© 2014, Wiley Periodicals, Inc. DOI: 10.1111/echo.12511

Echocardiography

Neutrophil-to-Lymphocyte Ratio May Predict Subclinical Atherosclerosis in Patients with Psoriasis € € ksel Kaya, M.D.,‡ Mahmut Ozdemir, Mustafa Yurtdasß, M.D.,* Yalin T. Yaylali, M.D.,† Yu M.D.,* € _Ilker Ozkan,  M.D.,§ and Nesim Aladag, M.D.* *Department of Cardiology, Van Region Training and Research Hospital, Van, Turkey; †Department of Cardiology, School of Medicine, Pamukkale University, Denizli, Turkey; ‡Department of Cardiology, School of Medicine, Kafkas University, Kars, Turkey; and §Department of Dermatology, Lokman Hekim Hospital, Van, Turkey

Background: Systemic inflammation beyond the skin may provide an explanation of the increased cardiovascular risk observed in psoriasis. It was hypothesized that neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are potential predictors of subclinical atherosclerosis measured by aortic velocity propagation (AVP) and carotid intima–media thickness (CIMT) in psoriasis. Methods: Fifty-one patients with psoriasis taking no antipsoriatic therapy and 37 age- and sex-matched healthy controls were prospectively enrolled. The Psoriasis Area and Severity Index (PASI) was calculated. Complete blood counts were obtained. Measurements of AVP and CIMT were performed. Results: The baseline clinical and demographic features, and white blood cell, platelet, neutrophil, lymphocyte, monocyte, and PLR were similar in both groups. NLR and high-sensitivity C-reactive protein (hs-CRP) were higher in the psoriasis group than the control group (P = 0.001, P < 0.001; respectively). The psoriasis group had lower AVP and higher CIMT values than those of controls (AVP: 48.9  18.1 vs. 64.3  14.5 cm/sec; P < 0.001, CIMT: 0.84  0.29 vs. 0.63  0.27 mm; P = 0.001, respectively). PASI was positively correlated with NLR and hs-CRP (r = 0.423, P = 0.002; r = 0.315, P = 0.024, respectively). There was an inverse association between AVP and CIMT (r = 0.749, P < 0.001). Binary logistic regression analysis demonstrated that NLR was the only variable able to predict lower AVP (≤41 cm/sec) and higher CIMT (>0.9 mm) values (P = 0.024 and 0.023; respectively). Conclusion: NLR is potentially an unrecognized predictor of subclinical atherosclerosis in patients with psoriasis. Future studies assessing the prognostic significance of NLR on cardiovascular event rates in psoriasis patients would be of great interest. (Echocardiography 2014;31:1095–1104) Key words: atherosclerosis, inflammation, intima–media thickness, propagation velocity, psoriasis

Psoriasis, a chronic systemic inflammatory disease affecting 2–3% of the world’s population with reduced life expectancy, is related to increases in inflammatory markers in the skin and blood.1 Large epidemiology trials have identified elevated rates of ischemic stroke, atrial fibrillation, myocardial infarction, and cardiovascular mortality among psoriasis patients with not only severe but also mild disease.2–6 Although the mechanisms underlying the increased risk of cardiovascular disease independent of traditional risk factors in psoriasis patients remain unclear, an accumulating evidence suggests that arterial inflammation may play a crucial role.7–14 Address for correspondence and reprint requests: Mustafa €lge Eg  itim ve Arasßtırma Hastanesi, KardYurtdasß, M.D., Van Bo € lu € mu € , 65100, Van, Turkey. Fax: +90 432 2121954; iyoloji Bo E-mail: [email protected]

In recent years, neutrophilia and relative lymphopenia have been demonstrated to be an independent predictor of mortality in patients with cardiovascular disease.15,16 Moreover, neutrophil-to-lymphocyte ratio (NLR) was introduced as a potential marker to identify inflammation in cardiac and noncardiac diseases.17–22 In addition to the antithrombotic effects, platelets also are thought to play an important role in the initiation and development of atherosclerosis by means of secreting proinflammatory cytokines, leukocyte transmigration and adhesion, as a result of binding of platelets to endothelial cells in the presence of shear stress.23 Likewise, platelet-to-lymphocyte ratio (PLR) has been reported to be associated with all cause mortality in patients with acute myocardial infarction.24 NLR and PLR may be used as cost-effective predictors of inflammation and cardiovascular complications. 1095

Yurtdasß, et al.

