C-reactive protein in patients with normal perfusion and mild to moderate perfusion defects who have undergone myocardial perfusion imaging with 99m-Tc sestamibi gated spect

Abstract

High-sensitivity C-reactive protein (CRP) has been extensively used in recent years to assess cardiovascular risk more thoroughly. A significant association between elevated CRP, a prevalence of coronary artery disease (CAD) and adverse cardiac events has been found. Stress myocardial SPECT perfusion imaging (MPI) is an accurate noninvasive technique for detecting CAD. The aim of our study was to find out if there are any differences in the CRP levels between patients with normal myocardial perfusion and mild to moderate perfusion defects, detected with 99m-Tc sestamibi gated SPECT MPI. We prospectively studied 127 patients (79 men, 48 women) suspected of having CAD or with previously confirmed CAD, who were referred for MPI. According to the findings of the stress study, they were divided into two groups: with normal/ near normal myocardial perfusion (n = 85) and with a mild to moderate perfusion defect (n = 42). Levels of CRP in the former group were significantly lower (2.7 mg/L vs. 4.2 mg/L, p = 0.01). There were significantly more men (78.6% vs. 54%, p = 0.000*) and smokers (26% vs. 15%, p = 0.003), also the rates of PCI were significantly higher (36% vs. 15%, p = 0.006) in patients with mild to moderate perfusion defects. The two groups did not differ significantly in age, type of stress, presence of most risk factors for CAD, previous myocardial infarction and CABG. The results of our study have shown that patients with mild to moderate perfusion defects on stress myocardial perfusion SPECT imaging have significantly higher levels of C-reactive protein, compared to those with normal/near normal myocardial perfusion.

Full text

Prilozi, Odd. biol. med. nauki, MANU, XXIX, 1, s. 67‡76 (2008)
Contributions, Sec. Biol. Med. Sci., MASA, XXIX, 1, p. 67–76 (2008)
ISSN 0351–3254
UDK : 616.12-073.916
C-REACTIVE PROTEIN IN PATIENTS WITH NORMAL PERFUSION
AND MILD TO MODERATE PERFUSION DEFECTS WHO HAVE
UNDERGONE MYOCARDIAL PERFUSION IMAGING WITH
99m-Tc SESTAMIBI GATED SPECT
Majstorov Venjamin,1 Pop Gjorceva Daniela,1 Vaskova Olivija,1
Vavlukis Marija,2 Peovska Irena,2 Maksimovic Jelena,2
Kuzmanovska Sonja,1 Zdraveska-Kocovska Marina1
1 Pathophysiology and Nuclear Medicine Institute, Skopje, R. Macedonia
2 Heart Diseases Institute, Medical Faculty, Skopje, R. Macedonia
Abstract: High-sensitivity C-reactive protein (CRP) has been extensively
used in recent years to assess cardiovascular risk more thoroughly. A significant asso-
ciation between elevated CRP, a prevalence of coronary artery disease (CAD) and ad-
verse cardiac events has been found. Stress myocardial SPECT perfusion imaging
(MPI) is an accurate noninvasive technique for detecting CAD.
The aim of our study was to find out if there are any differences in the CRP
levels between patients with normal myocardial perfusion and mild to moderate per-
fusion defects, detected with 99m-Tc sestamibi gated SPECT MPI.
We prospectively studied 127 patients (79 men, 48 women) suspected of ha-
ving CAD or with previously confirmed CAD, who were referred for MPI. According
to the findings of the stress study, they were divided into two groups: with normal/ near
normal myocardial perfusion (n = 85) and with a mild to moderate perfusion defect (n =
42). Levels of CRP in the former group were significantly lower (2.7 mg/L vs. 4.2
mg/L, p = 0.01). There were significantly more men (78.6% vs. 54%, p = 0.000*) and
smokers (26% vs. 15%, p = 0.003), also the rates of PCI were significantly higher (36%
vs. 15%, p = 0.006) in patients with mild to moderate perfusion defects. The two groups
did not differ significantly in age, type of stress, presence of most risk factors for CAD,
previous myocardial infarction and CABG.
