Coronary Heart Disease

Association Between Coronary Artery

Ectasia and NeutrophilLymphocyte Ratio
Sevket Balta, MD
1
, Sait Demirkol, MD
1
, Turgay Celik, MD
1
,
Ugur Kucuk, MD
1
, Murat Unlu, MD
2
, Zekeriya Arslan, MD
3
,
Ilknur Balta, MD
4
, Atila Iyisoy, MD
1
, Necmettin Kocak, MD
5
,
Hamidullah Haqmal, MD
1
, and Mehmet Yokusoglu, MD
1
Abstract
Atherosclerosis plays an important role in the etiopathogenesis of coronary artery ectasia (CAE). Inflammation markers may play
a part in the pathogenesis of CAE. We aimed to assess the association between the CAE and the neutrophillymphocyte (N/L)
ratio. Consecutive eligible patients (n 181) were divided into 3 groups: patients with CAE, those with newly diagnosed coronary
artery disease (CAD), and those with a normal coronary angiogram. The N/L ratio and mean platelet volume (MPV) were
measured as part of the automated complete blood count. There were no statistically significant differences in N/L ratio and MPV
between the CAE and the CAD groups. The N/L ratio and MPV were significantly higher in patients in both CAE and CAD groups
compared to those in the control group (P < .01). An increased N/L ratio may play a role not only in the pathogenesis of CAD but
also in the pathophysiology of CAE.
Keywords
coronary artery ectasia, atherosclerosis, neutrophil/lymphocyte ratio, mean platelet volume
Introduction
The most commonly used angiographic criterion for the defini-
tion of coronary artery ectasia (CAE) is the diameter of the ecta-
tic segment being at least 1.5 times larger compared to an
adjacent healthy segment.
1
The term ectasia is reserved to mean
a diffuse dilatation of a coronary artery, whereas an aneurysm is
a focal dilatation. Although the incidence may overestimate the
true frequency in the general population, CAE has been found
in 1% to 5% of the patients undergoing coronary angiography.
2
It is a form of coronary artery disease (CAD) yet puzzling the
clinicians regarding its cause, natural course, and treatment.
2
In 85%of the cases, CAE is accompanied by atherosclerotic
CAD.
3
Furthermore, they share common histopathological
characteristics of chronic low-grade vascular inflammation.
4
Inflammatory markers, such as C-reactive protein (CRP),
erythrocyte sedimentation rate, and interleukin 6 (IL-6) have
been found to increase significantly in atherosclerotic CAD and
to be associated with higher CAD morbidity and mortality.
5,6
Platelets, the counts and dimensions of subgroups of cells, and
parameters like the mean platelet volume (MPV) may be a link
in the pathophysiology of diseases prone to thrombosis and
inflammation. The MPV is the most commonly used measure
of platelet size.
7
The total white blood cell (WBC) count and its subtypes,
neutrophillymphocyte (N/L) ratio can be an indicator of sys-
temic inflammation.
8
The N/L ratio has also been demonstrated
to have a predictive power for death, myocardial infarction, and
high risk of CAD.
9
High N/L ratios are independently related to
increased cardiovascular events. These findings were sup-
ported by other studies.
10,11
In patients admitted for angio-
plasty, N/L ratio is an independent predictor of long-term
mortality.
12
Moreover, those clinical studies have shown a
possible relationship between N/L ratio and systemic
inflammation.
Although preliminary data have shown that N/L ratio is a
predictor of long-term cardiovascular risk, its role and impor-
tance in CAE have not been thoroughly evaluated. The purpose
of the present study is to determine the association between
CAE and N/L ratio.
1
Department of Cardiology, Gulhane Medical Academy, Ankara, Turkey
2
Department of Cardiology, Beytepe Hospital, Ankara, Turkey
3
Department of Cardiology, Gelibolu Hospital, Canakkale, Turkey
4
Department of Dermatology, Kecioren Training and Research Hospital,
Ankara, Turkey
5
Department of Public Health, Gulhane Medical Academy, Ankara, Turkey
Corresponding Author:
Sevket Balta, Department of Cardiology, Gulhane School of Medicine, Tevfik
Saglam St, 06018 Etlik, Ankara, Turkey.
