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Coronary Heart Disease

Association Between Coronary ArteryEctasia and NeutrophilLymphocyte Ratio

Sevket Balta, MD1

, Sait Demirkol, MD1

, Turgay Celik, MD1

,Ugur Kucuk, MD1, Murat Unlu, MD2, Zekeriya Arslan, MD3,

Ilknur Balta, MD4, Atila Iyisoy, MD1, Necmettin Kocak, MD5,

Hamidullah Haqmal, MD1, and Mehmet Yokusoglu, MD1

Abstract

Atherosclerosis plays an important role in the etiopathogenesis of coronary artery ectasia (CAE). Inflammation markers may playa 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 MPVbetween the CAE and the CAD groups. The N/L ratio and MPV were significantly higher in patients in both CAE and CAD groupscompared 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) havebeen 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, Turkey2 Department of Cardiology, Beytepe Hospital, Ankara, Turkey3 Department of Cardiology, Gelibolu Hospital, Canakkale, Turkey4 Department of Dermatology, Kecioren Training and Research Hospital,

Ankara, Turkey5 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

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DOI: 10.1177/0003319713480424

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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

140 mm Hg 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 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

(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 AMafter 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 forpost 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 similaramong 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.

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Patients with CAD and CAE had significantly higher MPVcompared 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 anddifferential leukocyte count. Tokgozoglu et al6 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 al5 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 al17 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 .068Sex (M), n (%) 33 (62) 44 (72) 45 (67) .533Diabetes mellitus, n (%) 13 (24) 14 (23) 20 (29) .647Dyslipidemia, n (%) 26 (49) 30 (49) 25 (37) .181

BMI, kg/m2 31.1+ 3.4 29.7+ 3.6 30.9+ 4.6 .115Hypertension, n (%) 16 (30) 18 (29) 10 (14) .078

SBP, mm Hgb 136.2+ 12.3 133.0+ 11.0 129.7+ 10.0 .012DBP, mm Hgb 81.8+ 8.9 81.9+ 7.2 80.3+ 8.8 .468

Alcohol consumption, n (%) 6 (11) 9 (14) 5 (7) .420Smoking, n (%) 27 (50) 32 (52) 23 (34) .074Total cholesterol, mg/dL 191+ 25 196+ 25 186+ 18 .051LDL-cholesterol, mg/dL 118+ 25 124+ 25 115+ 20 .071Triglyceride, mg/dL 149+ 72 154+ 53 150+ 54 .966HDL-cholesterol, mg/dL 47+ 8 44+ 7 45+ 10 .273Glucose, mg/dL 102+ 20 97+ 16 95+ 14 .091Urea, mg/dL 30.83+ 10.84 30.63+ 9.88 33.05+ 8.92 .324Creatinine, mg/dL 0.93+ 0.16 0.94+ 0.17 0.93+ 0.16 .922AST, U/L 26+ 13 26+ 13 27+ 13 .928

ALT, U/L 27+ 14 30+ 16 29+ 15 .940Ectasia group

I 4II 8III 24IV 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.aValues are mean+ SD or n (%).bIt is measured during diagnostic coronary angiography.

Table 2. Comparison of the Hematologic Parameters Among theStudy Groups.a

CAE Group(n 53)

CAD Group(n 61)

ControlGroup

(n 67) P

WBC, mm3 7532+ 1475 7463+ 1381 7358+ 1472 .800N/L ratio 2.41+ 1.19 2.52+ 1.30 1.90+ 0.77 .003MPV, fL 8.76+ 0.64 8.77+ 0.63 8.27+ 0.73

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participants with normal coronary arteries. Turhan et al18 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 alsoindicators 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 al31 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 al36

investigatedthe 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 weresignificantly higher in patients with coronary artery ectasia andcoronary 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 weresignificantly higher in patients with coronary artery ectasia andcoronary artery disease than in the control group.

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reflow, and there was a significant and positive correlation

between high-sensitivity CRP and N/L ratio.38 Gibson at al39

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 al40 inves-

tigated the relation between N/L ratio and cardiovascular

mortality. The authors found a significant relationship betweenN/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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e x p r e s s w r i t t e n p e r m i s s i o n . H o w e v e r , u s e r s m a y p r i n t , d o w n l o a d , o r e m a i l a r t i c l e s f o r

i n d i v i d u a l u s e .