The results of our study have shown that patients with mild to moderate per-
fusion defects on stress myocardial perfusion SPECT imaging have significantly higher

68 Majstorov Venjamin, Pop Gjorceva Daniela et al.
levels of C-reactive protein, compared to those with normal/near normal myocardial
perfusion.
Key words: C-reactive protein, coronary disease, diagnostic imaging.
Introduction
There is extensive evidence that inflammation is a key pathogenetic me-
chanism in the development of atherosclerosis and in promoting its progression,
leading finally to the atherothrombotic complications of cardiovascular disease
[1, 2]. One of the serum markers that enables detection of the inflammation and
is easy to measure is C-reactive protein (CRP), an acute-phase reactant.
Introduction of the high-sensitivity CRP (hs-CRP) testing in recent
years has given the investigators an opportunity to assess the cardiovascular risk
more thoroughly. A significant association between elevated serum or plasma
concentrations of hs-CRP, on the one hand, and the prevalence of coronary ar-
tery disease (CAD), the risk of recurrent cardiovascular events among those
with established disease, and higher risk of severe cardiovascular events in
apparently healthy individuals, on the other hand, has been documented in many
studies [3–5].
Some investigators claim that CRP is not merely an innocent bystander
of the atherosclerotic process, but could play an active role in promoting vas-
cular inflammation, although this remains controversial [6].
For many years now, stress myocardial perfusion imaging (MPI) with
radionuclides has been used as an accurate, well-established noninvasive techni-
que for detecting CAD. As the link between CRP and severe CAD has been de-
monstrated in the past [7], the aim of our study was to find out if there are any
differences in the CRP levels between patients with normal myocardial perfu-
sion and mild to moderate perfusion defects, detected with 99m-Tc sestamibi
gated SPECT myocardial perfusion imaging.
Methods
Study population
This prospective study involved 127 patients (79 men, 48 women) sus-
pected of having CAD or with previously confirmed CAD, who were referred
for myocardial perfusion imaging between December 2005 and July 2006 at the
Pathophysiology and Nuclear Medicine Institute, Medical School in Skopje.
Patients were selected on the basis of MPI findings: only those with
normal myocardial perfusion and mild to moderate perfusion defects on the
Contributions, Sec. Biol. Med. Sci., XXIX/1 (2008), 67–76

C-reactive protein in patients with normal… 69
stress images entered the study. Patients were not enrolled if they had had recent
myocardial infarction or coronary revascularization (within 6 months), left
bundle branch block, dilated cardiomyopathy or if they suffered from any acute
or chronic infection and inflammation, uncontrolled hypertension (BP > 21/12
kPa), chronic hepatic or renal disease.
In 58 patients an exercise treadmill test was performed, and the rest
were stressed with dipyridamole as a pharmacological stressor because were una-
ble to exercise for various reasons (e.g. poor condition, older age, comorbidity).
A detailed questionnaire which included clinical, historical and stress
data was filled in, with particular attention to the risk factors for CAD, previous
myocardial infarction (MI) and coronary revascularization.
Rest imaging
A one-day rest-stress protocol with 99m-Tc sestamibi was performed in all
patients. For the rest study 10–12 mCi of the tracer were injected intravenously, un-
der fasting conditions. Imaging started at least 1 hour after radioisotope injection.
Exercise myocardial perfusion protocol
Those who were able to exercise underwent a symptom-limited exercise
treadmill test with the standard Bruce protocol. At near-maximal exercise,
radiopharmaceutical (25 mCi) was injected intravenously and exercise was con-
tinued at maximal workload for one minute. SPECT acquisition was started 15
to 30 minutes later.
Dipyridamole myocardial perfusion protocol
Patients who underwent dipyridamole stress were instructed not to con-
sume caffeine-containing products for 24 hours before testing.
A dipyridamole infusion in doses of 0.56 mg/kg per body weight for 4
minutes was given. At peak vasodilator effect (3 minutes after the end of the in-
fusion), 25 mCi of the tracer were injected. Two to three minutes later patients
with side-effects were given aminophyllin as an antidote (125 to 250 mg). Re-
sults of blood pressure and 12-lead electrocardiograms were recorded at 2-mi-
nute intervals. Stress imaging started app.1 hour after the application of the
radiopharmaceutical.
