Auris Nasus Larynx 41 (2014) 179–184

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Auris Nasus Larynx

journal homepage: www.elsevier.com/locate/anl

Assessment of early atherosclerotic findings in patients with nasal

polyposis
Mustafa Sagit a,*, Bahadir Sarli b, Sabri Guler a, Mehmet Namuslu c, Huseyin Tugrul Celik c,
Serkan Kurtul b, Ferhat Korkmaz a, Mehmet Akif Somdas a
a
Kayseri Training and Research Hospital, Department of ENT, Turkey
b
Kayseri Training and Research Hospital, Department of Cardiology, Turkey
c
Turgut Ozal University School of Medicine, Department of Biochemistry, Turkey

A R T I C L E I N F O A B S T R A C T

Article history: Objective: To investigate early markers of atherosclerosis in patients with nasal polyposis (NP) through
Received 8 March 2013 measurements of carotid artery intima-media thickness (CIMT), flow-mediated vasodilatation (FMD) of
Accepted 20 September 2013 the brachial artery and serum paraoxonase-1 (PON-1) activity.
Available online 19 October 2013
Methods: Forty-five patients with NP were included in the study group and 45 healthy individuals in the
control group. The diagnosis of patients with NP was predicated on anterior rhinoscopy, endoscopic
Keywords: nasal examination and coronal paranasal sinus computed tomography (CT). Measurements of CIMT and
Nasal polyposis
FMD of the brachial artery were performed by high-resolution ultrasonography. Serum PON-1 activity
Carotid artery intima-media thickness
Flow-mediated vasodilatation
was evaluated by measuring the rate of paraoxon hydrolysis.
Paraoxonase Results: Mean CIMT values were found to be increased in the NP group compared to the control group.
Atherosclerosis However, mean FMD % values and serum PON-1 activity were significantly lower in the NP group
compared to the control group. Moreover; the endoscopic polyps’ scores and paranasal sinus CT scores
were positively correlated with CIMT and negatively correlated with FMD % values and PON-1 activity.
Disease duration also was positively correlated with CIMT and negatively correlated with FMD % values.
Conclusion: Impaired FMD, increased CIMT and decreased serum PON-1 activity may be considered to be
risk factors for accelerated atherosclerosis in patients with NP who may have subclinical atherosclerosis
and be at risk for cardiovascular events in the future.
ß 2013 Elsevier Ireland Ltd. All rights reserved.

1. Introduction association between NP and atherosclerosis has not been

investigated in detail [5–7].
Nasal polyposis (NP) is a chronic inflammatory disease of the Endothelial dysfunction as an early sign of atherosclerosis can
nasal and paranasal sinus mucosa. It frequently occurs bilaterally be evaluated non-invasively as an impairment of flow-mediated
and causes chronic nasal obstruction, rhinorrhoae and anosmia [1]. vasodilatation (FMD) of the brachial artery in high-resolution
Chronic nasal obstruction caused by NP may lead to increased ultrasonography [8]. FMD is defined as the percentage change in
upper respiratory tract resistance. This condition may result in brachial artery diameter from baseline to reactive hyperemia (FMD
cardiovascular complications. Systemic hypertension and in- %) [9,10]. An impairment of FMD is considered a sign of endothelial
creased pulmonary arterial pressure have been shown in patients dysfunction and is a predictor of future cardiovascular events
with NP [2,3]. In cases with NP, cardiopulmonary symptoms are [11,12].
usually mild or absent. However, chronic changes without marker Another clinically useful method that may indicate subclinical
symptoms may gradually occur [2,4]. Atherosclerosis has an atherosclerosis is the measurement of carotid artery intima-media
important role in this process. Numerous studies have demon- thickness (CIMT) by high-resolution ultrasonography [13]. In-
strated an association between obstructive sleep apnea syndrome creased CIMT is considered a marker of future cardiovascular and
(OSAS) and increased risk of atherosclerosis; however, the cerebrovascular events [14]. There is evidence of a correlation
between CIMT and cardiovascular disease, especially coronary
heart disease [15,16].
Paraoxonase-1 (PON-1) is synthesized in the liver and is a Ca2+-
* Corresponding author at: Kayseri Eğitim ve Araştırma Hastanesi, KBB Kliniği,
dependent serum esterase [17]. It primarily complexes with high-
Sanayi Mah. Atatürk Bulvarı Hastane Cad. No: 78, 38010 Kayseri, Turkey.
Tel.: +90 352 336 88 84; fax: +90 352 320 73 13.. density lipoprotein (HDL) and is responsible for the antioxidant
E-mail address: [email protected] (M. Sagit). activity of HDL [18]. PON-1 plays an important role in the protection

