Neutrophil to lymphocyte ratio: a novel marker for predicting hospital mortality of patients with acute type A aortic dissection

Abstract

Introduction:

The inflammatory process has been reported to be associated with aortic dissection (AD) from the development to the prognosis. The aim of the study was to investigate a relationship between the neutrophil to lymphocyte ratio (NLR) and in-hospital outcomes in patients with acute aortic dissection (AAD) who underwent surgical repair.

Methods:

One hundred and eighty-four patients who were admitted with the diagnosis of type A AAD who underwent surgical repair at two large tertiary hospitals. According to their NLR, 91 patients had high NLR (>6.0) and 93 patients had low NLR (⩽6.0).

Results:

The frequency of major bleeding, hospital-related infection, multi-organ dysfunction and mortality in hospital were higher in the high NLR group compared to the low NLR group. NLR, WBC count and operation duration were found to be independent predictors for in-hospital mortality.

Conclusions:

The novel inflammatory marker NLR may be used to predict worse outcomes and hospital mortality in patients with AAD treated by surgical repair.

Keywords

aortic dissection mortality NLR

Introduction

Acute aortic dissection (AAD) is a cardiovascular emergency with high mortality and worse postoperative course, even with emergent surgical intervention. The estimated annual incidence of AAD is 2.9–4.7 per 100,000 people.^1,2 Despite satisfactory surgical success in patients with AAD, many reports still show high hospital mortality rates after surgical treatment (15–35%).^1,3–6 Two risk stratification methods, including preoperative and intraoperative parameters, have been described by the International Registry of AAD³ (IRAD). According to the IRAD, the independent variables of mortality are advanced age, hypotension/shock, previous heart disease and postoperative renal, mesenteric or myocardial ischemia. However, in many current research studies, several biomarkers of vascular damage, thrombosis and inflammation have been evaluated as contributors in the diagnosis of AAD or as risk-prediction tools.^4,6–9 White blood cell (WBC) count and its subtypes are widely known as classic inflammatory biomarkers to predict cardiovascular outcomes. In addition, the neutrophil to lymphocyte ratio (NLR) has been evaluated as a prognostic biomarker for various cardiovascular diseases.^10–15

However, the relationships between admission NLR and hospital mortality in patients with AAD are not exactly clarified. The aim of the present study was to investigate any possible association between NLR and the hospital mortality of surgically treated patients with AAD.

Methods

In this observational and cross-sectional study, we retrospectively screened type A AAD patients who underwent emergent surgical repair between 2009 and 2013 in both Mehmet Akif Ersoy and Kartal Kosuyolu Education and Research Hospitals. Exclusion criteria consisted of: active or chronic inflammatory or autoimmune diseases, inflammatory rheumatic disease, anemia, clinical evidence of active infection, known malignancy, any hematological diseases, recent blood transfusion, acute and chronic renal disease, history of chronic obstructive pulmonary disease and previous open heart surgery. A total of 287 patients were screened and 103 subjects were excluded after applying the exclusion criteria. Finally, 184 patients were included in the study according to the inclusion and exclusion criteria. The patients were divided into two groups according to the NLR. The patients whose NLR was higher than 6.0 were included in the higher NLR group and those whose NLR was lower than 6.0 were included in the lower NLR group.

For each patient, clinical baseline characteristics, risk factor of cardiovascular disease, biochemical and hematologic laboratory data and all clinical outcomes were obtained from a review of the patient’s chart in the database of both hospitals.

In both hospitals, venous blood samples were collected at the time of admission to emergency service and were sent to the laboratory within minutes of collection. WBC and subtypes, such as neutrophils and lymphocytes, were obtained as a part of the automated complete blood count. NLR was calculated by dividing the neutrophil count by the lymphocyte count.

Statistical analysis

Continuous variables are given as the mean ± SD; categorical variables were defined as a percentage. NLR was divided into two categories, separated at the 50th percentiles to facilitate describing associations with baseline clinical characteristics and postoperative outcomes. According to their NLR, 91 patients had a high NLR (>6.0) and 93 patients had a low NLR (⩽6.0). Parametric values were compared between the two groups using the two-tailed Student t test. Categorical variables were also compared by the likelihood ratio Chi-square (γ2) or Fisher’s exact test. A value of p<0.05 was considered statistically significant. Multivariate logistic regression analysis, which included variables with p<0.05, was performed to identify the independent predictors for in-hospital mortality. The Statistical Package for the Social Sciences (SPSS) 15.0 software was used for all the statistical analyses (Version 15; SPSS Inc., Chicago, IL, USA).