Single photon emission computerized tomography (SPECT)
All patients underwent ECG-synchronized acquisition (gated SPECT)
for both studies with a rotating single head gamma-camera (Siemens e.cam Sig-
nature series).
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70 Majstorov Venjamin, Pop Gjorceva Daniela et al.
Image interpretation
Stress and rest images from the short-axis, horizontal long-axis and ver-
tical long-axis slices were compared by four experienced readers.
The left ventricle was divided into 17 segments [8]. Quantitative ana-
lysis of the perfusional and functional parameters of the left ventricle during the
rest and after stress was done with software package 4D-MSPECT. A summed
stress score (SSS) was obtained automatically by means of adding the scores for
the 17 segments of the stress images. A summed rest score (SRS) was similarly
obtained by means of adding the scores for the 17 segments of the rest images.
The sum of the difference between the stress and rest scores gave the summed
difference score (SDS).
C-reactive protein estimation
Blood samples for high sensitive C-reactive protein (hs-CRP) testing were
taken from all patients on the day of examination, in the morning. The sera were
kept frozen at -20°C temperature until the assays were done. CRP levels in the sera
were estimated with chemiluminescent immunometric assay (Immulite®/Immulite
1000® High Sensitivity CRP),with an analytical sensitivity of 0.1 mg/L.
Statistical analysis
Continuous variables were expressed as mean value ± SD. The mean
differences for continuous variables were compared by Student t test (2-tai-
led). Categorical variables were expressed as counts (percenttages) and com-
pared by means of a χ2 statistic. A p value < 0.05 was considered statistically
significant.
Results
Patients’ characteristics
The perfusional characteristics of the studied patients are shown in
Table 1. According to the findings of MPI on the stress study, they were divided
into two groups: group 1) with normal and near normal myocardial perfusion
(SSS 0–3); and group 2) with a mild to moderate perfusion defect (SSS 4–13),
as previously described (9). The two groups did not differ significantly in age,
type of stress, presence of most risk factors for CAD, previous myocardial
infarction and CABG. (Table 2).
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C-reactive protein in patients with normal… 71
Table 1 – Tabela 1
Perfusional characteristics of the patients
Perfuzioni karakteristiki na pacientite
Variables (n = 127) Range
SSS 3 ± 3.95 0–13
SRS 2.4 ± 3.8 0–20
SDS 1.4 ± 2.1 0–9
SSS – summed stress score; SRS – summed rest score;
SDS – summed difference score
Table 2 – Tabela 2
Characteristics of group 1 (SSS = 0–3) and group 2 (SSS = 4–13)
Karakteristiki na grupa 1 (SSS = 0–3) i grupa 2 (SSS = 4‡13)
Variables Group 1(n = 85) Group 2 (n = 42) p value
Age (y) 56.8 ± 10 58,4 ± 9 0.38
Hs-CRP 2.7 ± 2,3 4.2 ± 4.2 0.01
Sex (No. of males) 46 (54%) 33 (78,6%) 0.000*
Dipyridamole 43 (51%) 26 (62%) 0.2
DM 13 (15%) 11 (26%) 0.14
Hypertension 66 (78%) 33 (79%) 0.99
Smokers 6 (7%) 11 (26%) 0. 003
Hyperlipidaemia 23 (27%) 11/42 (26%) 0.9
PVD 6 (7%) 6 (14%) 0.2
Obesity 25 (29%) 18 (43%) 0.1
Previous MI 14 (16%) 12 (28.6%) 0.1
PCI 13 (15%) 15 (36%) 0.006
CABG 3 (3%) 4 (9%) 0.15
Hs-CRP – high sensitive C-reactive protein; DM – diabetes mellitus; PVD – peripheral
vascular disease; MI – myocardial infarction; PCI – percutaneous coronary intervene-
tions; CABG – coronary artery by-pass grafting
High sensitive C-reactive protein values
Levels of hs-CRP in group 1, compared to group 2, were significantly
lower (2.7 mg/L vs. 4.2 mg/L, p = 0.01). In group 2 there were significantly
more men (78.6% vs. 54%, p = 0.000*) and smokers (26% vs. 15%, p = 0.003),
also the rates of PCI were significantly higher (36% vs. 15%, p = 0.006).