0385-8146/$ – see front matter ß 2013 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.anl.2013.07.013
180 M. Sagit et al. / Auris Nasus Larynx 41 (2014) 179–184

of LDL and HDL from oxidation by hydrolyzing cell membrane lipids, p-nitrophenylphosphate) was measured by monitoring the in-
an important step in atherosclerosis [19,20]. Also, previous studies crease of absorbance at 412 nm at 37 8C. The amount of generated
have demonstrated that PON-1 activity is related to regulation of p-nitrophenol was calculated from the molar absorptivity coeffi-
endothelial functions [21]. Interestingly, PON-1 activity is decreased cient at pH 8, which was 17,000 M 1 cm 1 [25]. PON-1 activity was
in patients with hypercholesterolemia and type 2 diabetes mellitus, expressed as U/L serum.
which are risk factors for atherosclerosis [22].
The purpose of this study was to investigate early markers of 2.4. Flow mediated dilatation (FMD) measurement
atherosclerosis in patients with NP by the measurement of CIMT,
FMD of the brachial artery and serum PON-1 activity. In addition, Endothelial dysfunction was evaluated using FMD. An ultra-
we tried to find out whether early markers of atherosclerosis are sound probe with high frequency was used to obtain longitudinal
related with extension of polyps and disease duration. images of the brachial artery at a marked point 5–10 cm away from
the antecubital fossa (Siemens Medical Sol. Mountain View, CA).
2. Materials and methods All scans were done by the same examiner who was unaware of the
subject’s clinical status throughout the study. At baseline, two-
2.1. Study population dimensional images were gained to evaluate arterial diameter. For
inducing ischemia, a blood pressure cuff was inflated to 50 mm Hg
The study group was composed of 45 patients with nasal higher than systolic blood pressure for 5 min to occlude arterial
polyposis and the control group was composed of 45 healthy flow, and arterial diameter measurements were made within 60 s
subjects. Control subjects were recruited from the outpatient of cuff deflation. Arterial diameter was measured from the close
department of the Ear Nose Throat department in our hospital. wall to the remote wall at the intima-media interface or to the
Prior to subject enrollment, the study was approved by the ethics clearest echocardiography line. Images were obtained in end
committee of the Erciyes University Medical School, and written diastole with electrocardiogram gating. Measurements were
informed consent was obtained from each participant. reported as % change in diameter.
The diagnosis of patients with NP was predicated on anterior
rhinoscopy, endoscopic nasal examination and coronal paranasal 2.5. Carotid artery intima-media thickness measurement
sinus computed tomography (CT). The control group was also
examined for evidence of any paranasal sinus disease by anterior Carotid artery intima-media thickness (CIMT) measurements
rhinoscopy and endoscopic nasal examination. The Lund–Kennedy were made in the left lateral supine position while the neck was
staging system was used to stage nasal polyps in both nasal extended and the chin was turned away from the side being
cavities, based on the endoscopic appearances. Stage 0 for the examined. The left and right common carotid arteries were imaged
absence of polyp, stage 1 for polyps not prolapsing beyond the proximal to the bulb after obtaining the clearest visualization of
middle turbinate, stage 2 for polyps extended below the middle the IMT of the far wall. The mean IMT measurement was
turbinate, stage 3 for massive polyps occluding the entire nasal performed by manual tracing of the intima-media in the far wall
cavity and resulting in a maximum score of 3 per side [23]. The of the artery. The average of three end diastolic measurements was
Lund–Mackay staging system was used in the assessment of used for analysis. The mean value of the two sides (left and right)
