACE Investigators Worcester, Mass, Warsaw, Poland, Toronto, Ontario, Canada, São Paulo, Brazil,
Madrid, Spain, Graz, Austria, and Ann Arbor, Mich

Objective To examine the association between elevated leukocyte count and hospital mortality and heart failure in
patients enrolled in the multinational, observational Global Registry of Acute Coronary Events (GRACE).
Background Elevated leukocyte count is associated with adverse hospital outcomes in patients presenting with
acute myocardial infarction (AMI). The association of this prognostic factor with hospital mortality and heart failure in pa-
tients with other acute coronary syndromes (ACS) is unclear.
Methods We examined the association between admission leukocyte count and hospital mortality and heart failure
in 8269 patients presenting with an ACS. This association was examined separately in patients with ST-segment elevation
AMI, non-ST–segment elevation AMI, and unstable angina. Leukocyte count was divided into 4 mutually exclusive groups
(Q): Q1 ⬍6000, Q2 ⫽ 6000 –9999, Q3 ⫽ 10,000 –11,999, Q4 ⬎12,000. Multiple logistic regression analysis was
performed to examine the association between elevated leukocyte count and hospital events while accounting for the si-
multaneous effect of several potentially confounding variables.
Results Increasing leukocyte count was significantly associated with hospital death (adjusted odds ratio [OR] 2.8,
95% CI 2.1–3.6 for Q4 compared to Q2 [normal range]) and heart failure (OR 2.7, 95% CI 2.2–3.4) for patients pre-
senting with ACS. This association was seen in patients with ST-segment elevation AMI (OR for hospital death 3.2, 95%
CI 2.1– 4.7; OR for heart failure 2.4, 95% CI 1.8 –3.3), non-ST–segment elevation AMI (OR for hospital death 1.9, 95%
CI 1.2–3.0; OR for heart failure 1.7, 95% CI 1.1–2.5), or unstable angina (OR for hospital death 2.8, 95% CI 1.4 –5.5;
OR for heart failure 2.0, 95% CI 0.9 – 4.4).
Conclusion In men and women of all ages with the spectrum of ACS, initial leukocyte count is an independent pre-
dictor of hospital death and the development of heart failure. (Am Heart J 2004;147:42– 8.)

The pathophysiology of coronary artery disease in-
volves inflammation.1 A number of studies in different
population settings have noted the association be-
tween serum markers of inflammation and the devel-
opment of cardiac events in individuals with acute cor-
onary syndromes (ACS) and in those without known
cardiovascular disease.2–7 Serum markers of inflamma-
tion, such as fibrinogen and C-reactive protein, to-
gether with leukocyte count, are components of the
acute phase response.8 Activated leukocytes are in-