More profound differences in hs-CRP levels were found when patients
with no perfusion defects in the stress study (group 1a, SSS = 0) were compared
to group 2. The mean hs-CRP level in the former group was 2.4 mg/L (p =
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72 Majstorov Venjamin, Pop Gjorceva Daniela et al.
0.008 vs. group 2). For the other variables similar results were obtained as
previously between group 1 and group 2 (Table 3).
Table 3 – Tabela 3
Characteristics of group 1a (SSS = 0) and group 2 (SSS = 4–13)
Karakteristiki na grupa 1a (SSS = 0) i grupa 2 (SSS = 4–13)
Variables Group 1a (n = 57) Group 2 (n = 42) p value
Age (y) 56.3 ± 10.4 58.4 ± 9 0.31
Hs-CRP 2.4 ± 2 4.2 ± 4.2 0.008
Sex (No. of males) 31 (54%) 33 (78.6%) 0.01
Dipyridamole 28 (49%) 26 (62%) 0.2
DM 8 (14%) 11 (26%) 0.12
Hypertension 46 (80%) 33 (79%) 0.8
Smokers 3 (5%) 11 (26%) 0.003
Hyperlipidaemia 12 (21%) 11 (26%) 0.5
PVD 3 (5%) 6 (14%) 0.13
Obesity 18 (32%) 18 (43%) 0.24
Previous MI 8 (14%) 12 (28.6%) 0.08
PCI 7 (12%) 15 (36%) 0.006
CABG 2 (3.5%) 4 (9%) 0.2
Abbreviations as in Table 2.
Discussion
Interest in inflammatory markers, especially for CRP as a novel marker
in the assessment of cardiovascular risk and the presence of CAD, has gained
great attention in the past few years [3, 6]. To the best of our knowledge, this is
the first study that has looked into the levels of C-reactive protein in patients
who have undergone MPI, and showed that even mild to moderate perfusion
defects are followed with an increase of CRP.
The only variables that were significantly different between the patients
with normal/near normal myocardial perfusion and mild to moderate perfusion
defects were male gender, percentage of smokers and percutaneous coronary
interventions (PCI). Concerning the gender, it is well known that the prevalence
of CAD among men is higher compared to women [10], which was again con-
firmed by the results of our study.
Elevated levels of C-reactive protein, interleukin-6, fibrinogen and ot-
her inflammatory markers have been found in smokers in numerous studies,
verifying a low-grade systemic inflammation in this population [11]. On the
other hand, long-term smokers have a higher prevalence of atherosclerosis. In a
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C-reactive protein in patients with normal… 73
large group of patients with established coronary heart disease, Benderly et al.
found that elevated CRP levels in both sexes were associated with smoking, co-
morbidities, lower education level, and the use of cardiovascular drugs [12].
This could explain to some extent the higher levels of CRP in our patients with
mild to moderate perfusion defects.
Results from the large prospective Prevention of Renal and Vascular
Endstage Disease (PREVEND) study, in more than 8000 subjects without pre-
vious documented CAD, have shown that baseline CRP levels were associated
with angiographic characteristics and clinical consequences of plaque instability
in those who had coronary events and underwent coronary angiography during
the follow up of 6 years [13]. CRP contributed significantly to the multivariate
model after adjustment for age, gender, smoking, lipids and blood pressure. On
the basis of these finding, we can speculate that higher CRP levels in our sub-
jects with perfusion defect may be associated with the process of atherosclerosis
per se.
Another potential confounding factor in our study was the increased
rate of percutaneous coronary interventions (PCI) in patients with mild to mode-
rate perfusion defects. Systemic markers of inflammation increase after PCI and
the rise in inflammatory markers after PCI is attributed to the inflammatory
stimulus associated with coronary artery injury during balloon inflation and
coronary stent implantation.
It was shown that even diagnostic coronary angiography performed in
patients with stable angina triggers a systemic inflammatory response [14]. In
the same study there was a significant increase in CRP levels at 24 and 48 hours
in both the coronary angiography group (patients who underwent only diagno-
stic coronary angiography) and PCI group (patients who underwent PCI). At 4
weeks, CRP returned to baseline levels in both groups. Our study included only
patients with remote PCI, a minimum of 6 months prior to the myocardial per-
fusion study. This period was long enough, we believe, for the inflammatory
response related to PCI to subside.