Email: drsevketb@gmail.com
Angiology
64(8) 627-632
The Author(s) 2013
Reprints and permission:
sagepub.com/journalsPermissions.nav
DOI: 10.1177/0003319713480424
ang.sagepub.com
Material and Methods
Patient Selection
Between December 2010 and November 2012, patients were
selected from those undergoing coronary angiography in a ter-
tiary referral center due to suspicion of CAD. The study group
included 53 patients (33 men; mean age: 52.5 + 7.9 years)
with isolated CAE who had obstructive epicardial lesions
<20%. The CAD group consisted of 61 patients (44 men; mean
age: 52.4 + 4.8 years) with newly diagnosed CAD (stenotic
lesion 50%). The control group consisted of 67 participants
(45 men; mean age: 50.1 + 6.8 years) selected consecutively
from catheterized patients (during the same study period) with
normal coronary angiograms.
All participants were questioned for any cardiovascular drug
use, smoking, and alcohol consumption. All the groups were
evaluated by physical examination and biochemical analysis
and underwent transthoracic echocardiography for analysis of
structural heart disease. Hypertension was considered present
if systolic blood pressure was >140 mmHg and/or diastolic pres-
sure >90 mm Hg or if the individual was taking antihypertensive
medication. Diabetes was defined as a fasting blood glucose
level >126 mg/dL or current diet or medication to lower blood
glucose. Cigarette smoking was defined as >10 cigarettes/d at
the time of diagnosis. Image acquisition was performed in the
left lateral decubitus position using a Philips (iE33 6.0, Andover,
MA, USA) equipped with a 2.5-MHz transducer.
Exclusion criteria were refusal to participate in the study,
uncontrolled hypertension, anemia, uncontrolled diabetes
mellitus, left ventricular dysfunction (left ventricular ejection
fraction <50%) or hypertrophy, acute coronary syndromes,
valvular heart disease, congenital heart disease, abnormal thyr-
oid function tests, renal or hepatic dysfunction (creatinine > 1.5
mg/dL, aspartate aminotransferase and alanine transaminase
>2 the upper limit of normal, respectively), known malig-
nancy, local or systemic infection, previous history of infection
(<3 months), inflammatory diseases, and any medication that
could potentially interfere with measurement of N/L ratio and
MPV. The patients who had coronary stenotic lesions of >20%
as a CAD were also excluded from the CAE group.
13
The study was conducted in accordance with the Helsinki
Declaration. The local ethics committee approved the protocol.
Informed consent was obtained from all the study participants.
Assessment of CAE/Aneurysms
Coronary angiograms were performed via a femoral approach
using the Judkins technique without the use of nitroglycerin,
adenosine, or calcium channel blocker. All patients underwent
elective coronary artery angiography using Siemens Axiom
Artis DFC (Siemens Medical Solutions, Erlangen, Germany)
following appropriate preparation. Angiograms were recorded
on DICOM digital media (Siemens Medical Solutions, Erlan-
gen, Germany; 25 frames/ms) and were reviewed by 2
experienced angiographers who were unaware of the clinical
information. The CAE was defined as dilation of the coronary
artery >1.5-fold the diameter of the adjacent normal coronary
vessels.
14
The CAE classification, previously described by
Markis et al, was used.
3
In decreasing order of severity, diffuse
ectasia of 2 or 3 vessels was classified as type I, diffuse disease
in 1 vessel and localized disease in another vessel as type II,
diffuse ectasia of 1 vessel only as type III, and localized or seg-
mental ectasia as type IV.
Biochemical Measurements
Blood samples were drawn without stasis at 7 to 8 AM after 20
minutes of supine rest, following fasting for 12 hours. Total
plasma cholesterol, triglyceride, and high-density lipoprotein
cholesterol were measured by an enzymatic colorimetric
method using an Olympus AU 600 autoanalyzer and reagents
from Olympus Diagnostics GmbH (Hamburg, Germany).
Low-density lipoprotein cholesterol levels were calculated by
the Friedewald formula. Blood glucose was measured by the
glucose oxidase method. The blood was collected in tripotas-
sium EDTA (7.2 mg) tubes. We analyzed the blood samples
of all of the groups using an automatic blood counter immedi-
ately. Hematological parameters, including hemoglobin (Hb),
WBC count, platelet count, and MPV, were analyzed by LH
780 analyzer (Beckman Coulter Inc, Miami, Florida).