paranasal sinus CT scans. This system relies on a score of 0–2 was taken.
dependent on the absence, partial or complete opacification of
each sinus system and of the vital osteomeatal complex resulting 2.6. Statistical analysis
in a maximum score of 12 per side [24].
Exclusion criteria for all study participants included a history of All analyses were performed using SPSS 16.0 (SPSS for Windows
using topical or systemic corticosteroids in the previous 4 weeks, 16.0, Chicago, IL, USA). Continuous variables were defined as
smoking, alcohol abuse, hypertension, hypercholesterolemia, dia- mean  standard deviation. One-sample Kolmogorov–Smirnov test
betes mellitus, coronary heart disease, history of myocardial was used for adequacy of all parameters to normal distribution. If the
infarction, liver or renal disease, active infectious disease, bronchial distribution was normal, independent samples t test was used for
asthma, allergic rhinitis, major depression, neoplastic disease, statistical comparison of data between the two groups. If the
history of cerebrovascular disease or auto-immune disease such distribution was not normal, the Mann–Whitney U test was used.
as ankylosing spondylitis, systemic lupus erythematosus, rheuma- The Chi-square test was used to compare categorical variables
toid arthritis, or Behcet disease. Subjects taking any drug vasodila- between the two groups. The correlation between serum PON
tion or vasoactive substances or anti-oxidants such as anti-oxidant activity, mean CIMT values, brachial artery FMD values, disease
vitamins, angiotensin-converting enzyme inhibitors, beta-blocking duration, endoscopic polyps’ scores and CT scan scores was assessed
agents, diuretics or statins were also excluded from the study. by Spearman correlation analysis. A p value of less than 0.05 was
considered as statistically significant.
2.2. Blood sample collection
3. Results
Following a fasting period of 12 h, all blood samples were
collected in the morning from the antecubital vein. Blood samples The NP group comprised 29 men and 16 women with a mean
were immediately centrifuged at 3000 rpm for 10 min. Serum age of 41.58  10.7 years. The control group comprised 28 men and
samples were kept at 80 8C until analyses for measurement of 17 women with a mean age of 39.84  10.44 years. Age and sex
serum concentrations of total cholesterol, triglycerides, low- distribution were similar between the groups. The variables
density lipoprotein cholesterol (LDL-C), high-density lipoprotein triglycerides, total cholesterol, LDL-C and HDL-C were similar.
cholesterol (HDL-C) and serum paraoxonase-1 activity. However, serum PON-1 activity was significantly lower in the NP
group when compared to the control group (59.28  38.41 vs.
2.3. Measurement of serum paraoxonase-1 activity 114.68  58.41; p < 0.001) (Fig. 1). The demographic and clinical data
of the study population are presented in Table 1.
Measurement of serum PON-1 activity was performed in the Ultrasonographic results are presented in Table 2. The mean
absence of basal activity. The rate of paraoxon hydrolysis (diethyl- brachial artery diameter at baseline was 3.90  0.51 mm in NP
 M. Sagit et al. / Auris Nasus Larynx 41 (2014) 179–184 181

there was a significant negative correlation between CIMT and

FMD % values (r = 0.321; p = 0.032).
Disease duration was positively correlated with CIMT
(r = 0.486; p = 0.001) and negatively correlated with FMD % values
(r = 0.350; p = 0.018). However, there was no significant correla-
tion between serum PON-1 levels and disease duration
(r = 0.225; p = 0.138).
The endoscopic polyps scores were positively correlated with
CIMT (r = 0.414; p = 0.005) and negatively correlated with FMD %
values (r = 0.450; p = 0.002) and PON-1 activity (r = 0.428;
p = 0.003) (Fig. 4). Paranasal sinus CT scores were also positively
correlated with CIMT (r = 0.437; p = 0.003) and negatively corre-
lated with FMD % values (r = 0.495; p = 0.001) and PON-1 activity
(r = 0.309; p = 0.039) (Fig. 5).