Guest Editor for this manuscript was Raymond J. Gibbons, MD, Mayo Clinic, Roches-
From the aUniversity of Massachusetts Medical School, Worcester, Mass, bGrochowski ter, Minn.
Hospital, Warsaw, Poland, cCanadian Heart Research Centre and Terrence Donnelly Submitted March 7, 2003; accepted July 15, 2003.
Heart Centre, Division of Cardiology, St. Michael’s Hospital, University of Toronto, Reprint requests: Mark I. Furman, MD, FACC, Division of Cardiovascular Medicine,
Toronto, Ontario, Canada, dCTI-A Hospital Albert Einstein, São Paulo, Brazil, eHospi- University of Massachusetts Medical School, 55 Lake Avenue N, Worcester, MA,
tal Universitario Gregorio Marañon, Madrid, Spain, fMedizinische Universitätsklinik, 01655.
Klinische Abteilung für Kardiologi, Graz, Austria, and gUniversity of Michigan Health E-mail: mark.furman@umassmed.edu
System, Ann Arbor, Mich. 0002-8703/$ - see front matter
The GRACE project is supported by an unrestricted educational grant from Aventis © 2004, Elsevier Inc. All rights reserved.
Pharma (Bridgewater, NJ). doi:10.1016/j.ahj.2003.07.003
American Heart Journal
Volume 147, Number 1
volved in the rupture of atherosclerotic plaques char-
acteristic of acute coronary artery syndromes.9
Elevations in white blood cell (WBC) count have
been associated with the development of coronary ar-
tery disease10 and acute myocardial infarction (AMI) in
healthy individuals and with the development of recur-
rent cardiac events in patients with AMI.11–13 We and
others have demonstrated an association between
WBC count and short-term mortality after AMI.14 –17
Additionally, WBC count has been shown to be associ-
ated with the development of heart failure in patients
with myocardial infarction.18 –20 However, contempo-
rary data examining the association of this inflamma-
tory marker with adverse cardiac events in patients
with other manifestations of ACS, in particular patients
with unstable angina, are extremely limited. As part of
the GRACE study, a multinational population of pa-
tients with complete ACS, we examined the associa-
tion between admission leukocyte count, hospital mor-
tality, and the development of heart failure during the
initial hospitalization in 8269 patients presenting with
the spectrum of ACS. Our study sample consisted of
patients with ST-segment elevation myocardial infarc-
tion (STEMI), non-ST–segment elevation myocardial
infarction (NSTEMI), and unstable angina from 94 hos-
pitals in 14 countries.
Methods
Full details of the GRACE rationale and methodology have
been previously published and are briefly described.21–23
GRACE is designed to reflect a generalizable sample of pa-
tients with ACS within 18 geographic locations. Currently,
101 hospitals located in 14 countries (Argentina, Australia,
Austria, Belgium, Brazil, Canada, France, Germany, Italy, New
Zealand, Poland, Spain, United Kingdom, and United States)
across 4 continents are participating in this observational
study. These geographic regions were chosen to represent
care received and outcomes in patients with ACS in popula-
tions that vary by demographic, clinical and treatment char-
acteristics.
Details of the logistical aspects of this study have been pre-
viously published.21 In brief, all acute-care hospitals in a well-
defined geographic area have been recruited to participate in
this ongoing study. This methodology has led to the selection
of community and tertiary hospitals of varying size and capa-
bility that are representative of the capabilities of acute-care
hospitals in the respective study regions.
Patient recruitment
Patients entered in the registry had to be at least 18 years
old and alive at the time of hospital presentation, be admit-
ted for ACS as a presumptive diagnosis (i.e., have symptoms
consistent with acute ischemia), and have at least 1 of the
following: electrocardiographic changes consistent with ACS,
serial increases in serum biochemical markers of cardiac ne-
crosis, and/or documentation of coronary artery disease.21
The qualifying ACS must not have been precipitated or ac-
Furman et al 43
companied by a significant comorbidity, trauma, or surgery.
Where required, study investigators received approval from
their local hospital ethics or institutional review board.
Data collection
Data were collected at each site by a trained coordinator
using a standardized case report form. Demographic charac-
teristics, medical history, presenting symptoms, duration of
prehospital delay, biochemical and electrocardiographic find-
ings, treatment practices (which are at the discretion of each
patient’s physician), and a variety of hospital outcome data
were collected. All cases of ACS were assigned to one of the
following categories: STEMI, NSTEMI, and unstable angina.
Standard definitions of all patient-related variables, clinical
diagnoses, hospital complications, and other outcomes were
utilized, which were defined as follows:
● STEMI: new or presumed new ST-segment elevation ⱖ1 mm
seen in any location or new left bundle branch block on the
index or qualifying electrocardiogram with ⱖ1 positive car-
diac biochemical marker of necrosis (including troponin
measurements, whether qualitative or quantitative).
● NSTEMI: presence of ⱖ1 positive cardiac biochemical
marker of necrosis without new ST-segment elevation seen
on the index or qualifying electrocardiogram.
● Unstable angina: absence of ST-segment elevation on the
electrocardiogram and serum biochemical markers indica-
tive of myocardial necrosis within each hospital laboratory’s
normal range but with a discharge diagnosis of ACS. Patients
originally admitted for unstable angina but in whom myocar-
dial infarction occurred during the hospital stay were classi-
fied as having a myocardial infarction.
● Heart failure was defined as clinical or radiographic evidence
of pulmonary edema or bilateral basilar rales with an S3
gallop.
Standardized definitions were also used for selected hospi-
tal complications and outcomes.21
Data analysis
Admission leukocyte count was divided into mutually ex-
clusive groups (Q) based on clinically meaningful cutoff
points as follows: Q1 (below normal) ⬍6000; Q2 (normal) ⫽
6000 –9999; Q3 (mildly elevated) ⫽ 10,000 –11,999); Q4
(markedly elevated) ⫽ ⬎12,000. Differences in the distribu-
tion of categorical and continuous variables between patients
in the 4 WBC comparison groups were examined through
the use of ␹2 and 1-way analysis of variance (ANOVA) tests of
statistical significance respectively. Mantel-Haenszel ␹2 test
for trends was used to examine differences in hospital death
rates and the development of heart failure across quartiles of
WBC. A stepwise multiple logistic regression analysis was
performed to simultaneously control for the effects of several
potentially confounding variables in examining the associa-
tion between elevated leukocyte count, hospital mortality,
and heart failure. The factors controlled for in this analysis
were age, gender, time of symptom onset to presentation,
Killip class at presentation, medication use (angiotensin-con-
verting enzyme inhibitors, aspirin, ␤-blockers), use of percu-
taneous coronary interventions and thrombolytic therapy,
and medical history (hypertension, diabetes, coronary artery
 American Heart Journal
44 Furman et al
January 2004