Statistical Analysis
Continuous variables are expressed as mean +standard devia-
tion, median (minimum-maximum), and categorical variables
were defined as frequency, percentage. Data were tested for
normal distribution using Kolmogorov-Smirnov test. One-
way analysis of variance or Kruskal-Wallis test was used for
the comparison of continuous variables as appropriate. Tukey
test or Bonferroni-corrected Mann-Whitney U was used for
post hoc analysis. Chi-square test was used for the comparison
of categorical variables. Correlation between mean MPV and
N/L ratio was assessed by the Pearson correlation test. Statisti-
cal significance was defined as P < .05 2 sided. The SPSS
statistical software (windows 15.0; SPSS Inc, Chicago, Illinois)
was used for all calculations.
Results
The main characteristics of the study population are shown in
Table 1. Age, body mass index, lipid profiles, fasting levels
of glucose, and used medications including statins were similar
among all 3 groups. Regarding clinical parameters, only
systolic blood pressure was significantly higher in patients with
CAE compared to the other groups (Table 1). All other coron-
ary risk factors including smoking were similar between all the
groups.
Neutrophil/lymphocyte ratio levels were significantly
higher in patients with CAE and CAD than in the control group
(Table 2 and Figure 1: 2.41 +1.19, 2.52 +1.30, and 1.90 +
0.77, respectively, P .003). There was no significant differ-
ence in N/L ratio level among the subgroups defined according
to CAE severity.
628 Angiology 64(8)
Patients with CAD and CAE had significantly higher MPV
compared to control participants (8.76 + 0.64, 8.77 + 0.63,
and 8.27 + 0.73 fL, respectively, P < .001; Table 2 and Fig-
ure 2). According to CAE severity, there was no significant dif-
ference in N/L ratio and MPV among the subgroups. Regarding
correlation analysis, there was a moderate positive correlation
between N/L ratio and MPV (r .307, P .046).
Discussion
We demonstrated that the N/L ratio and MPV were signifi-
cantly increased not only in patients with CAD but also in
patients with CAE compared to the control participants. These
results suggest elevated serum N/L ratio, and MPV levels may
be associated with the atherosclerotic process, inflammation,
and endothelial dysfunction of CAE.
Although the underlying mechanism of abnormal luminal
dilatation is not fully understood, yet the histopathological
characteristics of CAE are similar to those of coronary athero-
sclerosis. So, it is not surprising that hypothesis for the etio-
pathogenesis of CAE is related to vascular endothelial
dysfunction and inflammation.
15
Recent studies have reported
that elevated levels of inflammatory indicators are markers of
atherosclerotic disease activity and also indicate an increased
risk of the progression of atherosclerosis.
15,16
The importance
of CAE lies in the fact that in 85% of the cases, it is accompa-
nied by atherosclerotic CAD. This inflammatory response in
CAE is presented as elevated inflammatory cytokines and
differential leukocyte count. Tokgozoglu et al
6
in their study
of patients with CAE found that serum IL-6 levels were
significantly higher in patients with CAE compared to normal
participants. Turhan et al
5
found increased plasma CRP levels
in patients with isolated CAE compared to patients with
obstructive CAD without CAE and patients with angiographi-
cally normal coronary arteries. Yilmaz et al
17
reported that
patients with isolated CAE have raised levels of plasma soluble
intercellular adhesion molecule-1 (ICAM-1), vascular cell
adhesion molecule-1 (VCAM-1), and E-selectin in comparison
to patients with obstructive CAD without CAE and control
Table 1. Baseline Demographic, Clinical, and Biochemical Parameters of All Groups.