4. Discussion

In this study we investigated whether early risk markers of

atherosclerosis are found in patients with NP. In the NP group, FMD
values and serum PON1 activity were significantly lower than in
Fig. 1. Comparison of serum paraoxonase-1 (PON-1) activity in nasal polyp (NP) the control group; on the other hand CIMT levels were significantly
patients compared with control group. higher (Figs. 1–3). Moreover; the endoscopic polyps scores and
paranasal sinus CT scores were positively correlated with CIMT and
negatively correlated with FMD % values and PON-1 activity. To the
patients and 3.76  0.46 mm in the control group. Measurements of best of our knowledge, there is no study that has assessed the
baseline brachial artery diameters showed no significant difference association between NP and cardiovascular disease by use of
between the two groups. In contrast, endothelium-dependent FMD markers of subclinical atherosclerosis.
was found to be impaired in patients with NP compared to control Although NP is a common disease, affecting 2%–4% of the
subjects. The mean FMD % values of the NP patients were significantly population [26], the main mechanism of the tendency to
lower compared to the controls (10.30  5.28 vs. 17.78  4.83; cardiovascular disease in NP patients has not been investigated
p < 0.001) (Fig. 2). On the other hand, the mean CIMT values were adequately. In cases of chronic nasal obstruction due to NP, the
found to be increased in the NP group compared to the control group condition may lead to increased upper respiratory tract resistance,
(0.75  0.15 mm vs. 0.64  0.11 mm; p < 0.001) (Fig. 3). which leads to chronic hypoxia and hypercapnia because of
There was no significant correlation between serum PON-1 alveolar hypoventilation [27,28]. This condition may continue
levels and CIMT values in NP patients (r = 0.095; p = 0.536). We toward the cardiovascular system complications of NP. It has also
also saw no significant correlation between serum PON-1 levels been shown that chronic intermittent hypoxemia is one of the
and FMD % values in NP patients (r = 0.003; p = 0.982). However, main factors for atherosclerosis in patients with OSAS [29] and

Table 1
Demographic characteristics and laboratory parameters of study groups.

Parameters NP patients (n = 45) Control subjects (n = 45) p value

Age (years) 41.58  10.70 39.84  10.44 0.439

Gender (male/female) 29/16 28/17 0.827
Disease duration (months) 48.73  30.05 _ _
Polyp scores 3.84  1.16 _ _
CT scores 13.91  5.51 _ _
Total cholesterol (mg/dl) 165.37  22.71 160.11  15.51 0.202
LDL-cholesterol (mg/dl) 111.57  25.99 105.64  20.52 0.233
HDL-cholesterol (mg/dl) 35.82  9.56 37.24  11.52 0.526
Triglyceride (mg/dl) 88.17  23.81 83.28  18.02 0.275
Paraoxonase-1 (U/L) 59.28  38.41 114.68  58.41 <0.001*

Abbreviations: LDL, low-density lipoprotein; HDL, high-density lipoprotein.

*
Statistical analysis was performed with Mann–Whitney U test; p < 0.001.

Table 2
Brachial artery and carotid artery IMT measurements in patients with NP and control subjects.

NP patients (n = 45) Control subjects (n = 45) p value

Brachial artery
Baseline diameter (mm) 3.90  0.51 3.76  0.46 0.191
FMD (%)* 10.30  5.28 17.78  4.83 <0.001**
Carotid artery
IMT (mm) 0.75  0.15 0.64  0.11 <0.001**

Abbreviations: NP, nasal poliposis; FMD, flow-mediated dilatation; IMT, intima-media-thickness.

