AnatolJCardiol 15 8 640 647
AnatolJCardiol 15 8 640 647
AnatolJCardiol 15 8 640 647
Murat Yüksel, Abdulkadir Yıldız, Mustafa Oylumlu, Abdurrahman Akyüz, Mesut Aydın,
Hasan Kaya, Halit Acet, Nihat Polat, Mehmet Zihni Bilik, Sait Alan
Department of Cardiology, Faculty of Medicine, Dicle University; Diyarbakır-Turkey
ABSTRACT
Objective: In this study, we aimed to explore the association between platelet-to-lymphocyte ratio (PLR) and the severity of atherosclerosis in
coronary artery disease (CAD).
Methods: Clinical and laboratory data of 388 patients who underwent coronary angiography were evaluated retrospectively. Gensini score,
which indicates the severity of atherosclerosis, was calculated for all of the patients. Patients with CAD were categorized as mild and severe
atherosclerosis, according to their Gensini score. Eighty patients with normal coronary arteries formed the control group. Mean PLR values of
the three study groups were compared. Also, PLR value was tested for whether it showed a positive correlation with Gensini score.
Results: The mean PLR of the severe atherosclerosis group was significantly higher than that of the mild atherosclerosis and controls groups
(p<0.001). Also, PLR was positively correlated with Gensini score in CAD patients. A cut-off value of 111 for PLR predicted severe atherosclero-
sis with 61% sensitivity and 59% specificity. Pre-procedural PLR level was found to be independently associated with Gensini score, together
with WBC, age, and low HDL level, in the multivariate analysis.
Conclusion: Our study suggests that high PLR appears to be additive to conventional risk factors and commonly used biomarkers in predicting
severe atherosclerosis. (Anatol J Cardiol 2015; 15: 640-7)
Keywords: atherosclerosis, coronary artery disease, Gensini score, platelet-lymphocyte ratio
that presented with STEMI showed poorer outcomes compared Abbott Laboratory, Abbott Park, Illinois, USA). Plasma low-densi-
to the low PLR group, and PLR was found to be an independent ty lipoprotein cholesterol (LDL) concentrations were calculated
predictor of in-hospital mortality in patients with STEMI (17). using the Friedewald equation (18).
Gensini score was established to expose the severity and
extent of coronary atherosclerosis. There are many studies Coronary angiography and assessment of coronary
demonstrating the relationship between systemic inflammation atherosclerosis severity
and coronary atherosclerosis; however, to our knowledge, there Selective coronary angiography was performed for all
are no data about the relationship between PLR and severity of patients enrolled in the study by Judkins technique through the
coronary atherosclerosis yet. In this context, we aimed to inves- femoral artery using the Allura Xper FD10 (Philips, Amsterdam,
tigate the usefulness of a recently defined cardiovascular risk the Netherlands). All of the coronary angiograms were evaluat-
marker, PLR, in predicting the severity of coronary atherosclero- ed by 2 interventional cardiologists who were blinded to the
sis. patient information and to each other. A thorough review of each
coronary angiogram established the lesion location and percent-
Methods age of luminal stenosis among all coronary artery lesions.