Results

One hundred and eighty-four patients (mean age, 53.1±11.4 years; 134 men and 50 women) were enrolled. The baseline characteristics of the study subjects are shown in Table 1. There were no significant differences between the high and low NLR groups with respect to gender, age, family history and smoking. Frequencies of diabetes mellitus, hypertension, Marfan’s syndrome and chronic obstructive pulmonary disease were similar between the groups. Levels of serum creatinine, (alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were higher in the high NLR group compared to the low NLR group (1.53±0.74 vs. 1.35±0.30; p=0.03, 98.9±228.9 vs. 30.4±23.2; p=0.005, 115.2±243.1 vs. 39.4±40.1; p=0.005, respectively). The computed tomography and echocardiographic findings and the operation characteristics were similar between the two groups (Table 2). However, the frequency of coronary involvement was higher in the high NLR group (31% vs. 15%; p=0.007). Moreover, no significant difference was found between the two groups in terms of the standard medical therapy.

Table 1.

The baseline characteristics of the study patients.

	Higher NLR	Lower NLR	P-value
	Group (n=91)	Group (n=93)
Age (years)	54 ± 11	52 ± 11	0.162
Gender, female (%)	25 (27)	25 (27)	0.399
Body mass index, (kg/m²)	27.6 ± 3.6	27.4 ± 4.1	0.500
Type II Diabetes Mellitus, (n, %)	22 (24)	20 (22)	0.399
Hypertension, (n, %)	55 (60)	65 (70)	0.177
Dyslipidemia, (n, %)	12 (13)	18 (20)	0.176
Current smoking, (n, %)	32 (35)	32 (33)	0.519
Family history of CAD, (n, %)	5 (5)	8 (9)	0.297
Marfan’s syndrome, (n, %)	2 (2)	3 (3)	0.487
SBP, (mm Hg)	120.9 ± 34.2	135.8 ± 30.6	0.004
DBP, (mm Hg)	65.5 ± 19.2	72.5 ± 17.3	0.017
Heart rate, (beats/min)	89.8 ± 16.9	91.5 ± 19.3	0.544
Glucose, (mg/dL)	141.2 ± 42.1	134.2 ± 39.1	0.245
ALT, U/L	98.9 ± 228.9	30.4 ± 23.2	0.005
AST, U/L	115.2 ± 243.1	39.4 ± 40.1	0.004
Serum creatinine (mg/dL)	1.53 ± 0.74	1.35 ± 0.32	0.026
WBC (×10³/mm³)	14.23 ± 4.7	12.1 ± 4.4	0.002
Neutrophil, 10³/ml	12.12 ± 4.1	8.9 ± 3.8	<0.001
Lymphocyte,10³/ml	1.32 ± 0.58	2.55 ± 1.20	<0.001
Basophil,10³/ml	0.10 ± 0.13	0.10 ± 0.10	0.535
Eosinophil,10³/ml	0.17 ± 0.14	0.21 ± 0.19	0.081
Hemoglobin (gr/dL)	12.7 ± 1.6	12.8 ± 1.7	0.924
Platelet counts, (×103/mm³)	204.8 ± 76.1	219.6 ± 83.7	0.205
CRP	4.8 ± 3.15	4.5 ± 3.3	0.745
Troponin I (ng/ml)	1.35 ± 2.0	1.20 ± 2.4	0.623

Variables are expressed as mean ± standard deviation for normally distributed data and median value for non-normally distributed data; percentage (%) for categorical variables. (Student-t, Mann-Whitney U and Chi-square tests). NLR, neutrophil lymphocyte ratio; CAD, coronary artery disease; SBP, systolic blood pressure; DBP, diastolic blood pressure; ALT, alanine amino transaminase; AST, aspartate aminotransferase; p<0.05 was accepted as statistically significant.

Table 2.

Comparison of NLR groups in terms of computed tomography, echocardiography and operation characteristics.

	Higher NLR	Lower NLR	P value
	Group (n=91)	Group (n=93)
The time of surgery after symptoms (hours)	12.5 ± 13.2	15.0 ± 19.9	0.346
Cross clamp duration, (minutes)	88.8 ± 50.6	77.7 ± 42.7	0.116
Operation duration, (minutes)	180.9 ± 67.6	166.7 ± 60.4	0.096
Aortic valve replacement, (n, %)	19 (21)	16 (17)	0.327
Left ventricle ejection fraction, %	56.1 ± 5.7	57.1 ± 5.8	0.345
Bicuspid Aortic Valve, (n, %)	5 (5)	9 (10)	0.215
Ascending aorta diameter, mm	5.4 ± 0.96	5.3 ± 0.87	0.768
Coronary involvement, (n, %)	28 (31)	14 (15)	0.007
Pericardial Effusion, (n, %)	22 (24)	19 (20)	0.332
Cardiac Tamponade, (n, %)	2 (2)	3 (3)	0.510

