Jurnal Bu Sulis 1
Jurnal Bu Sulis 1
Jurnal Bu Sulis 1
Atherosclerosis
journal homepage: www.elsevier.com/locate/atherosclerosis
Neopterin predicts the risk for fatal ischemic heart disease in type 2 diabetes
mellitus
Long-term follow-up of the HUNT 1 study
Inga Thorsen Vengen a , Ane Cecilie Dale b,c , Rune Wiseth b,c , Kristian Midthjell d , Vibeke Videm a,e,
a
Department of Laboratory Medicine, Childrens and Womens Health, Norwegian University of Science and Technology, Norway
Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Norway
c
Department of Cardiology, Trondheim University Hospital, Trondheim, Norway
d
Department of Public Health, Norwegian University of Science and Technology, Norway
e
Department of Immunology and Transfusion Medicine, Trondheim University Hospital, NO-7006 Trondheim, Norway
b
a r t i c l e
i n f o
Article history:
Received 19 December 2008
Received in revised form 1 April 2009
Accepted 2 April 2009
Available online 11 April 2009
Keywords:
Heart diseases
Diabetes mellitus
Inammation
Epidemiology
a b s t r a c t
Aims: Neopterin has emerged as a novel predictor of coronary events. The study aim was to compare
the predictive value of neopterin and C-reactive protein (CRP) on long-term risk for fatal ischemic heart
disease (IHD) in persons with newly diagnosed diabetes compared to persons without diabetes.
Methods and results: In 19841986 a large population study, HUNT 1, was conducted in Norway. During the
study, 205 patients were diagnosed with formerly unknown diabetes. A matched control group without
diabetes was selected from the HUNT 1 population. Fatal IHD was registered until 2004. Blood samples
were drawn at baseline and serum was analysed for neopterin and CRP. Cox regression analysis with
correction for age, gender, hypertension, body mass index, established cardiovascular disease and total
cholesterol was used to estimate hazard ratios (HR) for fatal IHD. In the diabetes group, neopterin and CRP
were independent predictors of fatal IHD, HR 2.59 (1.116.01) and 2.45 (1.055.69), respectively. Neither
CRP nor neopterin were signicant predictors of fatal IHD in the control group.
Conclusion: In subjects with diabetes, both neopterin and CRP were independent predictors of fatal IHD,
suggesting that these two markers reect different aspects of the pathogenesis underlying fatal coronary
events.
2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
Diabetes mellitus type 2 is considered both a metabolic and
an inammatory disease [1]. Individuals with impaired glucose
metabolism are at increased risk for fatal ischemic heart disease
(IHD) [2], and there is rm evidence that inammation is central in the pathogenesis of atherosclerosis. It has therefore been
suggested that diabetes accelerates the atherosclerotic process by
increasing inammation [3], and hyperglycemia is associated with
increased markers of inammation [4]. Obesity is common among
diabetes patients, and inammatory mediators released from visceral and subcutaneous fat are both pro-inammatory and may lead
to decreased insulin sensitivity [5]. Hyperglycemia is also associated with endothelial dysfunction [6].
Several inammatory markers have been suggested for prediction of risk for future coronary events. C-reactive protein (CRP)
measured in high-sensitivity assays (hs-CRP) is most widely studied [7,8]. However, the predictive value of CRP has been disputed
and there is a search for stronger predictors among inammatory
markers [9]. Monocytes and macrophages are central in all stages
of atherosclerosis, and neopterin is a soluble marker of monocyte
activation. Neopterin has been identied as a prognostic factor in
acute coronary syndromes [10,11], in survivors of acute myocardial
infarction [12], as well as for rapid disease progression in patients
with stable angina pectoris [13].
In previous studies assessing the predictive power of different
inammatory markers on future IHD, the presence of diabetes most
often has been treated as a confounding factor in the statistical analyses. With the increasing prevalence of subjects with diabetes and
their known risk for IHD, it could be argued that the diabetes population should be analysed separately in order to get further insight
into differences between subjects with and without diabetes.
The aim of the present study was to evaluate baseline CRP and
neopterin as prognostic markers for fatal IHD among subjects with
diabetes during long-term follow-up.
240
Table 1
Background characteristics.
Gender (male/female)
Age, years
BMI, kg/m2
Waist-hip ratio
Random glucose, mmol/L
Fasting glucose, mmol/L
Total cholesterol, mmol/L
HDL-cholesterol, mmol/L
Total cholesterolHDL-cholesterol
ratio
Creatinine, mol/L
Hypertensiona , number (%)
Smoking, number (%)
Previous CVDb , number (%)
Newly diagnosed
diabetes (n = 200)
105/95
67 (6568)
29.7 (29.030.3)
0.92 (0.900.93)
10.6 (10.011.1)
6.8 (6.57.0)
6.7 (6.56.8)
1.24 (1.201.29)
5.6 (5.45.8)
102/96
67 (6568)
26.2 (25.726.7)
0.88 (0.870.89)
5.2 (5.15.4)
5.0 (4.85.1)
7.3 (7.17.5)
1.46 (1.411.51)
5.2 (5.05.5)
86.4 (83.289.5)
135 (68%)
42 (23%)
44 (22%)
86.2 (84.488.0)
98 (49%)
35 (21%)
27 (14%)
2.3. Follow-up
Information on causes of death was obtained by linking data
from our study to the Cause of Death Registry at Statistics Norway,
which receives all death certicates of Norwegian citizens. Deaths
were classied according to the International Classication of Disease (ICD-9 and ICD-10). Death from IHD was dened by ICD-9:
410414 and ICD-10: I20-25. We calculated the individual person
time at risk from the date of the comprehensive baseline clinical
examination until the date of death from IHD, death from other
causes or until the end of follow-up on December 31, 2004. The
study protocol conformed to the Helsinki declaration, and the study
was approved by The Data Inspectorate and recommended by the
Regional Committee for Medical Research Ethics.