CAD was defined as the presence of stenosis of at least 50%
Study population of the vessel diameter in any of the main coronary arteries,
The present study is a single-center and retrospectively according to the American College of Cardiology/American
designed study, consisting of 388 eligible consecutive patients Heart Association (ACC/AHA) lesion classification (19). The
who underwent selective coronary angiography between May Gensini scoring system was used to identify the severity of CAD
and July 2013 in our clinic. Informed consent was obtained from (20). This method classifies and scores the degree and extent of
all of the participants, and the study was approved by the local the stenosis of the coronary arteries. This system scores 1 point
ethics committee. for 1% to 25% stenosis, 2 points for 26% to 50%, 4 points for 51%
A thorough physical examination was performed for all of to 75%, 8 points for 76% to 90%, 16 points for 91% to 99% steno-
the patients included in the study, and they were asked for their sis, and 32 points for total occlusion. The score is then multiplied
history of previous myocardial infarction, hypertension, diabetes by a factor representing the importance of the lesion’s location
mellitus, smoking and non-cardiac diseases and family history in the coronary arterial system. For the location, scores are
of CAD. Arterial hypertension was considered in patients with at multiplied by 5 for a left main lesion; 2.5 for the proximal left
least three repeated measurements of blood pressure above 140 anterior descending (LAD) or left circumflex (LCX) artery; 1.5 for
mm Hg systolic and 90 mm Hg diastolic or active use of antihy- the mid-segment LAD and LCX; 1 for the distal segment of the
pertensive medication. Diabetes mellitus was defined as fasting LAD and LCX, first diagonal branch, first obtuse marginal branch,
plasma glucose levels above 126 mg/dL in at least two different right coronary artery, posterior descending artery, and interme-
measurements or active use of anti-diabetic drugs. Smoking diate artery; and 0.5 for the second diagonal and second obtuse
was defined as current smoking or ex-smokers who forwent marginal branches.
smoking in the past 6 months. A positive family history for CAD According to their coronary angiograms, patients were cat-
was considered a history of CAD or sudden cardiac death in a egorized into three groups. The first group consisted of 80
first-degree relative before the age of 55 years for men and 65 patients with normal coronary arteries (control group). The rest
years for women. of the patients with coronary artery disease were divided into
Patients with moderate or advanced valvular heart disease, two according to their Gensini score: (21, 22) those with mild
clinically decompensated congestive heart failure, malignancy, atherosclerosis (n=156; Gensini score <25 points) and severe
hematological disorder, severe renal or hepatic insufficiency, atherosclerosis (n=152; Gensini score ≥25 points).
active infection or systemic inflammatory conditions, or autoim-
mune disorders and patients using steroids were excluded. Statistical analysis
Continuous variables were defined as means and standard
Biochemical and hematological parameters deviation; categorical variables were given as percentages.
After an overnight fasting, peripheral venous blood samples The normality of distribution for continuous variables was con-
were drawn from patients. Total and differential leukocyte firmed with the Kolmogorov-Smirnov test. According to the
counts were measured by an automated hematology analyzer distribution pattern of the continuous variables, the indepen-
(Abbott Cell- Dyn 3700; Abbott Laboratory, Abbott Park, Illinois, dent-sample t-test or the Mann-Whitney U test was used for
USA). Absolute cell counts were used in the analyses. PLR was continuous variables, and the chi-square test was used for
computed as platelet count divided by lymphocyte count. Total categorical variables. One-way analysis of variance (ANOVA)
and high-density lipoprotein cholesterol (HDL), triglycerides, and or Kruskal-Wallis test was used to compare 3 groups. When
fasting plasma glucose levels were measured using the Abbott there was a significant difference between the three study
Architect C16000 auto-analyzer (Architect C16000 auto-analyzer; groups, the comparison of two groups in terms of the relevant
Yüksel et al.
