Background: Atherosclerosis is a complex inflammatory disease. The neutrophil-to-lymphocyte ratio (NLR) is a systemic inflammatory marker that is correlated with adverse cardiovascular outcomes. Aim: The aim of this study was to investigate the association between NLR and severity of coronary artery disease. Study Design and Methodology: It is a hospital-based observational study. A total of 90 participants were included in the study. All the participants were divided into three groups based on the result of coronary angiography report using both Syntax and Gensini scores. NLR was calculated as the ratio of neutrophil count to lymphocyte count. Results: The NLR was evaluated for the severity of coronary arterial stenosis. A significantly higher (Chi-square value [50.35], df , P < 0.001) NLR ratio was seen in patients with severe coronary stenosis based on Syntax scoring. A significantly higher (Chi-square value [60.93], df , P < 0.001) NLR ratio was seen in patients with severe coronary arterial stenosis based on Gensini scoring. In logistic regression analyses, NLR was an independent predictor of coronary artery disease. An NLR of 2.15 or higher predicted the severity of coronary artery disease. Conclusion: In this study, it was found that NLR was significantly elevated in patients with significant coronary artery stenosis estimated by both Syntax and Gensini scores.
Keywords: Coronary artery disease, neutrophil–lymphocyte ratio, Syntax and Gensini scores
|How to cite this URL:|
Gordhanbhai PS, Ravindra T S, Yeldo D. Association between neutrophil-to-lymphocyte ratio and severity of coronary artery disease. APIK J Int Med [Epub ahead of print] [cited 2022 Dec 4]. Available from: https://www.ajim.in/preprintarticle.asp?id=361013
| Introduction|| |
Cardiovascular disease (CVD) is a group of diseases that include the heart and blood vessels, thereby including coronary artery disease (CAD), coronary heart disease (CHD), and acute coronary syndrome (ACS) among other conditions. It is known that CAD results from a complex process known as atherosclerosis; atherosclerotic plaque formation in coronary vessels is built up not only from cholesterol but also may be by the presence of inflammatory response in plaques. Although numerous inflammatory markers including C-reactive protein (CRP), tumor necrosis factor-α, and interleukin (IL-1), IL-6 are known as indicators of inflammatory process, recent studies have shown that white blood cell (WBC) and its subtypes are useful for predicting the inflammatory process in CVD. CVDs are the major cause of morbidity and mortality, accounting for about 17 million of 36 million non-communicable disease deaths out of the total 57 million deaths that occurred during 2008. According to the Global Burden of Disease study, age-standardized estimates (2010), nearly a quarter (24.8%) of all deaths in India is accountable to CVD. The years of life lost accountable to CVD in India increased by 59% from 1990 to 2010 (23.2 million to 37 million). The relationship between neutrophil–lymphocyte ratio (NLR) and CAD has been shown in several studies, but there is only limited data available with the severity of coronary atherosclerosis measured using both the Syntax and Gensini scoring systems., Considering the potential role of neutrophils and lymphocytes, in the genesis and evolution of atheromatous plaques, the NLR may be a sensitive predictor for likelihood in having a cardiovascular event.
| Materials and Methods|| |
It was a hospital-based observational study conducted in Mallige Medical Centre, Bengaluru, from September 2018 to April 2020. Ninety eligible patients who underwent elective coronary angiography (CAG) were included based on inclusion and exclusion criteria. Their data including history, risk factors, total leukocyte count and differential count, platelet count, level of cardiac markers (Troponin, CK-MB), and inflammatory marker (CRP) were collected. The severity of CAD was evaluated with both the Syntax and Gensini scoring systems. Statistical analysis was performed using IBM, SPSS Statistics version 25 (IBM Corp., New York, NY, USA). A Pearson's product–moment correlation was run to assess the relationship between NLR, platelet lymphocyte ratio (PLR), and severity of coronary artery stenosis such as Syntax and Gensini scores. A multiple regression model was constructed to predict the severity of CAD based on variables such as age, gender, total leukocyte count, NLR, PLR, hypertension, serum lipids (low-density lipoproteins [LDL], high-density lipoprotein [HDL], triglycerides, and total cholesterol), diabetes mellitus, smoking, and family history of CAD. A P < 0.05 was considered statistically significant.