2.4. Statistical analysis
Baseline characteristics are displayed by proportions or means
with 95% condence intervals (CI), stratied according to diabetes
status. Spearmans rank correlation coefcient was used to evaluate
the correlation between neopterin and CRP concentrations. Due to
non-normal distribution, the data were analysed with Mann Whitney U-test. The Chi-square test was used to compare categorical
variables.
Incidences of IHD mortality were plotted in KaplanMeier plots.
Cox regression analysis was used to estimate hazard ratios (HR) and
95% CI of death from IHD according to the baseline concentrations
of the biomarkers. Neopterin and CRP concentrations were divided
into tertiles (neopterin <7.9, 7.910.5, >10.5 nmol/L, CRP < 1.09,
1.092.86, >2.86 mg/L). Departures from the proportional hazards
assumption was evaluated using graphical procedures (loglog
plots).
All statistical tests were two-sided and p-values below 0.05 were
considered statistically signicant. Data were analysed with SPSS
for Windows (version 15.0 SPSS Inc., Chicago, IL, USA).
3. Results
Background characteristics are shown in Table 1. Subjects with
newly diagnosed diabetes had a higher BMI, were more often
241
Table 2
Concentrations of neopterin and CRP (means and 95% CI), stratied according to previous CVD and diabetes status.
Diabetes
Biomarker
Previous CVD
No previous CVD
p-value
Yes
Neopterin (nmol/L)
CRP (mg/L)
44
13.2 (11.115.3)
3.56 (2.494.63)
156
9.6 (9.010.3)
2.98 (2.333.62)
0.001
0.094
No
Neopterin (nmol/L)
CRP (mg/L)
27
10.0 (8.911.2)
1.81 (1.362.26)
171
9.7 (9.110.3)
1.95 (1.692.22)
0.29
0.71
Fig. 1. The correlation of neopterin and CRP concentrations in patients with newly
diagnosed diabetes. Panel A: All samples. Panel B: Samples from patients with
CRP < 10 mg/L only.
hypertensive, and more often had established cardiovascular disease than the control group. Concentrations both of total and
HDL-cholesterol were lower in the diabetes group, resulting in a
higher total cholesterol/HDL-cholesterol ratio. Mean individual person time at risk was 12.6 years (range: 0.119.7). During follow-up,
Table 3
Hazard ratio for the tertiles for neopterin and CRP in serum from participants with newly diagnosed diabetes and their control group.
No. of deaths
Hazard ratioa
Condence
interval
Hazard ratiob
Condence
interval
10
12
22
10.6
14.2
35.8
1.0
1.39
2.59
(Reference)
(0.583.37)
(1.116.01)
1.0
1.48
2.39
(Reference)
(0.613.62)
(1.015.69)
794.7
740.6
868.2
8
14
22
10.1
18.9
25.3
1.0
1.79
2.45
(Reference)
(0.744.33)
(1.055.69)
1.0
1.85
2.12
(Reference)
(0.754.55)
(0.895.05)
959.3
927.3
700.6
11
5
12
11.5
5.4
17.1
1.0
0.43
1.24
(Reference)
(0.151.26)
(0.512.98)
1.0
0.43
1.19
(Reference)
(0.141.28)
(0.492.89)
1105.5
867.4
628.8
8
10
10
7.2
11.5
15.9
1.0
1.14
1.66
(Reference)
(0.433.03)
(0.594.65)
1.0
1.28
1.45
(Reference)
(0.483.37)
(0.524.09)
Adjusted for: age, gender, hypertension, BMI, previous cardiovascular disease and total cholesterol.
Adjusted for: age, gender, hypertension, BMI, previous cardiovascular disease, total cholesterol and opposite biomarker.
Neopterin: Tertile I: <7.9 nmol/L, Tertile II: 7.910.5 nmol/L, Tertile III: >10.5 nmol/L.
CRP: Tertile I: <1.09 mg/L, Tertile II: 1.092.86 mg/L, Tertile III: > 2.86 mg/L.
