Prognostic Value of Neopterin Levels in Treated

Patients With Hypertension and Chest Pain But

Without Obstructive Coronary Artery Disease
Pablo Avanzas, MD, Ramo n Arroyo-Espliguero, MD, Juan Cosin-Sales, MD,
Juan Quiles, MD, Emmanouil Zouridakis, MD, and Juan Carlos Kaski, MD, DSc
We sought to assess the relation between circulating
levels of inflammation markers, such as neopterin
and C-reactive protein, and the development of adverse cardiovascular events in patients with hypertension but without obstructive coronary artery disease.
We observed that patients who developed adverse
events during follow-up had significantly higher neopterin levels compared with patients without
events. 2004 by Excerpta Medica, Inc.
(Am J Cardiol 2004;93:627 629)

eopterin is a pteridine-derivative marker of immune cell activation produced by activated macN

rophages. Results of previous studies have shown
1

that serum neopterin levels are increased in patients

with acute myocardial infarction (AMI)2 and that increased neopterin concentrations are associated with
the presence of complex vulnerable coronary lesions
in patients with unstable coronary syndromes.3 Moreover, it has been shown that increased serum neopterin
levels predict acute coronary events in women with
chronic stable angina.4 Little is known, however, regarding the prognostic value of neopterin in patients
with risk factors, i.e., with hypertension but without
obstructive coronary artery disease (CAD). This study
assessed the prognostic value of C-reactive protein
(CRP) and neopterin serum concentrations in patients
with hypertension and angina but without obstructive
CAD.

We studied 58 patients from a series of 260 consecutive patients entered prospectively into our angina
database from November 1998 to February 1999.
These patients were referred to our unit for diagnostic
coronary angiography. All had exertional stable angina, a positive electrocardiographic (ECG) exercise
test response (1 mm horizontal or downsloping STsegment depression), or reversible myocardial perfusion defects on cardiac scintigraphy. For the purpose
of the present study, we selected treated patients with
hypertension (mean age 61 10 years; 75.9% men)
who had (1) typical exertional chest pain brought on
by exertion and relieved by rest, sublingual nitrates, or
From the Coronary Artery Disease Research Unit, Department of Cardiological Sciences, St. Georges Hospital Medical School, London,
United Kingdom; and the Division of Cardiology, Hospital Universitario, Guadalajara, Spain. Dr. Kaskis address is: Department of Cardiological Sciences, St. Georges Hospital Medical School, Cranmer
Terrace, London SW17 0RE, United Kingdom. E-mail: jkaski@
sghms.ac.uk. Manuscript received June 2, 2003; revised manuscript
received and accepted November 4, 2003.
2004 by Excerpta Medica, Inc. All rights reserved.
The American Journal of Cardiology Vol. 93 March 1, 2004

both, and (2) coronary artery stenosis of 50% in

diameter. None of the patients included in the study
had ongoing systemic or cardiac inflammatory processes apart from atherosclerosis. All patients gave
written informed consent before study entry, and the
study protocol was approved by the local research
ethics committee.
Venous blood was collected at the time of diagnostic coronary angiography. Serum neopterin concentration was measured using a commercially available immunoassay (enzyme-linked immunosorbent
assay kit; Immuno-biological Laboratories, Hamburg,
Germany). The within-coefficient variability in the 7.7
nmol/L range was 3% and in the 20 nmol/L range
was 4%. Measurements of CRP were performed on
the COBAS Integra (Roche Diagnostics, Lewes, East
Sussex, United Kingdom) using the CRP-latex assay
in the high-sensitivity application (analytic range 0.2
to 12 mg/L) and the normal application (analytic range
2 to 160 mg/L). Analytic precision of the high-sensitivity CRP-latex assay was 7.6% at a level of 1.02
mg/L, 3.3% at a level of 1.79 mg/L, and 1.3% at a
level of 4.36 mg/L. Samples outside the analytic range
of the high-sensitivity CRP-latex assay were analyzed
by the CRP-latex assay in the normal application. The
analytic precision of the normal CRP-latex assay was
2.4% at a level of 29.5 mg/L and 1.3% at a level of
113 mg/L.
Coronary angiography was performed according to
the Judkins technique, and images of the coronary tree
in all patients were obtained as routine, standardized
projections with the digital Philips Integris 3000 system (Philips, Eindhoven, The Netherlands) using an
automated quantitative coronary artery stenosis assessment program. Two experienced cardiologists
who were blinded to the patients clinical characteristics and biochemical results reviewed all of the angiographic images.
Patients were followed up for 1 year, and study end
points were: (1) AMI defined according to World
Health Organization criteria, i.e., increased cardiac
enzymes, characteristic ECG changes, and prolonged
typical chest pain; (2) readmission to the coronary
care unit with Braunwalds class IIIb unstable angina5; and (3) cardiac death.
Results for normally distributed continuous variables were expressed as mean values SD, and
continuous variables with non-normal distribution
(CRP and neopterin) were presented as median values
(interquartile intervals). Analysis of normality of the
continuous variables was performed using the Kolmogorov-Smirnov test. Comparisons between contin0002-9149/04/$see front matter
doi:10.1016/j.amjcard.2003.11.035