a
CAE Group (n 53) CAD Group (n 61) Control Group (n 67) P
Age, years 52.5 + 7.9 52.4 +4.8 50.1 + 6.8 .068
Sex (M), n (%) 33 (62) 44 (72) 45 (67) .533
Diabetes mellitus, n (%) 13 (24) 14 (23) 20 (29) .647
Dyslipidemia, n (%) 26 (49) 30 (49) 25 (37) .181
BMI, kg/m
2
31.1 + 3.4 29.7 +3.6 30.9 + 4.6 .115
Hypertension, n (%) 16 (30) 18 (29) 10 (14) .078
SBP, mm Hg
b
136.2 + 12.3 133.0 +11.0 129.7 + 10.0 .012
DBP, mm Hg
b
81.8 + 8.9 81.9 +7.2 80.3 + 8.8 .468
Alcohol consumption, n (%) 6 (11) 9 (14) 5 (7) .420
Smoking, n (%) 27 (50) 32 (52) 23 (34) .074
Total cholesterol, mg/dL 191 + 25 196 +25 186 + 18 .051
LDL-cholesterol, mg/dL 118 + 25 124 +25 115 + 20 .071
Triglyceride, mg/dL 149 + 72 154 +53 150 + 54 .966
HDL-cholesterol, mg/dL 47 + 8 44 +7 45 + 10 .273
Glucose, mg/dL 102 + 20 97 +16 95 + 14 .091
Urea, mg/dL 30.83 + 10.84 30.63 +9.88 33.05 + 8.92 .324
Creatinine, mg/dL 0.93 + 0.16 0.94 +0.17 0.93 + 0.16 .922
AST, U/L 26 + 13 26 +13 27 + 13 .928
ALT, U/L 27 + 14 30 +16 29 + 15 .940
Ectasia group
I 4
II 8
III 24
IV 9
Abbreviations: CAE, coronary artery ectasia; CAD, coronary artery disease; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure;
LDL, low-density lipoprotein; HDL, high-density lipoprotein; ALT, alanine transaminase; AST, aspartate transaminase; SD, standard deviation.
a
Values are mean +SD or n (%).
b
It is measured during diagnostic coronary angiography.
Table 2. Comparison of the Hematologic Parameters Among the
Study Groups.
a
CAE Group
(n 53)
CAD Group
(n 61)
Control
Group
(n 67) P
WBC, mm
3
7532 + 1475 7463 + 1381 7358 + 1472 .800
N/L ratio 2.41 + 1.19 2.52 + 1.30 1.90 + 0.77 .003
MPV, fL 8.76 + 0.64 8.77 + 0.63 8.27 + 0.73 <.001
Platelet
count, 10
9
/L
254 + 67 250 + 57 257 + 70 .861
Abbreviations: CAE, coronary artery ectasia; CAD, coronary artery disease;
WBC, white blood cell; N/L, neutrophils to lymphocytes; MPV, mean platelet
volume; SD, standard deviation.
a
Values are mean +SD.
Balta et al 629
participants with normal coronary arteries. Turhan et al
18
found
that patients with CAE with or without obstructive CAD have
elevated plasma levels of ICAM-1 and VCAM-1 compared to
patients with normal coronary artery and obstructive CAD.
A complete blood count is an easy and cheap examination.
The MPV is the most commonly used measure of platelet size.
7
Platelet activation is a link to thrombosis and inflammation. The
MPV has been investigated in connection with both thrombosis
and inflammation.
19
The MPV is an indicator of platelet activa-
tion, which is central to processes involved in CAD pathophy-
siology and endothelial dysfunction.
20,21
Similar to a previous
study, we have shown that MPV is higher in patients with CAE
and CAD compared to those of controls.
22
The N/L ratio is
another simple and easy accessible inflammatory marker.
23
The association between N/L ratio and atherosclerosis in the
general population has been poorly understood. The relation-
ship between N/L ratio and CAE is not precisely defined, but
inflammation and oxidative stress are likely to play a role.
We considered that inflammation is associated with endothelial
dysfunction and atherosclerosis in patients with CAE. The
WBC count is one of the useful inflammatory biomarkers in
clinical practice. Leukocyte subtype and N/L ratio are also
indicators of systemic inflammation.
10,11,24
These markers
have prognostic importance in cardiovascular disease.
The relation between atherosclerosis progression and leuko-
cyte subtype was evaluated in a previous study. The N/L ratio is
determined to be a more accurate marker of cardiac adverse
events rather than differential leukocyte count.
12
Progression
rate was significantly high in patients with high N/L ratio, and
it was a predictor of progression of atherosclerosis.
25
More
recently, N/L ratio has been proposed as a useful biomarker
to predict cardiovascular risk.
26
In addition, the relation
between inflammation and early marker of CAD, including
metabolic syndrome (MetS)
27
and cardiac syndrome X
(CSX),
21
CAE was evaluated in a previous study.