Table I. Baseline characteristics: entire population of acute coronary syndromes

Quartile 1 Quartile 2 Quartile 3 Quartile 4

(<6000) (6–9999) (10–11,999) (>12,000)
Characteristic (n ⴝ 1284) (n ⴝ 3963) (n ⴝ 1416) (n ⴝ 1606) P

Demographic (%)
Age (y)
⬍45 5.6 6.2 9.4 10.8 ⬍.001
46–54 14.6 15.0 21.6 19.4 ⬍.001
55–64 21.5 24.0 21.5 23.0 ⬍.001
65–74 29.8 28.9 28.7 22.5 ⬍.001
ⱖ75 28.5 26.0 22.1 24.3 ⬍.001
Men 67.8 67.4 67.7 66.7 .53
Killip class on admission
I 88.9 84.0 79.6 71.2 ⬍.001
II 8.5 12.6 15.3 16.9 ⬍.001
III 1.9 2.7 4.8 9.2 ⬍.001
IV 0.7 0.7 0.4 2.8 ⬍.001
Medical history (%)
Coronary artery disease 33.4 32.2 23.4 17.7 ⬍.001
Diabetes 24.6 23.5 25.4 23.9 .85
Heart failure 7.2 8.5 9.9 12.0 ⬍.001
Hypertension 57.7 59.4 56.9 55.0 .018
Transient ischemic 8.3 7.7 8.2 9.1 .25
attack/stroke
Tobacco user (former and current) 52.3 56.4 65.1 65.8 ⬍.001
Percutaneous coronary 17.2 17.3 12.5 8.2 ⬍.001
intervention
Coronary artery bypass surgery 15.2 13.5 7.4 7.1 ⬍.001
Hospital treatments (%)
Aspirin 94.0 94.4 95.5 93.1 .43
␤-Blocker 78.8 83.1 85.1 79.1 .82
Statins 54.0 56.2 57.6 53.5 ⬍.05
Angiotensin-converting enzyme 53.3 58.3 62.8 68.4 ⬍.001
inhibitor
Percutaneous coronary 31.1 32.8 35.9 35.6 ⬍.005
intervention
Thrombolytic agent 13.5 13.5 22.0 30.6 ⬍.001

disease, congestive heart failure, myocardial infarction,
stroke, and smoking). These variables were controlled for
due to differences in their distribution between respective
comparison groups and/or due to their previously acknowl-
edged impact on the hospital end points under study. Addi-
tionally, the geographic region of patient recruitment (North
America, South America, Europe or Australia/New Zealand)
was controlled for in the analyses.
Sponsorship and data management
Funding and sponsorship for the GRACE study are pro-
vided by Aventis Pharmaceuticals (Bridgewater, NJ). A Steer-
ing Committee and a Publication Committee were established
from within the Scientific Advisory Committee. These com-
mittees oversee acquisition, analysis, and publication of the
data in an independent manner. Data are entered into the
database by Premier Research, Philadelphia, PA, and are
stored and analyzed at the Center for Outcomes Research of
the University of Massachusetts Medical School, Worcester,
Mass. The authors had unrestricted access to the data in the
preparation of this manuscript.
Results
Baseline characteristics
The study population consisted of 8269 patients
who presented to participating hospitals with an
ACS and for whom information about WBC was
available at the time of hospital admission. The base-
line characteristics of the study population are
shown in Table I. Of the 8269 ACS patients, 2968
had a diagnosis of STEMI, 2698 NSTEMI, and 2603
unstable angina. Patients in the upper quartiles of
WBC count, as compared to the lower quartiles of
WBC count, were more likely to be older, present
with a higher Killip class on admission, and smoke
cigarettes. These patients were also more likely to
American Heart Journal
Furman et al 45
Volume 147, Number 1