*
Data are given as a percentage of change in baseline values.
**
Statistical analysis was performed with independent samples t test; p < 0.001.
182 M. Sagit et al. / Auris Nasus Larynx 41 (2014) 179–184

Fig. 2. Comparison of flow-mediated vasodilatation (FMD) of the brachial artery in Fig. 3. Comparison of carotid artery intima-media thickness (CIMT) in nasal polyp
nasal polyp (NP) patients compared with control group. (NP) patients compared with control group.

similar problems may occur in patients with NP. In this study, we reduced FMD in NP patients as compared to healthy control
demonstrated that the endoscopic polyps scores and paranasal subjects. We found a significant negative correlation between
sinus CT scores were positively correlated with CIMT and CIMT and FMD % values in NP patients. Increases of CIMT and
negatively correlated with FMD % values and PON-1 activity. decreases of FMD values in patients with NP may indicate
According to our findings, early markers of atherosclerosis levels subclinical atherosclerosis and present a risk for future cardiovas-
are related with the further growth of polyps. Eventually, the cular events. We also found that disease duration was positively
degree of nasal obstruction may associate with arising early correlated with CIMT and negatively correlated with FMD % values
markers of atherosclerosis in patients with NP. As is well known, in NP patients. This makes logic, because the development of
atherosclerosis is one of the most important problems in the atherosclerosis is time-dependent and progressive.
development of cardiovascular disease. NP is a chronic inflammatory disease and oxidative stress plays
Atherosclerosis can be assessed by both vascular functional and an important role in the pathogenesis of this disease [35,36]. It is
structural parameters. The measure of CIMT has been commonly well established that oxidative stress and inflammation have
used as an early marker of atherosclerosis in clinical and important roles in the development, progression, and outcome of
epidemiological studies [30,31]. The measurement of CIMT by atherosclerosis [37]. Oxidative stress affects normal endothelial
high-resolution ultrasonography is an applicable method for functions, inducing prothrombotic, proinflammatory, proliferative
evaluating subclinical atherosclerosis in the population. Increased and vasoconstrictor mechanisms that cause atherosclerosis [18].
CIMT is a reliable indicator of early atherosclerosis [14,32]. In the The PON-1 enzyme exhibits significant anti-oxidant properties and
present study, CIMT was increased in NP patients compared to plays a role in oxidative stress pathophysiology [18]. PON-1 is an
control subjects, indicating possible subclinical atherosclerosis. important enzyme for protecting LDL-C from oxidation; in the
Endothelial dysfunction represents a key early step in the pathogenesis of atherosclerosis, oxidized LDL has a critical role
development of atherosclerosis. It is characterized by a reduction leading to impaired endothelial function because of the reduced
of endothelium-derived vasodilators, especially nitric oxide, bioavailability of nitric oxide [38]. Therefore, PON-1 plays a role in
whereas vasoconstrictors are increased [11]. This can be evaluated regulation of endothelial function and the prevention of athero-
non-invasively as impairment of FMD of the brachial artery by genesis [21]. PON-1 activity has been shown to be decreased in
high-resolution ultrasonography [8]. Impaired FMD of the brachial disorders that have high cardiovascular risk, such as obesity,
artery is related to both cardiovascular risk factors and future familial hypercholesterolemia and diabetes mellitus [39]. It has
cardiovascular events [33,34]. In the present study, we observed also been shown that PON-1 activity is associated with coronary

Fig. 4. Correlation between endoscopic polyp scores and carotid artery intima-media thickness (CIMT), flow-mediated vasodilatation (FMD) and serum paraoxonase-1 (PON-
1) activity.
 M. Sagit et al. / Auris Nasus Larynx 41 (2014) 179–184 183

Fig. 5. Correlation between computed tomography (CT) scores and carotid artery intima-media thickness (CIMT), flow-mediated vasodilatation (FMD) and serum
paraoxonase-1 (PON-1) activity.

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