28
The N/L
ratio in MetS and CSX may be the early markers of developing
cardiovascular events.
29,30
Zazula et al
31
investigated the
relation between N/L ratio and the patient with suspicion of
acute coronary syndrome. The N/L ratio was significantly higher
in patients with unstable angina, ST-segment elevation myocar-
dial infarction (STEMI), and non-STEMI groups compared to
patients diagnosed with noncardiac chest pain. The N/L ratio has
also been associated with poor outcomes in patients who under-
went coronary angiography. The maximum N/L ratio value may
be a useful marker to predict subsequent mortality in patients
admitted for STEMI.
32
The N/L ratio levels give independent
information about CAD severity in patients with acute myocar-
dial infarction.
33
The N/L ratio is independently associated with
CAD severity and 3-year follow-up outcomes.
34
It is also a
significant independent predictor of major adverse cardiac
events (MACEs) in diabetic patients.
35
Neutrophillymphocyte ratio may appear additive to
conventional risk factors and commonly used biomarkers.
Inflammation plays a crucial role in the pathogenesis of in-
stent restenosis. In a previous study, Turak et al
36
investigated
the N/L ratio in patients undergoing coronary stent implanta-
tion. The authors found higher N/L ratio in patients with a high
rate of stent restenosis compared to patients with a low rate of
stent restenosis. Although WBCs are in the normal range, sub-
types of WBCs may predict cardiovascular mortality. The N/L
ratio is also an inflammatory marker of MACEs in both acute
coronary syndromes and stable CAD. The lowest N/L ratio had
fewer MACEs compared to the highest N/L ratio.
35
The N/L
ratio was a strong independent predictor of long-term mortality
after STEMI treated with very early revascularization.
37
Inhos-
pital MACEs were significantly higher in patients with no
Figure 2. Comparison of Neutrophil/lymphocyte ratio levels of
patients among the 3 groups. Neutrophil/lymphocyte ratio levels were
significantly higher in patients with coronary artery ectasia and
coronary artery disease than in the control group.
Figure 1. Comparison of Neutrophil/lymphocyte ratio levels of
patients among the 3 groups. Neutrophil/lymphocyte ratio levels were
significantly higher in patients with coronary artery ectasia and
coronary artery disease than in the control group.
630 Angiology 64(8)
reflow, and there was a significant and positive correlation
between high-sensitivity CRP and N/L ratio.
38
Gibson at al
39
investigated leukocyte subtypes such as the N/L ratio in
patients with undergoing CABG. An elevated N/L ratio is asso-
ciated with a poor survival after CABG. Hartaigh et al
40
inves-
tigated the relation between N/L ratio and cardiovascular
mortality. The authors found a significant relationship between
N/L ratio and cardiovascular deaths. It is therefore possible that
specific subtypes such as the N/L ratio may contribute to the
prediction of cardiovascular outcomes.
Because of all of these interactions, etiology of the relation-
ship between N/L ratio and CAE may be inflammation and
atherosclerosis. Therefore, we aimed to investigate the N/L
ratio in patients with CAE and CAD compared to normal
participants. In the present study, N/L ratio and MPV were sig-
nificantly increased in patients with CAE. There were positive
correlations between MPV and N/L ratio in our study. Hence,
N/L ratio was used in routine clinical practice as an inflamma-
tory marker. It suggests that endothelial dysfunction and ather-
osclerosis may modulate the effect of CAE risk factors.
The main limitation of our study was the relatively small
sample size. We also did not analyze markers of inflammation
such as CRP, although the role of inflammation was previously
reported in these patients. Finally, intravascular ultrasound
(IVUS) provides more precise values about the presence and
distribution of atherosclerosis in vessel lumen and throughout
the wall. We did not have the opportunity to perform IVUS
in this study.
Our findings show that patients with CAE have significantly
increased N/L ratios. These data suggest that the N/L ratio is
higher in patients with CAE and CAD compared to patients
with otherwise normal coronary angiograms. The relation
between CAE and higher N/L ratio suggests that, besides
endothelial dysfunction, the presence of atherosclerosis may
also contribute to the etiopathogenesis of CAE. Further studies
are needed to clarify the role of N/L ratio in CAE complicated
CAD, especially in relation to angiographic and clinical
parameters.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
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