642 Platelet/lymphocyte ratio and CAD Anatol J Cardiol 2015; 15: 640-7
Table 1. Comparison of baseline demographic characteristics and cardiovascular risk factors of the study population*
Control group Mild atherosclerosis Severe atherosclerosis
(n=80) (n=156) (n=152) P
Age, years 57.8±10.5 59.8±10.8 63.7±12.2 <0.001a
Male, n (%) 47 (60) 92 (59) 102 (67) 0.288
Coronary risk factors
Family history, n (%) 6 (8) 15 (10) 19 (13) 0.473
Smoking, n (%) 27 (34) 39 (25) 49 (32) 0.237
Hypertension, n (%) 27 (34) 56 (36) 70 (46) 0.105
Diabetes, n (%) 20 (25) 37 (24) 46 (30) 0.412
Biochemical parameters
Total cholesterol, mg/dL 180 (154-213) 178 (152-212) 175 (146-206) 0.810*
LDL, mg/dL 110 (85-128) 113 (89-139) 109 (87-136) 0.793*
HDL, mg/dL 40 (33-48) 36 (31-42) 34 (29-39) <0.001*, b
Triglyceride, mg/dL 125 (92-201) 140 (105-190) 136 (91-197) 0.456*
Glucose, mg/dL 108.9±27.8 129.7±61.8 146.1±69.5 <0.001c
Creatinine, mg/dL 0.79±0.15 0.87±0.20 1.01±0.55 <0.001d
Hematologic parameters
Hemoglobin, g/dL 13.5±1.6 13.6±1.5 13.7±1.6 0.548
WBC, x10 /L 9
8.3±2.4 8.5±2.6 10.1±3.4 <0.001e
Platelet, x109/L 248±63 241±57 279±58 <0.001f
Lymphocyte, x10 /L 9
2.5±0.9 2.4±0.9 2.3±1.1 0.337
PLR 106.2±36.9 113.8±60.8 141.7±73.1 <0.001g
MPV, fL 8.3±1.3 8.3±1.5 8.4±1.4 0.715
HDL - high-density lipoprotein; LDL - low-density lipoprotein; MPV - mean platelet volume; N/S - non-significant, PLR- platelet-to-lymphocyte ratio; SD-standard deviation; WBC- white
blood cell count;
*Values are mean±SD; median (25-75 percentiles), or n (%). Comparison between three groups was performed with one-way ANOVA or *Kruskal-Wallis test.
For the results of post hoc tests or Mann-Whitney U test with Bonferroni correction, the significance levels are:
P1 (control vs. mild atherosclerosis); P2 (control vs. severe atherosclerosis); P3 (mild vs. severe atherosclerosis)
a
P1=0.450 (N/S); P2=0.001; P3=0.010
b
P1=0.006; P2<0.001; P3=0.027 (N/S due to Bonferroni correction)
c
P1=0.044; P2<0.001; P3=0.058 (N/S)
d
P1=0.317 (N/S); P2<0.001; P3=0.005
e
P1=0.797 (N/S); P2<0.001; P3<0.001
f
P1=0.509 (N/S); P2=0.004; P3<0.001
g
P1=0.729 (N/S); P2<0.001; P3=0.001
parameter was performed with post hoc tests in one-way (SPSS Inc, Chicago, Illinois, USA). A two-tailed p value <0.05
ANOVA and with Mann-Whitney U test after Bonferroni cor- was considered statistically significant.
rection in Kruskal-Wallis test. Correlations were assessed
using either Pearson’s correlation test or Spearman’s rank test Results
according to the distribution pattern of the variable. Independent
associations between Gensini score and independent vari- A total of 308 patients with coronary artery disease (men
ables were assessed by backward stepwise multiple linear 63%, mean age: 62±12 years) and 80 control subjects (59% male,
regression analysis by including all parameters showing p mean age: 59±10 years) with normal coronary arteries were
value of less than 0.1 on univariate analysis [patient age, PLR, enrolled in the study. Baseline demographic, biochemical, and
white blood cell (WBC), high-density lipoprotein (HDL), serum hematological characteristics of the groups are outlined in Table
creatinine]. Standardized β regression coefficients and their 1. The study groups were comparable in terms of gender and
significance from the multiple linear regression analysis were traditional coronary risk factors, while patients in the severe
reported. Receiver operating characteristic (ROC) curve analy- atherosclerosis group were older compared to the mild athero-
sis was used to determine the optimum cut-off level of pre- sclerosis group and controls (p=0.038 and p=0.033, respectively).
procedural PLR values to predict severe coronary atheroscle- Fasting serum glucose was significantly higher in the severe
rosis. Statistical analyses were performed using SPSS 16.0 atherosclerosis group than the mild atherosclerosis group
Yüksel et al.