Conclusion
The results of our study indicated that patients with mild to moderate
perfusion defects on stress myocardial perfusion SPECT imaging have signi-
ficantly higher levels of C-reactive protein, compared to those with normal/near
normal myocardial perfusion.
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74 Majstorov Venjamin, Pop Gjorceva Daniela et al.
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Rezime
C-REAKTIVEN PROTEIN KAJ PACIENTI SO NORMALNA
PERFUZIJA I LESNI DO UMERENI PERFUZIONI ISPADI
ISPITUVANI SO MIOKARDNA PERFUZIONA
SCINTIGRAFIJA SO 99M-Tc SESTAMIBI GATED SPECT
Majstorov Venjamin,1 Pop \or~eva Daniela,1 Vaskova Olivija,1
Vavlukis Marija,2 Peovska Irena,2 Maksimovi} Jelena,2
Kuzmanovska Sowa,1 Zdraveska-Ko~ovska Marina1
1 Institut za patofiziologija i nuklearna medicina,
Skopje, R. Makedonija
2 Institut za srcevi zaboluvawa, Medicinski fakultet,
Skopje, R. Makedonija
Apstrakt: Visoko senzitivniot C-reaktiven protein (CRP) vo
poslednite godini ~esto se koristi za pokompletna procena na kardio-
vaskularniot rizik. Pronajdena e zna~ajna povrzanost pome|u poka~eniot
CRP, od edna strana, i prevalencata na koronarnata arteriska bolest (KAB)
i nesakanite srcevi zbidnuvawa, od druga strana. So stres miokardnata
SPECT perfuziona scintitomografija (MPS) e potvrdena neinvazivna
metoda za detekcija na KAB.
Celta na studijata be{e da utvrdime dali postojat razliki vo ni-
voata na CRP pome|u pacientite so normalna miokardna perfuzija i onie
so lesni do umereni perfuzioni ispadi, detektirani so 99m-Tc sestamibi gated
SPECT MPS.
Prospektivno bea ispitani 127 pacienti (79 ma`i, 48 `eni) sus-
pektni za KAB ili so prethodno potvrdena KAB, upateni za MPS. Sogla-
sno naodite od stres studijata, tie bea podeleni vo dve grupi: so normal-
na/skoro normalna miokardna perfuzija (n = 85) i so lesen do umeren per-
fuzionen ispad (n = 42). Vrednostite na CRP vo prvata grupa bea signifi-
kantno poniski (2,7 mg/L vs. 4,2 mg/L, p = 0,01). Zna~itelno pove}e ispita-
nici od grupata so lesen do umeren perfuzionen ispad bea ma`i (78,6% vs.
54%, p = 0,000*) i pu{a~i (26% vs. 15%, p = 0,003), isto taka brojot na perku-
tanite koronarni intervencii (PKI) be{e zna~itelno povisok (36% vs.
15%, p = 0,006). Ne be{e utvrdena zna~ajna razlika pome|u dvete grupi po
Prilozi, Odd. biol. med. nauki, XXIX/1 (2008), 67–76

76 Majstorov Venjamin, Pop Gjorceva Daniela et al.
Contributions, Sec. Biol. Med. Sci., XXIX/1 (2008), 67–76
odnos na vozrasta, vidot na primenetiot stres, prisustvoto na pove}eto
rizik faktori za KAB, kako i zastapenosta na miokardni infarkti i
aorto-koronarni premostuvawa.
Rezultatite od na{ata studija poka`aa deka pacientite so lesen do
umeren perfuzionen ispad na stres miokardnata perfuzija imaat signifi-
kantno povisoki vrednosti na CRP, sporedeno so onie koi imaat nor-
malna/skoro normalna miokardna perfuzija.
Klu~ni zborovi: C-reaktiven protein, koronarna bolest, dijagnosti~ki
vizuelizacioni tehniki.
Corresponding Author:
Majstorov Venjamin, MD., Ms
Pathophysiology and Nuclear Medicine Institute,
Vodnjanska 17
Skopje, R. Macedonia
Tel. 02/3112-831; 070/275-856
E-mail: venmaj@mt.net.mk