As atherosclerosis is often asymptomatic, accurate assessment of subclinical atherosclerosis by noninvasive techniques has important therapeutic and prognostic implications.25 The color M-mode velocity propagation has been established as a valuable noninvasive tool in various applications, including pulmonary vascular resistance, early diastolic ventricular performance, and subclinical atherosclerosis.26–32 Therefore, to improve clinical outcomes, noninvasive imaging modalities, including the color M-mode–derived propagation velocity of the descending thoracic aorta, aortic velocity propagation (AVP), and carotid intima–media thickness (CIMT) have been proposed to measure and monitor arterial stiffness or subclinical atherosclerosis.28–33 Many trials have demonstrated that AVP and CIMT are simple and practical methods, and correlate well with the presence of carotid and coronary atherosclerosis, and brachial endothelial dysfunction.28–32 Although psoriasis has been suggested to be associated with inflammation and subclinical atherosclerosis,3–14 the relationship between NLR, PLR, the severity of psoriasis, and subclinical atherosclerosis has not yet been fully elucidated in patients with psoriasis. A better understanding of the relationship of NLR, PLR, AVP, and CIMT might be relevant in improving patient selection for more aggressive primary prevention measures to halt atherosclerosis progression in patients with this heterogeneous disorder. The benefits of cardiovascular treatment have not yet been definitively established. Dowlatshahi et al.34 recently challenged the contention by reporting that psoriasis is not associated with atherosclerosis and incident cardiovascular events. Although inflammation in these patients may be indeed widespread throughout the vascular tree, there is an unmet need for further research and outcome trials in this field. To our knowledge, no previous reports of subclinical atherosclerosis measured by AVP and its relationship with disease severity in psoriasis patients have been published. The aim of this prospective randomized controlled study was to investigate whether NLR and PLR are related with subclinical atherosclerosis measured by AVP and CIMT in this patient population. Methods: This prospective study consisted of 51 patients with psoriasis (age, 20–52 years; 19 female), and 37 age- and sex-matched healthy controls (age, 19–49 years; 17 female) with no evidence of psoriasis or other systemic inflammatory disease. Severity of psoriasis in patients was calculated using the Psoriasis Area and Severity Index (PASI). Exclusion criteria were a history of cardiovascular disease, diabetes mellitus, heavy smoking

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(defined as smoking ≥25 cigarettes per day), uncontrolled hypertension (described as systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 95 mmHg), left ventricular ejection fraction (LVEF) 30 kg/m2), and concomitant inflammatory disease with clinical or biochemical evidence. Patients taking any antipsoriatic agents or medications within the last 6 months, and with erythrodermic and arthritic psoriasis were also excluded to eliminate their potential confounding effects on vascular functions. Informed consent was obtained from all participants. The study protocol complied with the Declaration of Helsinki and was approved by the Investigational Review Board of Kafkas University, School of Medicine. Laboratory Analysis: After a 12-h overnight fast, all blood samples were taken from an antecubital vein. Complete blood counts with automated differential counts, consisting of platelet, white blood cell, neutrophil, lymphocyte, and monocyte were obtained on 3 consecutive days and averaged (Coulter LH 750 analyzer; Beckman Coulter, Galway, Ireland). NLR and PLR were estimated as the ratio of the neutrophil and platelet-to-lymphocyte counts. Fasting plasma total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and creatinine were measured using a Cobas Integra 800 automated analyzer (Roche Diagnostics, Manheim, Germany). High-sensitivity C-reactive protein (hs-CRP) was calculated using a latexenhanced immunoturbidimetric method with the lower limit of detection at 0.15 mg/L (Cobas c systems; Roche-Hitachi, Rotkreuz, Switzerland). Normal value for hs-CRP was accepted as 41 cm/sec) and CIMT (>0.9 or ≤0.9 mm), which are recommended as indicative of asymptomatic organ damage by Gunes et al.,28,31 and European Society of Cardiology (ESC) hypertension guidelines,33 respectively. The variables with a P < 0.25 in the univariate analysis were included in the binary logistic regression analysis to evaluate their relations with subclinical atherosclerosis measured by both AVP and CIMT. Receiver operating characteristic (ROC) curve was generated to define the predictive value of NLR. The area under the curve (AUC) was calculated and the cutoff point was determined with the maximal sensitivity and specificity for both AVP and CIMT. Statistical significance was described as P < 0.05. All analyses were performed using a software program SPSS (Version 15.0, SPSS Inc, Chicago, IL, USA). Results: The baseline clinical and demographic features, and laboratory findings of the patients and controls are shown in Table I. Age, blood pressures, lipid profiles, body mass index, and heart rate did not differ between the 2 groups. In the psoriasis group, patients had a mean PASI value of 16  11, and a mean psoriasis duration of 7  5 years. White blood cell, neutrophil, lymphocyte, monocyte, platelet, and PLR were similar in both groups. NLR and hs-CRP were higher in the psoriasis group than the control group (P = 0.005, P < 0.001; respectively). Echocardiographic measurements, and AVP and CIMT values of both groups are shown in Table II. There were no statistically significant differences between the 2 groups in terms of echocardiographic measurements. The psoriasis group had lower AVP and higher CIMT values than those of controls (AVP: 48.9  18.1 vs. 64.3  14.5 cm/sec; P < 0.001, CIMT: 0.84  0.29 vs. 0.63  0.27 mm; P = 0.001, respectively). In the psoriasis group, AVP was negatively correlated with neutrophil, NLR, PLR, hs-CRP, and PASI, and positively with lymphocyte count; whereas CIMT positively correlated with neutrophil, NLR, PLR, hs-CRP, and PASI, and negatively with lymphocyte count (Table III). AVP and CIMT were not associated with the white blood cell, monocyte and platelet counts, and the echocardiographic measurements. PASI was positively correlated