The in-hospital events in patients with AAD are summarized in Table 3. The frequency of major bleeding, hospital-related infection, multi-organ dysfunction and mortality in the hospital period were higher in the high NLR group compared to the low NLR group [(19% vs. 5%; p=0.005), (25% vs. 14%; p=0.041), (17% vs. 8%; p=0.032), (30% vs. 10%; p=0,001), respectively]. Moreover, the NLR [OR 1.182, 95% confidence interval (CI) 1.030–1.276; p=0.012], WBC count [OR 1.161, 95% CI 1.072–1.257; p=0.002] and operation duration [OR 1.013, 95% CI 1.006–1.019; p<0.001] were found as independent predictors for in-hospital mortality in patients with AAD in multivariate logistic regression analysis (Table 4). The receiver operating characteristic (ROC) curve analysis was performed to detect the best cut-off value of the NLR in the prediction of in-hospital mortality. An NLR value >6.5 yielded an area under the curve (AUC) value of 0.71 [95% confidence interval (CI) 0.631-0.789, p<0.001]. Furthermore, a NLR value >6.5 demonstrated a sensitivity of 71% and specificity of 63% for the prediction of in-hospital mortality (Figure 1).

Table 3.

The in-hospital events and mortality out of hospital in patients with acute type A aortic dissection according to their neutrophil-lymphocyte ratio.

	Higher NLR Group (n=91)	Lower NLR Group (n=93)	P value
In-hospital mortality, (n,%)	28 (30)	10 (10)	0.001
Re-operative surgery, (n,%)	7 (8)	2 (2)	0.079
Multi-organ dysfunction, (n,%)	16 (17)	7 (8)	0.032
Major bleeding, (n,%)	17 (19)	5 (5)	0.005
Acute renal failure, (n %)	15 (16)	11 (12)	0.112
Stroke, (n,%)	9 (10)	3 (3)	0.06
Extremity emboli, (n,%)	0	1 (1)	0.505
Hospital-related infection, (n,%)	23 (25)	13 (14)	0.041

NLR= neutrophil lymphocyte ratio; p<0.05 was accepted as statistically significant.

Table 4.

Univariate and multivariate logistic regression analyses for predictors of in-hospital cardiovascular mortality in acute type A aortic dissection.

	Univariate				Multivariate
	Β	p	OR	(95% CI)	p	OR	(95% CI)
AVR	1.075	0.009	2.931	1.305−6.583
Hemoglobin	0.247	0.028	1.281	1.027−1.598
CCD	0.012	0.001	1.012	1.005−1.020
WBC	0.149	<0.001	1.161	1.072−1.257	0.002	1.149	1.052−1.254
Operation duration	0.013	<0.001	1.013	1.007−1.019	<0.001	1.013	1.006−1.019
NLR	0.168	<0.001	1.182	1.077−1.298	0.012	1.147	1.030−1.276
ALT	0.002	0.028	1.002	1.000−1.004
SBP	−0.012	0.042	0.989	0.978−1.000

CI: confidence interval; OR: odds ratio; AVR: aortic valve replacement; CCD: cross-clamp duration, WBC: white blood cell; NLR: neutrophil to lymphocyte ratio; ALT: alanine amino transaminase; SBP: systolic blood pressure.

Discussion

In the present, two large tertiary training and research hospitals study, we found a relationship between higher NLR and in-hospital mortality in the large patient group with AAD. The higher NLR predicts, not only in-hospital mortality, but also in-hospital worse outcomes in patients with AAD, after surgery. In patients with AAD who had higher NLR level, they also had more coronary involvement. Depending on these results, it may be concluded that NLR might be used as a prognostic predictor in patients with AAD.

Aortic dissection has been defined as separation of the aortic wall layers and it is a life-threatening cardiovascular disease with high mortality rates. Recent studies have shown that inflammation plays an important role in dissection of the aorta. Infiltration of the aortic wall with inflammatory cells, such as lymphocytes, macrophages and neutrophils, increases the expression of proteases and cytokines, cell adhesion molecules and releases reactive oxygen species. These cells also contribute to apoptosis of smooth muscle cells in the aortic artery and, finally, lead to medial degradation. This process has been considered to be the principal mechanism for dissection of the aorta.^7,9 The activation of inflammatory and hemostatic pathways has been investigated, both in acute aortic syndromes and abdominal aorta aneurysm (AAA). So, many studies have shown that the luminal thrombus of AAAs appears to be a reservoir of proteases delivered by neutrophils. Neutrophils adsorbed onto the surface of the luminal thrombus liberate proteases which diffuse to the aneurismal wall, causing extracellular matrix (ECM) destruction and vascular smooth muscle cell death.^16–22 Matrix metalloproteinases (MMPs), a group of enzymes that degrade the ECM, play a potential role in the onset of aortic dissection.^23,24 Li et al. have shown that MMP-8 increased in the early phases of acute aortic dissection.²⁵ Kurihara et al. have demonstrated that increased circulating levels of MMP-9 correlated with the presence of MMP-9-positive neutrophils that accumulated in the aortic tissues of AAD patients. In this study, neutrophil infiltration was observed in the intima of pre-dissecting aorta as well as in the dissected media and neutrophil depletion attenuates AAD incidence significantly in a mouse model.²⁶ In type A dissection in humans, plasma levels of MMP-9 increase as early as 1 hour after symptom onset, suggesting that infiltrating neutrophils are the most likely source of MMP-9 in AAD aortas.²⁷ Also, del Porto et al. have shown that there was a significant decrease in total T lymphocytes and T helper fractions and an increase in neutrophil counts in the peripheral blood of patients with AAD.⁸ On the other hand, systemic inflammatory markers, such as leukocytosis and C-reactive protein, were also reported to be independently associated with higher in-hospital and long-term mortality in patients with aortic dissection after surgery.^28–31