627

Patients who developed adverse

events during follow-up had significantly higher neopterin levels (7.6
Clinical Events
[5.7 to 11.75] vs 5.4 nmol/L [3.6 to
6.9], p 0.01) than patients without
Absent
Present
Characteristics
(n 49)
(n 9)
p Value
events. CRP levels were also higher
in patients with events (3.5 [2.3 to
Age (yrs)
62 10
61 11
0.9
9.1] vs 2.6 mg/L [1.2 to 4.7], p
Men
36 (73%)
8 (89%)
0.43
Systolic blood pressure (mm Hg)
136 (20%)
132 (21%)
0.66
0.3) compared with patients without
Diastolic blood pressure (mm Hg)
78 (10%)
77 (9%)
0.67
events, but the difference did not
Diabetes mellitus
1 (2%)
2 (22%)
0.06
reach statistical significance (Figure
Hyperlipidemia*
23 (47%)
6 (67%)
0.47
1). Nine patients (15%) had 1 of
Smoking
21 (43%)
4 (44%)
0.9
Mean stenosis severity in the coronary tree
37 7
38 6
0.9
the events in the combined study end
Aspirin
41 (84%)
9 (100%)
0.33
point during the 1-year follow-up (4
blockers
26 (53%)
6 (67%)
0.49
patients had unstable angina, 2 paNitrates
26 (53%)
6 (67%)
0.49
tients had AMI, and 3 patients had
Angiotensin-converting enzime inhibitors
7 (14%)
1 (11%)
0.9
sudden cardiac death). Patients who
Calcium antagonists
22 (45%)
6 (67%)
0.29
Total cholesterol
developed unstable angina or AMI
mmol/L
6.1 1.3
61
0.8
during follow-up underwent coromg/dl
240 50
235 36
nary angiography. One of the 2 paTriglycerides
tients with AMI underwent primary
mmol/L
1.5 1
2.1 1
0.18
mg/dl
138 89
187 107
coronary angioplasty. Univariate
Neopterin (nmol/L)
5.4 (3.66.9) 7.6 (5.711.7)
0.01
analysis showed that diabetes melliC-reactive protein (mg/L)
2.6 (1.24.7) 3.5 (2.39.1)
0.3
tus (p 0.06) and neopterin serum
Data are expressed as mean SD, median (interquartile interval), or number (percent) for categorical
concentrations (p 0.01) were assovariables.
ciated with the study end point. We
*Hyperlipidemia total cholesterol 5.4 mmol/L1.
performed backward stepwise binary
logistic regression analyses in which
we included these variables as well
as conventional cardiovascular risk factors and CRP
levels. Neopterin levels remained the only independent predictor of the combined end point (odds ratio
1.5, 95% confidence interval 1.1 to 1.9, p 0.01).
TABLE 1 Baseline Characteristics of 58 Patients With Hypertension but Without
Obstructive Coronary Artery Disease (CAD)

FIGURE 1. Differences in neopterin and CRP levels between patients with and without adverse events.

uous variables were analyzed using the unpaired Students t test and the Mann-Whitney U test as
appropriate. Discrete variables were analyzed using
the chi-square test. We assessed independent predictors of end points using a binary logistic regression
analysis. Differences were considered to be statistically significant if the null hypothesis could be rejected with 95% confidence. The SPSS 11.5 statistical software package (SPSS Inc., Chicago, Illinois)
was used for all calculations.
Baseline clinical and biochemical characteristics of
the 58 patients included in the study are listed in Table
1. Mean coronary artery stenosis severity was similar
in patients with (38%) and without (37%) events.
628 THE AMERICAN JOURNAL OF CARDIOLOGY

VOL. 93

Information regarding neopterin and its prognostic

value in patients with heart disease is limited. Auer et
al6 showed in patients with acute coronary syndromes
that neopterin levels measured 72 hours after the onset
of symptoms were significantly higher in patients who
developed serious cardiovascular events during 22
3 months of follow-up compared with patients without
adverse cardiovascular events. Garca-Moll et al4
showed that high neopterin levels were a predictor of
cardiovascular risk in women with CAD. The main
finding of this study is that high neopterin levels
predict cardiac adverse events in patients with hypertension but without obstructive CAD, even after adjusting for confounding factors. Fifteen percent of our
patients developed 1 of the events in the combined
study end point despite the absence of obstructive
CAD. This finding is of importance because although,
on average, patients with chest pain and normal or
near-normal coronary angiographic results have
good long-term prognosis despite positive exercise
ECG stress test results, neopterin levels may identify
subjects who are at a higher risk of developing adverse
events. Therefore, patients with high neopterin levels
may require aggressive risk factor modification and
intensive medical treatment irrespective of the severity of their coronary artery stenosis. Although we
defined stenoses of 50% in diameter as nonobstructive, the radiographic appearance on angiograms can
MARCH 1, 2004