Table II. Hospital death rates and occurrence of heart failure according to diagnosis of acute coronary syndrome and white blood cell
count

Hospital death Hospital heart failure

Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4
(%) (%) (%) (%) P (%) (%) (%) (%) P

ST-segment elevation 8.1 4.4 8.2 11.5 ⬍.001 17.2 19.2 20.8 30.1 ⬍.001
myocardial infarction
(n ⫽ 2968)
Non-ST–segment elevation 3.2 3.5 7.4 8.5 ⬍.001 14.3 16.6 21.4 34.0 ⬍.001
myocardial infarction
(n ⫽ 2698)
Unstable angina 1.2 2.1 3.2 7.1 ⬍.001 7.1 8.4 14.7 22.9 ⬍.001
(n ⫽ 2603)

have a history of heart failure and less likely to have Figure 1

prior coronary artery disease or hypertension or to
have undergone percutaneous coronary intervention
or coronary bypass surgery (Table I).

White blood cell count and hospital outcomes

In patients with STEMI, NSTEMI, or unstable angina,
WBC count was directly associated with hospital death
and heart failure (Table II). After controlling for age,
Killip class on admission, time of symptom onset to
presentation, past medical history, and for hospital
medications and interventional procedures, increasing
leukocyte count was significantly associated with hos-
pital death and development of heart failure in patients
with STEMI (Figure 1), NSTEMI (Figure 2) and unstable
angina (Figure 3). There was no independent effect of
geographic region (North America, South America, Eu-
rope, or Australia/New Zealand) on the influence of
WBC quartiles on death or the development of heart Adjusted OR and 95% CI for patients with ACS (STEMI, NSTEMI,
failure (Figure 4). and unstable angina). Q2 is the referent quartile.
When WBC was expressed as a continuous variable,
a 1 ⫻ 103 cells/mm increase in baseline WBC was as-
sociated with an approximate 6% increase in the odds
of dying and a 7% increase in the odds of developing been associated with coronary artery disease and
heart failure after controlling for potentially confound- ACS.25,26 Furthermore, the confluence of thrombosis
ing variables. and inflammation, as reflected in the formation of leu-
kocyte-platelet aggregates, is also associated with the
occurrence of stable angina,27 unstable angina,28,29 and
Discussion AMI,30,31 and is seen in those undergoing percutane-
The present multinational study demonstrates that, ous coronary interventions.32,33
in patients with the full spectrum of ACS, WBC count
is independently associated with hospital death and White blood cell count and hospital mortality
the development of heart failure. This association is WBC count was found to be associated with short-
consistent among patients with a diagnosis of STEMI, term mortality from AMI in a large population-based
NSTEMI, or unstable angina. study of 2863 patients presenting with an initial AMI
Coronary artery disease, and especially ACS (unstable among patients ⬎65 years of age in the Cooperative
angina, NSTEMI, and STEMI), are increasingly being Cardiovascular Project and in those in the OPUS-TIMI
seen as thromboinflammatory disorders.1,24 Indeed, 16 trial.14,17,34 Cannon et al showed a trend (which
platelet activation and markers of inflammation have did not reach statistical significance) between WBC