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with NLR and hs-CRP levels (r = 0.423, P = 0.002; r = 0.315, P = 0.024, respectively). There was an inverse association between AVP and CIMT (r = 0.749, P < 0.001; Fig. 3). Univariate analysis of the 2 groups according to the values of AVP (≤41 or >41 cm/sec) and CIMT (>0.9 or ≤0.9 mm) in patients with psoriasis are shown in Tables IV and V, respectively. Echocardiographic measurements were similar with a P > 0.25 in both AVP and CIMT subgroups in psoriasis patients (data not shown). Binary logistic regression analysis demonstrated that NLR was the only variable able to predict lower AVP (≤41 cm/sec) and higher CIMT (>0.9 mm) values (P = 0.024 and 0.023; respectively) (Tables VI and VII, respectively). The ROC curve analysis showed that the AUC of NLR was 0.73, and the cutoff value was 2.32 with the maximal sensitivity (70%) and specificity (65%) for the lower value of AVP, and 0.77, and the cutoff value 2.23 with the maximal sensitivity (79%) and specificity (65%) for the higher value of CIMT (Fig. 4). There were no correlations mentioned above in the control group. Discussion: This study is the first to our knowledge to show that psoriasis patients have significantly lower AVP and higher CIMT, NLR, and hs-CRP values than those of healthy controls, and that there is a significant association between AVP and CIMT in these patients. Our results are consistent with previous studies, which reported that psoriasis is associated with atherosclerosis.2–14 As psoriasis is a heterogeneous disorder, NLR may predict an adverse course in some psoriasis patients with asymptomatic vascular disease. Hence, its assessment could be incorporated into the currently used management algorithm. Measurement of AVP is a comfortable, quick, and reproducible method and it does not add any cost compared with other ultrasonographic indices of arterial stiffness such as aortic distensibility, augmentation index, and pulse-wave velocity.28 Several studies have recently shown that significant correlations between AVP and carotid atherosclerosis measured by CIMT were present in various patient groups, supporting the findings of this study.29,30,32 Diminished AVP may be an indicator of atherosclerotic involvement of the thoracic aorta and may be used for the identification of the severity and/or extent of aortic atherosclerosis.28,31 A common consequence of atherosclerosis is an increase in the stiffness and thickness of the arterial wall, resulting in decreased vascular elasticity and compliance.25 Balci et al.9 reported that psoriasis patients had impaired endothelial function and

NLR and Subclinical Atherosclerosis in Psoriasis

TABLE I Clinical, Demographic, and Laboratory Characteristics of Both Groups

Clinical and demographic features Age (years) Gender (female/male) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Current smoker, n (%) Family history, n (%) Body mass index (kg/m2) Heart rate (beats/min) PASI Disease duration (years) Laboratory measurements Total cholesterol (mg/dL) HDL-C (mg/dL) LDL-C (mg/dL) Triglyceride (mg/dL) Creatinine (mg/dL) eGFR (mL/min per 1.73 m2) hs-CRP (mg/L) Blood components White blood cell count (9103 mm 3) Neutrophil count (9103 mm 3) Lymphocyte count (9103 mm 3) Monocyte count (9103 mm 3) Platelet count (9103 mm 3) Neutrophil-to-Lymphocyte ratio Platelet-to-Lymphocyte ratio

Psoriasis Group (n = 51)

Control Group (n = 37)

39  9 19/32 130  13

37  9 17/20 126  10

0.299 0.413 0.161

78  9

75  8

0.066

9 (18) 4 (8) 26.3  2.1 70  13 16  11 75

5 (14) 5 (14) 25.4  2.3 66  11 – –

0.372 0.386 0.071 0.139 – –

      

0.266 0.255 0.204 0.605 0.316 0.400

Neutrophil-to-lymphocyte ratio may predict subclinical atherosclerosis in patients with psoriasis.

Systemic inflammation beyond the skin may provide an explanation of the increased cardiovascular risk observed in psoriasis. It was hypothesized that ...
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