Anatol J Cardiol 2015; 15: 640-7 Platelet/lymphocyte ratio and CAD 643
ROC Curve
160 1.0
0.8
140
0.6
Sensitivity
120
PLR
0.4
100
0.2
Area under curve=0.645,
95% Cl: 0.587-0.703;
80 p<.001
Controls Mild Severe
Atherosclerosis Atherosclerosis 0.0
(Gensini (Gensini 0.0 0.2 0.4 0.6 0.8 1.0
score <25) score ≥25)
1-Specificity
Figure 1. Mean platelet-to-lymphocyte ratio (PLR) of controls and mild Figure 2. The receiver operating characteristic (ROC) curve analysis of
and severe atherosclerosis groups platelet-to-lymphocyte ratio for predicting severe atherosclerosis
(p=0.045) and controls (p<0.001); also, it was significantly higher
Table 2. Multivariate linear regression analysis to determine
in mild atherosclerosis than control subjects (p=0.033). The independent variables significantly associated with Gensini score
mean serum creatinine level of the severe atherosclerosis group
was significantly higher than that of the mild atherosclerosis Dependent Independent
variable variables B β t P VIF
and control groups (p=0.003 and p<0.001, respectively), while it
was comparable between the latter two groups (p=0.284). The Gensini Age 0.574 0.192 3.891 <0.001 1.112
severe atherosclerosis group had significantly lower HDL levels PLR 0.076 0.141 2.873 0.004 1.097
compared to controls (p<0.001), whereas it was similar between WBC 3.019 0.265 5.514 <0.001 1.055
the severe and mild atherosclerosis groups (p=0.137). Glucose 0.036 0.064 1.284 0.200 1.127
Among hematological parameters, hemoglobin levels were
Creatinine 8.678 0.097 1.953 0.052 1.123
similar between all three groups. WBC was significantly higher
HDL -0.505 -0.133 -2.787 0.006 1.044
in the severe atherosclerosis group than in the other two groups
HDL - high-density lipoprotein; PLR - platelet-to-lymphocyte ration; WBC - white blood
(p<0.001 for both), whereas it was similar between the mild ath- cell count. B - standardized β regression coefficients
erosclerosis and control groups (p=0.779).
The severe atherosclerosis group had significantly higher
severe atherosclerosis with a sensitivity of 61% and specificity
platelet counts compared to the mild atherosclerosis group
of 59% (area under ROC curve=0.645, 95% CI: 0.587-0.703;
(p<0.001) and controls (p=0.001), though platelet counts of the
p<0.001; Fig. 2). Also, fasting plasma glucose was positively cor-
last two groups were similar (p=0.671). Lymphocyte count was
related with Gensini score (r=0.256, p<0.001). This correlation
comparable between all three groups (p=0.337). PLR was signifi-
cantly higher in the severe atherosclerosis group compared to was valid after the exclusion of 92 diabetic cases from the study
the mild atherosclerosis (p<0.001) and control groups (p<0.001) population (r=0.221, p<0.001).
(142±73, 114±61, and 106±37 respectively, p<0.001 for ANOVA; Independent associations between Gensini score and
Fig.1). PLR was also significantly higher in patients with CAD independent variables were assessed by multivariate linear
(n=308) compared to controls (n=80) (128±68 vs. 106±37, p<0.001). regression analysis by including all parameters showing cor-
PLR was found to be correlated with age (r=0.285; p<0.001), relation with a p value of less than 0.1 on univariate analysis
CRP (r=0.245; p=0.001) (CRP was available for only 144 partici- (patient age, PLR, WBC, HDL, serum creatinine, fasting serum
pants), fasting serum glucose level (r=0.187; p=0.014), and neu- glucose). Pre-procedural PLR was independently associated
trophil count (r=0.922; p<0.001). Also, PLR values of patients with with Gensini score (β=0.141, p=0.004), together with WBC
CAD (n=308) correlated significantly with their Gensini scores (β=0.265, p<0.001), HDL (β=-0.133, p=0.006), and age (β=0.192,
(r=0.268, p<0.001). Using a cut-off level of 111, PLR predicted p<0.001; Table 2).