46 Furman et al
Figure 2
Adjusted OR and 95% CI for patients with STEMI. Q2 is the refer-
ent quartile.
Figure 3
Adjusted OR and 95% CI for patients with NSTEMI. Q2 is the ref-
erent quartile.
count and mortality in 3027 patients with unstable
angina enrolled in OPUS-TIMI.16,34 A low lymphocyte
count has been shown to be associated with subse-
quent cardiac events (recurrent admission for unstable
angina requiring intravenous drug therapy and/or ur-
gent revascularization, AMI, and death) in a small se-
ries of patients with unstable angina.35 However, this
limited study did not show any association between
leukocyte count and death. In 280 patients presenting
to an emergency department with unstable angina,
Lloyd-Jones demonstrated an association between ad-
mission leukocytosis and 1-year mortality.36 However,
American Heart Journal
January 2004
Figure 4
Adjusted OR and 95% CI for patients with unstable angina. Q2 is
the referent quartile.
this association was markedly diminished after adjust-
ing for other covariates.36 The present study demon-
strates an association between elevation in WBC count
and hospital mortality in patients with unstable angina
that persists after adjusting for numerous potentially
confounding covariates. The discordant results of these
other studies with ours probably reflects our larger
sample size and possible differences in working defini-
tions of unstable angina.34 –36
It is unclear whether leukocytosis is simply a marker
for hospital mortality in patients with ACS or a direct
or indirect causative agent. The hypothesis that WBC
count may be a direct cause of mortality in patients
with AMI is based on the association between eleva-
tions in WBC count and reduced epicardial blood flow
and myocardial perfusion in patients receiving throm-
bolytic agents for the treatment of STEMI,17,18 and the
direct involvement of leukocytes in reperfusion inju-
ry.37 However, these factors do not pertain to the asso-
ciation between WBC count and mortality in patients
with unstable angina demonstrated in our present
study. This is because reperfusion injury has not been
shown to be a direct factor in mortality from unstable
angina. Therefore, WBC count more likely represents a
marker of inflammation, and the amount of inflamma-
tion may be directly related to plaque instability and
subsequent recurrent cardiac events.38
White blood cell count and heart failure
Our study is consistent with the extremely limited
data suggesting an association of WBC count with the
development of heart failure in patients with AMI. In a
single-center study, WBC was associated with the de-
velopment of heart failure in a retrospective cohort
American Heart Journal
Volume 147, Number 1
study of 185 patients.19 Peripheral monocytosis was
associated with decreased ejection fraction in patients
presenting to a single hospital with an initial myocar-
dial infarction.20 In 975 patients enrolled in the TIMI
10A and 10B trials, WBC count was associated with
30-day mortality and development of heart failure.18
Our current data extends these findings to include pa-
tients with STEMI, NSTEMI, and unstable angina.
Heart failure is an inflammatory state and the degree
of inflammation is associated with progression of the
disease state.39 In AMI, myocardial injury elicits an in-
flammatory response and reperfusion injury exacer-
bates this inflammatory response.40 Our current results
may suggest that the inflammatory state at the time of
presentation with ACS (as represented by the admis-
sion leukocyte count) is related to the development of
heart failure in ACS patients with (STEMI, NSTEMI)
and without (unstable angina) myocardial injury.
Study strengths and limitations
Strengths of the present study include the large pop-
ulation of patients hospitalized during recent calendar
years, inclusion of patients with the full clinical spec-
trum of ACS (STEMI, NSTEMI, and unstable angina)
from multiple geographic sites, and the use of regres-
sion techniques to elicit the effects of WBC count
from other factors. However, the methods used in col-
lecting data for the GRACE project are subject to a
number of limitations that may limit the ability to gen-
eralize the study findings. The requirement by institu-
tional review boards in some centers for patient con-
sent may have resulted in the exclusion of dying