- Patients undergoing elective CAG.
- Clinically significant valvular heart disease
- Significant congestive heart failure, ACS, and percutaneous coronary intervention within the past 6 months
- History of malignancies and/or treatment with chemotherapy
- Severe renal or liver disease
- Ongoing infections or systemic inflammatory conditions and autoimmune disease
- History of using glucocorticoid therapy within the past 3 months.
The Syntax score was designed to determine the post-procedural risk related to CAG or surgical revascularization and is a visual estimate of CAD burden and complexity. The score ranges from 0 to >60 in very complex coronary anatomy lesions [Figure 1]. The Syntax calculator is available online at https://syntaxscore.org/.
Gensini score is a widely used means of quantifying angiographic atherosclerosis, where a zero score suggests the absence of atherosclerotic disease. The Gensini score accounts for the degree of artery narrowing as well as locations of narrowing [Figure 2].
| Results|| |
The mean age of patients was 54.4 ± 9.81 years and the age distribution was depicted in [Figure 3]. There were 69 (76.7%) males and 21 (23.3%) females, respectively [Figure 4].
Among study participants, 44 (48.9%) were smokers and 46 (51.1%) were nonsmokers [Figure 5]. A positive family history of CAD was observed in 26 (28.9%) patients [Figure 6]. There were 26 (28.9%) diabetics and 64 (71.1%) nondiabetics [Figure 7]. There were 52 (57.8%) hypertensives and 38 (42.2%) nonhypertensives [Figure 8]. Hyperlipidemia was present in 48 (53.3%) patients [Figure 9]. Serum CRP was positive in 23 (25.6%) patients [Figure 10].
The descriptive characteristics of study participants are shown in [Table 1]. The mean leukocyte count was 10,117.20 ± 2529 cells/mm3. The mean NLR was 2.52 ± 0.69 and the mean PLR was 107.99 ± 33.6. The mean NLR ratio in males was 2.51 ± 0.74 and in females was 2.54 ± 0.46, respectively. The difference in NLR ratio between males and females was not statistically significant (independent t-test, P = 0.086). The mean PLR in males was 104 ± 33.09 and in females was 120 ± 33.04. The difference in PLR ratio between males and females was statistically significant (independent t-test, P = 0.05). The mean troponin-T levels was 1.22 ± 1.4 and the mean CPK-MB was 43.44 ± 47.42, respectively. The mean systolic blood pressure was 128 ± 25.1 mmHg and the mean diastolic blood pressure was 79.22 ± 10.91 mmHg, respectively. The mean Syntax score was 20.09 ± 11.3 and the mean Gensini score was 38.4 ± 25.9, respectively.
The severity of coronary artery stenosis as per Syntax scores is shown in [Figure 11]. The severity of coronary stenosis as per Gensini scores is shown in [Figure 12].
On Pearson's correlation analysis, a significant correlation [Figure 13] was found between NLR and Syntax score (Pearson's correlation coefficient, r = 0.374, P < 0.001).
|Figure 13: Correlation between NLR and Syntax score. NLR: Neutrophil-to- lymphocyte ratio|
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The correlation between NLR and Gensini scores [Figure 14] was found to be significant (Pearson's correlation coefficient, r = 0.271, P = 0.007).
|Figure 14: Correlation between Gensini and NLR. NLR: Neutrophil-to- lymphocyte ratio|
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The NLR was evaluated for the severity of coronary stenosis. A significantly higher (Chi-square value (50.35), df , P < 0.001) NLR ratio was seen in patients with severe coronary stenosis based on Syntax scoring [Table 2] and [Figure 15]].
A significantly higher (Chi-square value (60.93), df , P < 0.001) NLR ratio was seen in patients with severe coronary stenosis based on Gensini scoring [Table 3] and [Figure 16].
A significantly higher (Chi-square value (47.19), df (1), P < 0.001) CRP was found in patients with severe coronary stenosis based on Syntax scoring [Table 4] and [Figure 17].