Yüksel et al.
644 Platelet/lymphocyte ratio and CAD Anatol J Cardiol 2015; 15: 640-7
In addition, the patients with CAD (n=308) were further Total Gensini Scores
divided into three tertiles based upon their PLR values (lower 60
than 97.8, higher than 131.7, and those in between). The mean
Gensini score of patients in the high PLR tertile was signifi-
cantly higher than that of the middle and lower tertiles (p=0.002 50
and p<0.001, respectively), while mean Gensini scores of the
middle and lower PLR tertiles were similar (p=0.564; Fig. 3).
40
Discussion
30
The association between neutrophil-to-lymphocyte ratio, a
novel hematological indicator of inflammatory status in the body,
and various cardiac disorders has been studied extensively in 20
previous researches (23-30), including the prediction of severe
atherosclerosis in patients undergoing coronary angiography
(22, 31, 32). Similarly, PLR, a recent hematological parameter 10
indicating the inflammatory and prothrombotic state, has been
shown to be associated with poor prognosis in patients with
0
cardiovascular diseases; however, there are limited data about Low Middle High
the association between PLR and coronary artery disease PLR Tertile PLR Tertile PLR Tertile
severity.
In the present study, we found that high PLR level was inde- Figure 3. Mean Gensini scores of patients in each PLR tertile
PLR - platelet-to-lymphocyte ration
pendently associated with the severity of coronary atheroscle-
rosis. Patients with high pre-procedural PLR had significantly logic mechanisms underlying these findings are speculative.
higher Gensini scores, and there was a positive correlation However, it is reasonable that the lymphocyte count indicates an
between PLR values and Gensini scores of patients with CAD. early marker of physiologic stress and systemic inflammation. In
Additionally, this study showed that pre-procedural PLR >111 our study, the PLR values of participants were positively corre-
predicted severe atherosclerosis with a sensitivity of 61% and lated with CRP levels, and they showed a significant positive
specificity of 59%. PLR was independently associated with correlation with neutrophil count, supporting that PLR may indi-
Gensini score, together with age, WBC, and low HDL, in the mul- cate an inflammatory state in the body.
tivariate analysis. To our best knowledge, this study is the first Increased proliferation in megakaryocytic series and relative
report investigating the relationship between PLR and severity of thrombocytosis are two results of the ongoing inflammatory
atherosclerosis. state in the body, which results in a prothrombotic condition. It
The initiation, progression, and propagation of atherosclero- is reported that healthy adults with increased platelet counts
sis in the coronary arterial wall are influenced by multiple fac- have an augmented risk of thrombotic complications. The circu-
tors. Inflammation plays a crucial role at all stages of atheroscle- lating platelets may contribute to the initiation of atheromatous
rosis, from initiation through progression and, finally, in the plaque formation and trigger its complications (10). High platelet
thrombotic consequences of this disease (1, 22, 32, 33). and low lymphocyte counts in the circulation have been sug-
Lymphocytopenia is a common finding in chronic inflammatory gested to be risk indicators of worse cardiovascular outcomes
states because of increased lymphocyte apoptosis. Moreover, in previous studies (6-10, 34, 35). A recently developed new
the leukocyte production in bone marrow makes a shift towards prognostic marker, high PLR, integrates the predictive risk of
increasing neutrophils and decreasing lymphocytes in response these 2 parameters into 1. The advantage of PLR calculation
to stress. Lymphocytes represent a more convenient immune could be that it reflects the condition of both aggregation and
response, while neutrophils cause a destructive inflammatory inflammatory pathways, and it may be more valuable than either
reaction (7). The diagnostic and prognostic usefulness of a low platelet or lymphocyte count alone in the prediction of coronary
lymphocyte count was demonstrated in patients with acute atherosclerotic burden. Several new studies suggesting a rela-
coronary syndrome and stable CAD, respectively (6, 34). Low tionship between PLR and CAD have been published. Azab et al.