patients from the registry. Restriction of the registry to
patients who are admitted may result in the exclusion
of patients dying early in the emergency room. Assays
for measuring WBC may vary among hospitals and the
timing of the sampling for initial WBC probably differs
among the hospitals in the study.
Conclusions
The results from this multinational observational
study of the entire spectrum of patients with ACS re-
veal that elevated initial leukocyte count appears to be
an independent predictor of hospital death in patients
with STEMI, NSTEMI, or unstable angina. These find-
ings are consistent with other studies that have docu-
mented an association between leukocyte count and
adverse short-term outcomes in patients with AMI or
unstable angina. These results suggest that clinicians
should consider WBC count as another indicator of
potentially poor hospital outcome in evaluating the
prognosis of patients with ACS.
The authors of this report would like to express
their gratitude to the physicians and nurses partici-
Furman et al 47
pating in GRACE. Further information about GRACE,
along with a complete list of participants, is avail-
able at www.outcomes.org/grace.
References
1. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med
1999;340:115–26.
2. Danesh J, Collins R, Appleby P, et al. Association of fibrinogen,
C-reactive protein, albumin, or leukocyte count with coronary heart
disease: meta-analyses of prospective studies. JAMA 1998;279:
1477– 82.
3. Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin,
and the risk of cardiovascular disease in apparently healthy men.
N Engl J Med 1997;336:973–9.
4. Liuzzo G, Biasucci LM, Gallimore JR, et al. The prognostic value of
C-reactive protein and serum amyloid a protein in severe unstable
angina. N Engl J Med 1994;331:417–24.
5. Toss H, Lindahl B, Siegbahn A, et al. Prognostic influence of in-
creased fibrinogen and C-reactive protein levels in unstable coro-
nary artery disease. FRISC Study Group: Fragmin during Instability
in Coronary Artery Disease. Circulation 1997;96:4204 –10.
6. Lindahl B, Toss H, Siegbahn A, et al. Markers of myocardial dam-
age and inflammation in relation to long-term mortality in unstable
coronary artery disease. FRISC Study Group: Fragmin during In-
stability in Coronary Artery Disease. N Engl J Med 2000;343:
1139 – 47.
7. Blankenberg S, Rupprecht HJ, Bickel C, et al. Circulating cell adhe-
sion molecules and death in patients with coronary artery disease.
Circulation 2001;104:1336 – 42.
8. Ernst E, Hammerschmidt DE, Bagge U, et al. Leukocytes and the
risk of ischemic diseases. JAMA 1987;257:2318 –24.
9. van der Wal AC, Becker AE, van der Loos CM, et al. Site of inti-
mal rupture or erosion of thrombosed coronary atherosclerotic
plaques is characterized by an inflammatory process irrespective
of the dominant plaque morphology. Circulation 1994;89:36 – 44.
10. Yarnell JW, Baker IA, Sweetnam PM, et al. Fibrinogen, viscosity,
and white blood cell count are major risk factors for ischemic
heart disease: the Caerphilly and Speedwell collaborative heart
disease studies. Circulation 1991;83:836 – 44.
11. Friedman GD, Klatsky AL, Siegelaub AB. The leukocyte count as a
predictor of myocardial infarction. N Engl J Med 1974;290:
1275– 8.
12. Zalokar JB, Richard JL, Claude JR. Leukocyte count, smoking, and
myocardial infarction. N Engl J Med 1981;304:465– 8.
13. Lowe GD, Machado SG, Krol WF, et al. White blood cell count
and haematocrit as predictors of coronary recurrence after myo-
cardial infarction. Thromb Haemost 1985;54:700 –3.
14. Furman MI, Becker RC, Yarzebski J, et al. Effect of elevated leuko-
cyte count on in-hospital mortality following acute myocardial in-
farction. Am J Cardiol 1996;78:945– 8.
15. Burr ML, Holliday RM, Fehily AM, et al. Haematological prognos-
tic indices after myocardial infarction: evidence from the diet and
reinfarction trial (DART). Eur Heart J 1992;13:166 –70.
16. Haines AP, Howarth D, North WR, et al. Haemostatic variables
and the outcome of myocardial infarction. Thromb Haemost 1983;
50:800 –3.
17. Barron HV, Harr SD, Radford MJ, et al. The association between
white blood cell count and acute myocardial infarction mortality in
patients ⱖ65 years of age: findings from the cooperative cardio-
vascular project. J Am Coll Cardiol 2001;38:1654 – 61.