be quite deceiving and may not reflect the true severity

of the intraluminal atherosclerotic disease. Moreover,
angiographic severity does not determine plaque vulnerability because most acute coronary syndromes
have been shown to occur in arteries with angiographically insignificant stenosis. Current concepts regarding plaque instability imply a significant role of
inflammation. Our results agree with this notion and
indicate that neopterin, a marker of macrophage activity and immune activation, may help identify patients with vulnerable plaques, irrespective of the severity of their coronary narrowing. The high event rate
in this patient group is somehow surprising, but all
subjects had risk factors, were symptomatic, and required angiography. Moreover, our results agree with
the findings of Suwaidi et al7 who reported that 14%
of patients with chest pain and endothelial dysfunction
had serious adverse events despite having mild CAD.
In our study, CRP and neopterin levels were higher in
patients who developed events, but only with multivariate analysis did neopterin remain an independent
predictor of cardiovascular adverse events. Whether
this finding indicates that neopterin is a better prognostic marker than CRP in this particular study population requires further investigation.
The main limitation of this study was the relatively

small size of the patient population investigated, and

thus a lack of statistical power may explain why CRP
levels did not differ significantly at follow-up between
patients with and without events. Moreover, the small
population size did not allow us to identify a prognostic cut-off level for neopterin, and this is an issue that
requires further work. Our results nevertheless suggest
that neopterin may be useful in identifying patients
who are at a higher risk among those with hypertension, stable angina, and nonobstructive CAD.

1. Huber C, Batchelor JR, Fuchs D, Hausen A, Lang A, Niederwieser D,

Reibnegger G, Swetly P, Troppamir J, Wachter H. Immune response-associated

production of neopterin. Release from macrophages primarily under control of
interferon-gamma. J Exp Med 1984;160:310 316.
2. Gupta S, Fredericks S, Schwartzman RA, Holt DW, Kaski JC. Serum neopterin
in acute coronary syndromes. Lancet 1997;349:12521253.
3. Garcia-Moll X, Coccolo F, Cole D, Kaski JC. Serum neopterin and complex
stenosis morphology in patients with unstable angina. J Am Coll Cardiol 2000;
35:956 962.
4. Garcia-Moll X, Cole D, Zouridakis E, Kaski JC. Increased serum neopterin: a
marker of coronary artery disease activity in women. Heart 2000;83:346 350.
5. Braunwald E. Unstable angina. A classification. Circulation 1989;80:410 414.
6. Auer J, Berent R, Lassnig E, Weber T, Eber B. Prognostic significance of
immune activation after acute coronary syndromes. J Am Coll Cardiol 2002;39:
1878.
7. Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes DR Jr, Lerman
A. Long-term follow-up of patients with mild coronary artery disease and
endothelial dysfunction. Circulation 2000;7;101:948 955.

Predicting Mortality in Patients With ST-Elevation

Myocardial Infarction Treated With Primary
Percutaneous Coronary Intervention (PAMI Risk Score)
Srinivas Addala, MD, Cindy L. Grines, MD, Simon R. Dixon, MBChB,
Gregg W. Stone, MD, Judith A. Boura, MS, Anthony B. Ochoa, MD,
Gregory Pellizzon, MD, William W. ONeill, MD, and Joel K. Kahn, MD
We performed a pooled analysis of the Primary Angioplasty in Myocardial Infarction (PAMI) trials to
examine predictors of death after primary percutaneous coronary intervention. Using these data, we
developed a risk score with a range of 0 to 15 points.
The PAMI risk score was found to be a strong predictor of late mortality. 2004 by Excerpta Medica,
Inc.
(Am J Cardiol 2004;93:629 632)

andomized clinical trials of patients with STsegment

elevation
myocardial
infarction
R
(STEMI) comparing primary percutaneous coronary
intervention (PCI) with thrombolytic therapy have
From the William Beaumont Hospital, Royal Oak, Michigan; and
Lenox Hill Heart and Vascular Institute, New York, New York. Dr.
Kahns address is: Division of Cardiology, William Beaumont Hospital, 3601 West 13 Mile Road, Royal Oak, Michigan 48073. E-mail:
kahn642@aol.com. Manuscript received July 16, 2003; revised
manuscript received and accepted November 3, 2003.
2004 by Excerpta Medica, Inc. All rights reserved.
The American Journal of Cardiology Vol. 93 March 1, 2004

shown the superiority of PCI in terms of epicardial

flow and outcome.13 Therefore, primary PCI has become the preferred reperfusion strategy for STEMI at
many centers.4 However, clinical outcome and survival varies greatly according to the baseline risk
profile. Risk scores have been described for patients
with STEMI in general5 8 and for patients eligible for
and treated with thrombolytic agents.9,10 Few data are
available for patients treated with PCI.10 A reliable
early method to predict risk of death in patients
presenting with STEMI who are eligible for PCI
may be valuable in selecting high-risk patients for
novel or aggressive therapies and in counseling
families on risk. Therefore, we analyzed a large
patient group to develop a clinical risk score that
could be applied early to patients treated with PCI
for STEMI.

We analyzed the baseline characteristics and clinical outcome of 3,252 patients who underwent primary PCI therapy for STEMI enrolled in various
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629