lymphocyte count was found to be significantly related with the (15) have shown that higher PLR values are associated with an
survival in a population-based analysis of patients with known increase in long-term all-cause mortality in patients admitted
or suspected stable CAD by Ommen et al. (6), and they suggest- with non-ST-segment elevation myocardial infarction (NSTEMI).
ed that low lymphocyte count is a potential addition to clinical In a recent study by Acar et al. (36), PLR was found to be inde-
prognostic models in patients with stable CAD and that it may pendently related with coronary collateral development in
have possible independent prognostic value. The pathophysio- patients with chronic total occlusions. In our previous study, we
Yüksel et al.
Anatol J Cardiol 2015; 15: 640-7 Platelet/lymphocyte ratio and CAD 645
showed that high pre-procedural PLR value is a significant and not give an idea about the cause-and-effect relationship
independent predictor of no-reflow development in patients between PLR and coronary atherosclerosis. Although we
undergoing primary coronary angioplasty (16). In the present found significant associations, further large-scale, prospec-
study, we found that pre-procedural PLR value correlated posi- tive studies are needed to clarify and confirm the association
tively with the amount of coronary atherosclerotic burden in between PLR and coronary artery disease severity and
CAD patients. Also, we showed that patients with high pre-pro- whether it is a result or cause of severe atherosclerosis.
cedural PLR value are more likely to exhibit severe atheroscle- Despite these limitations, to our knowledge, this is one of the
rosis on coronary angiography. We found that PLR is indepen- first studies evaluating the relationship between PLR on
dently associated with Gensini score, with a β coefficient of admission and the severity of coronary atherosclerosis
0.141 in the multivariate analysis. It means that a 10-unit assessed by Gensini score.
increase in PLR value is associated with a 1.41-point increase in
Gensini score. Conclusion
Diabetes mellitus (DM), a systemic disease characterized by
hyperglycemia, is a well-known major risk factor for CAD. High In conclusion, we suggest that high PLR appears to be addi-
serum glucose is associated with earlier micro- and macro- tive to conventional risk factors and commonly used biomarkers
vascular complications of DM. Furthermore, it has been demon- in predicting severe atherosclerosis, and PLR value correlates
strated that fasting glucose may also be independently associ- positively with Gensini score. When we consider that PLR is a
ated with the development and severity of atherosclerosis in calculation of routine complete blood count parameters that
non-diabetic patients (37, 38). Patients in all 3 groups of our study does not require any additional expense and is a readily avail-
had similar DM rates, and fasting plasma glucose was positively able marker, it can help to identify individuals at high risk for
correlated with Gensini score. After the exclusion of 92 diabetic advanced CAD who might need a more aggressive therapeutic
cases from the study population, fasting plasma glucose was approach and closer clinical follow-up.
still correlated significantly with Gensini score. This indicates
that the initiation and progression of coronary atherosclerosis Conflict of interest: None declared.
accelerate with increases in fasting plasma glucose, even in
non-diabetic patients. So, our results are in line with the litera- Peer-review: Externally peer-reviewed.
ture.
HDL works for protection against CAD, and low plasma level Authorship contributions: Concept - M.Y., A.Y., H.K.; Design - M.Y.,
H.K., A.A., M.A., N.P.; Supervision - S.A., M.Y., M.Z.B.; Resource - S.A.;
of HDL is another important risk factor for the initiation and pro-
Material - M.Z.B., N.P., H.A., M.A.; Data collection and/or processing -
gression of coronary atherosclerosis. The inverse association
A.A., H.A., N.P., M.Z.B., M.Y.; Analysis and/or Interpretation - M.Y., M.O.,
between HDL level and coronary artery disease is strong and
H.K.; Literature search - M.Y., M.O.; Writing - M.Y.; Critical review - H.K.,
consistent in population-based studies (39). Thus, in our patient M.O., A.Y.
population, it is reasonable to find that plasma HDL level was
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