48 Furman et al
18. Barron HV, Cannon CP, Murphy SA, et al. Association between
white blood cell count, epicardial blood flow, myocardial perfu-
sion, and clinical outcomes in the setting of acute myocardial in-
farction: a thrombolysis in myocardial infarction 10 substudy. Cir-
culation 2000;102:2329 –34.
19. Kyne L, Hausdorff JM, Knight E, et al. Neutrophilia and congestive
heart failure after acute myocardial infarction. Am Heart J 2000;
139:94 –100.
20. Maekawa Y, Anzai T, Yoshikawa T, et al. Prognostic significance
of peripheral monocytosis after reperfused acute myocardial in-
farction: a possible role for left ventricular remodeling. J Am Coll
Cardiol 2002;39:241– 6.
21. Rationale and design of the GRACE (Global Registry of Acute
Coronary Events) Project: a multinational registry of patients hospi-
talized with acute coronary syndromes. Am Heart J 2001;141:
190 –9.
22. Steg PG, Goldberg RJ, Gore JM, et al. Baseline characteristics,
management practices, and in-hospital outcomes of patients hospi-
talized with acute coronary syndromes in the Global Registry of
Acute Coronary Events (GRACE). Am J Cardiol 2002;90:358 – 63.
23. Eagle KA, Goodman SG, Avezum A, et al. Practice variation and
missed opportunities for reperfusion in ST-segment-elevation myo-
cardial infarction: findings from the Global Registry of Acute Coro-
nary Events (GRACE). Lancet 2002;359:373–7.
24. Fuster V, Lewis A. Conner Memorial Lecture: mechanisms leading
to myocardial infarction: insights from studies of vascular biology.
Circulation 1994;90:2126 – 46.
25. Nurden AT, Macchi L, Bihour C, et al. Markers of platelet activa-
tion in coronary heart disease patients. Eur J Clin Invest 1994;
24(Suppl 1):42–5.
26. Blake GJ, Ridker PM. Novel clinical markers of vascular wall in-
flammation. Circ Res 2001;89:763–71.
27. Furman MI, Benoit SE, Barnard MR, et al. Increased platelet reac-
tivity and circulating monocyte-platelet aggregates in patients with
stable coronary artery disease. J Am Coll Cardiol
1998;31:352– 8.
28. Ott I, Neumann FJ, Gawaz M, et al. Increased neutrophil-platelet
adhesion in patients with unstable angina. Circulation 1996;94:
1239 – 46.
29. Furman MI, Kereiakes DJ, Krueger LA, et al. Leukocyte-platelet
aggregation, platelet surface P-selectin, and platelet surface glyco-
protein IIIa after percutaneous coronary intervention: effects of
dalteparin or unfractionated heparin in combination with abcix-
imab. Am Heart J 2001;142:790 – 8.
30. Neumann FJ, Marx N, Gawaz M, et al. Induction of cytokine ex-
pression in leukocytes by binding of thrombin-stimulated platelets.
Circulation 1997;95:2387–94.
American Heart Journal
January 2004
31. Furman MI, Barnard MR, Krueger LA, et al. Circulating monocyte-
platelet aggregates are an early marker of acute myocardial in-
farction. J Am Coll Cardiol 2001;38:1002– 6.
32. Michelson AD, Barnard MR, Krueger LA, et al. Circulating mono-
cyte-platelet aggregates are a more sensitive marker of in vivo
platelet activation than platelet surface P-selectin: studies in ba-
boons, human coronary intervention, and human acute myocardial
infarction. Circulation 2001;104:1533–7.
33. Mickelson JK, Lakkis NM, Villarreal-Levy G, et al. Leukocyte acti-
vation with platelet adhesion after coronary angioplasty: a mecha-
nism for recurrent disease? J Am Coll Cardiol 1996;28:345–53.
34. Cannon CP, McCabe CH, Wilcox RG, et al. Association of white
blood cell count with increased mortality in acute myocardial in-
farction and unstable angina pectoris: OPUS-TIMI 16 Investigators.
Am J Cardiol 2001;87:636 –9, A10.
35. Zouridakis EG, Garcia-Moll X, Kaski JC. Usefulness of the blood
lymphocyte count in predicting recurrent instability and death in
patients with unstable angina pectoris. Am J Cardiol 2000;86:
449 –51.
36. Lloyd-Jones DM, Camargo CA Jr, Giugliano RP, et al. Effect of
leukocytosis at initial examination on prognosis in patients with
primary unstable angina. Am Heart J 2000;139:867–73.
37. Entman ML, Smith CW. Postreperfusion inflammation: a model for
reaction to injury in cardiovascular disease. Cardiovasc Res 1994;
28:1301–11.
38. Kristensen SD, Ravn HB, Falk E. Insights into the pathophysiology
of unstable coronary artery disease. Am J Cardiol 1997;80:5–9E.
39. Sharma R, Anker SD. Immune and neurohormonal pathways in
chronic heart failure. Congest Heart Fail 2002;8:23– 8, 48.
40. Frangogiannis NG, Smith CW, Entman ML. The inflammatory re-
sponse in myocardial infarction. Cardiovasc Res 2002;53:31– 47.
Appendix
GRACE Scientific Advisory Committee: Keith A.A.
Fox, UK; Joel M. Gore, USA (GRACE Co-Chairs); Kim
A. Eagle, USA; Philippe Gabriel Steg, France (GRACE
Publication Committee Co-Chairs); Giancarlo Agnelli,
Italy; Frederick A. Anderson Jr, USA; Álvaro Avezum,
Brazil; David Brieger, Australia; Andrzej Budaj, Poland;
Christopher P. Cannon, USA; Marcus D. Flather, UK;
Robert J. Goldberg, USA; Shaun G. Goodman, Canada;
Christopher B. Granger, USA; Dietrich C. Gulba, Ger-
many; Enrique P. Gurfinkel, Argentina; Brian M. Ken-
nelly, USA; Werner Klein, Austria; José López-Sendón,
Spain; Gilles Montalescot, France; and Frans Van de
Werf, Belgium.