242
4. Discussion
Fig. 2. Neopterin, CRP and death from IHD in patients with newly diagnosed
diabetes. Survival curves according to tertile of neopterin (panel A) or CRP
(panel B) concentration at baseline. Neopterin: Tertile I: <7.9 nmol/L, Tertile II:
7.910.5 nmol/L, Tertile III: >10.5 nmol/L. CRP: Tertile I: <1.09 mg/L, Tertile II:
1.092.86 mg/L, Tertile III: >2.86 mg/L. The highest tertile of both markers were signicant predictors of fatal IHD; neopterin HR 2.59 (1.116.01), p = 0.027 and CRP 2.45
(1.055.69), p = 0.038. The model was adjusted for age, gender, hypertension, body
mass index, previous CVD and total cholesterol.
243
244
[14] Dale AC, Nilsen TI, Vatten L, Midthjell K, Wiseth R. Diabetes mellitus and risk of
fatal ischaemic heart disease by gender: 18 years follow-up of 74 914 individuals
in the HUNT 1 study. Eur Heart J 2007;28:29249.
[15] Holmen J, Midthjell K, Bjartveit K, et al. The North-Trndelag Health Survey
198486. Purpose, background and methods. Participation, non-participation
and frequency distributions. Verdal: Statens Institutt for folkehelse, Senter for
samfunnsmedisinsk forskning. Report no. 4; 1990.
[16] WHO Expert Committee on Diabetes Mellitus, second report. Technical Report
Series, no. 646. Geneva: World Health Organization; 1980. p. 180.
[17] Claudi T, Midthjell K, Holmen J, et al. Cardiovascular disease and risk factors
in persons with type 2 diabetes diagnosed in a large population screening:
the Nord-Trndelag Diabetes Study, Norway. J Intern Med 2000;248:492
500.
[18] Neurauter G, Wirleitner B, Laich A, et al. Atorvastatin suppresses interferongamma-induced neopterin formation and tryptophan degradation in human
peripheral blood mononuclear cells and in monocytes cell lines. Clin Exp
Immunol 2003;131:2647.
[19] Berdowska A, Zwirska-Korczala K. Neopterin measurement in clinical diagnosis.
J Clin Pharm Therap 2001;26:31929.
[20] Videm V, Wiseth R, Gunnes S, Madsen HO, Garred P. Multiple inammatory markers in patients with signicant coronary artery disease. Int J Cardiol
2007;118:817.
[21] 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;35:95662.
[22] Avanzas P, Arroyo-Espliguero R, Cosn-Sales J, et al. Markers of inammation and
multiple complex stenosis (pancoronary plaque vulnerability) in patients with
non-ST segment elevation acute coronary syndromes. Heart 2004;90:84752.
[23] Liuzzo G, Goronzy J, Yang H, et al. Monoclonal T-cell proliferation and plaque
instability in acute coronary syndromes. Circulation 2000;102:28838.
[24] Cirillo P, Pacileo M, DE Rosa S, et al. Neopterin induces pro-atherothrombotic
phenotype in human coronary endothelial cells. J Thromb Haemost
2006;10:224855.
[25] Heinrich PC, Castell JV, Andus T. Interleukin-6 and the acute phase reaction.
Biochem J 1990;265:62136.
[26] Wilson AW, Ryan MC, Boyle AJ. The novel role of C-reactive protein in cardiovascular disease: risk marker or pathogen. Int J Cardiol 2006;106:2917.
[27] Noto D, Cottone S, Cefal AB, et al. Interleukin 6 plasma levels predict with high
sensitivity and specicity coronary stenosis detected by coronary angiography.
Thromb Haemost 2007;98:13627.
[28] Danesh J, Collins R, Appleby P, Peto R. Association of brinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses
of prospective studies. JAMA 1998;279:147782.
[29] Ip M, Rainer TH, Lee N, et al. Value of serum procalcitonin, neopterin and Creactive protein in differentiating bacterial from viral etiologies in patients
presenting with lower respiratory tract infections. Diagn Microbiol Infect Dis
2007;59:1316.
[30] Avanzas P, Arryo-Espliguero R, Quiles J, Roy D, Kaski JC. Elevated serum
neopterin predicts future adverse cardiac events in patients with chronic stable
angina pectoris. Eur Heart J 2005;26:45763.
[31] Avanzas P, Arroyo-Espliguero R, Cosin-Sales J, et al. Prognostic value of neopterin
levels in treated patients with hypertension and chest pain but without obstructive coronary artery disease. Am J Cardiol 2004;93:6279.
[32] Kaski JC, Consuegra-Sanchez L, Fernandez-Berges DJ, et al. Elevated serum
neopterin levels and adverse cardiac events at 6 months follow-up in
Mediterranean patients with non-ST-segment acute coronary syndrome.
Atherosclerosis 2008;28:17683.
[33] Esposito K, Nappo F, Marfella R, et al. Inammatory cytokine concentrations
are acutely increased by hyperglycemia in humans: role of oxidative stress.
Circulation 2002;106:206772.
[34] Bowden DW, Lange LA, Langefeld CD, et al. The relationship between C-reactive
protein and subclinical cardiovascular disease in the Diabetes Heart Study
(DHS). Am Heart J 2005;150:10328.
[35] Bertz L, Barani J, Gottster A, et al. Are there differences of inammatory
bio-markers between diabetic and non-diabetic patients with critical limb
ischemia? Int Angiol 2006;25:3707.