We hypothesized that, particularly given the relationship between inflammatory cells such as neutrophils, lymphocytes and acute aortic dissection, the NLR would predict outcome in this setting. In our study, we have shown that the pre-operative NLR, duration of operation and WBC level were independent predictors of in-hospital mortality for patients with AAD undergoing surgery. Patients with higher NLR (>6.0) were particularly at high risk for worse outcomes in the hospital period. Higher NLRs were also found associated with increased frequency of major bleeding, hospital-related infection and multi-organ dysfunction after the surgery. However, there were no significant differences in out of hospital mortality between the NLR groups.

NLR, a simple, inexpensive, widely available marker of inflammatory states, has been proposed as a prognostic marker and seemed to be related with worse clinical outcomes in various cardiovascular diseases.^10–15 It was used to predict mortality of myocardial infarction, percutaneous coronary intervention, coronary artery bypass grafting, chronic critical limb ischemia and elective major vascular surgery.^10,15,32,33 However, only one study has investigated the association between NLR and hospital mortality in surgically treated patients with AAD.³⁴ Differently from our study, in the Lafci et al. study, patients were divided into two groups: patients dying in hospital (Group 1, n: 33) and those discharged alive (Group 2, n: 71). NLR was significantly higher in patients with acute type A aortic dissection. They have reported that patients with higher NLR levels had a significantly higher mortality rate. They have also shown platelet count and surgical variables, including cross-clamp time, cardiopulmonary bypass time and intensive care unit duration, to be other independent predictors of in-hospital mortality. In this study, ROC analysis revealed that using a cut-off point of 8, admission NLR level predicts mortality with a sensitivity of 70% and a specificity of 53% in acute type A aortic dissection. In our study, the patients were divided into two groups separated at the 50th percentiles according to their NLR levels. Therefore, 91 of them had higher NLR (>6.0) and 93 patients had lower NLR (⩽ 6.0). In the higher NLR group, the hospital mortality rate was significantly higher than the lower NLR group with a rate of 30%-%10 (p<0.001). Furthermore, in our study, we found that using a cut-off point of 6.5, admission NLR level predicts in-hospital mortality with a sensitivity of 71% and a specificity of 63% in acute type A aortic dissection. [AUC value: 0.71; 95% confidence interval (CI) 0.631-0.789, p<0.001]. Also, in our study, not only hospital mortality, but also worse in-hospital events were significantly higher in the high NLR group. Interestingly, coronary involvement was more in the high NLR group than the low NLR group and it was statistically significant (p<0.007). Additionally, multi-organ dysfunction, major bleeding and hospital-related infections occurred more in the higher NLR group than the lower NLR group in the hospital period.

In conclusion, higher NLR levels are associated with a worse survival in the in-hospital period after AAD surgery. This prognostic utility is independent of other recognized risk factors. The predictors of mortality in AAD are not completely elucidated. Although two risk models, including preoperative and intraoperative variables, have been developed by the IRAD. We don’t have enough studies investigating hematological parameters for risk classification in the onset of aortic dissections. NLR may be used as a risk prediction tool. Further studies are needed to explain the underlying mechanism of increased NLR and to determine the clinical relevance of this marker in the management of acute aortic dissections.

The limitations of our study were as follows: (1) This was a non-randomized, two-center study that included a relatively small number of patients who were retrospectively enrolled from our database; it might be subject to selective bias; (2) We have not included the operating surgeons in our data, which could be a possible confounding variable; (3) NLR might be a useful marker in risk scoring, while the cut-off points and normal ranges should be further determined by randomized multicenter trials; (4) Another limitation of our study is the lack of measurement of known important inflammatory markers, such as interleukins and TNF, pro-BNP, fibrinogen or myeloperoxidase, since they were not routinely obtained in our study population.

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

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