A significantly (Chi-square value (59.18), df , P < 0.001) higher CRP was found in patients with severe coronary stenosis based on Gensini scoring [Table 5] and [Figure 18].
| Discussion|| |
The results of this study suggest that a significantly higher (P < 0.001) NLR was seen in patients with severe CADs as assessed by Syntax and Gensini scores. A significantly higher PLR, CRP, and total leukocyte count were seen in severe coronary stenosis in comparison to moderate and mild coronary stenosis. The cardiac markers (troponin T and CPK-MB); however, did not significantly correlate with the NLR ratio. On the multivariate regression model, age blood pressure, CPK-MB, PLR, NLR, CRP, gender, family history, HDL, total leukocyte count, smoking, diabetes, LDL, serum triglycerides, total cholesterol, and statistically significantly predicted severity of coronary stenosis.
Kaya et al. conducted a single-center observational study in 172 eligible consecutive patients who underwent CAG for suspected or known coronary atherosclerosis. The authors found that the NLR was significantly (P < 0.001) higher in the severe atherosclerosis group compared with mild atherosclerosis and control groups. NLR showed a significant correlation with Gensini score. After multivariate analysis, high levels of NLR were independent predictors of severe atherosclerosis together with glucose and high-density lipoprotein. Our study also found a significant correlation between NLR and Gensini score. Apart from high level of NLR, age blood pressure, CPK-MB, PLR, NLR, CRP, gender, family history, HDL, total leukocyte count, smoking, diabetes, LDL, serum triglycerides, and total cholesterol could predict the severity of CAD on multivariate analysis.
Al Tahhan et al. conducted a cross-sectional and found that there was a strong relationship between NLR, PLR, CRP level, and CHD r = 526 (P = 0.001), r = 0.317 (P = 0.001), and r = 0.699 (P = 0.001), respectively. When study parameters were evaluated according to Syntax scores, a negative correlation was observed for Syntax scores above 21 and above 31 with NLR, PLR, and CRP. The results of this study suggested that the severity of CAD is associated with NLR, PLR, and CRP levels to some extent in the patient with angina for chronic stable chest. The results of this study were in sharp contrast to our study where NLR, PLR, and CRP had a strong and positive correlation with higher Syntax score and consequently, the severity of CAD. The authors cited ethnic differences for the difference in observations. The results of the present study were like most other population-based studies.
Sharma et al. conducted a study to evaluate the association of NLR in CAD. The study suggested that NLR was a simple indicator that could be effectively used for the diagnosis of CAD with a cutoff of 2.13 in the Western Indian population. There was a striking difference between this study and our study in terms of methodology. The odds ratio and cutoff limit for NLR could not be estimated due to the absence of a control group (patients with normal CAG). However, NLR significantly correlated with CRP and CAD disease severity scores (Syntax and Gensini) except for troponin T and CPK-MB in the South Indian population.
Dur et al. aimed to examine the association between inflammation, as indicated by high-sensitivity CRP and NLR, and the complexity and severity of CAD assessed using Syntax severity score in patients with ACS. The authors found that a total of 87 patients (65 males and 22 females) with acute myocardial infarction were included in this study. Patients were classified into low (NLR ≤2.7, n = 63) and high (NLR >2.7, n = 24) NLR groups. Univariate analysis demonstrated that Syntax score was significantly higher in the high NLR group than in the low NLR group (23.6 ± 12.7 vs. 13.9 ± 8.7, P < 0.001). Similar to NLR, a significant correlation was revealed among high-sensitivity CRP, troponin levels, and severity of Syntax scores that indicated their predictive value in the severity of AMI.
Tabrez et al. conducted a study in Saudi Arabian patients to evaluate the importance of NLR as a biomarker in CAD. The authors acknowledge that due to steadily expanding rise in death rate due to CAD, there is an earnest need is to discover novel prognostic biomarkers for CVD. In this endeavor, inflammation has been a prominent focus due to its importance in the formation and behavior of atheromatous plaques. This study stems from the fact that NLR is an inflammatory biomarker to predict cardiovascular events at an early stage. One hundred patients with CAD participated in this study. The authors found that total cholesterol and LDLs showed a significant increase (13%). However, a significant (P < 0.05) decline was seen in non-HDL cholesterol compared to the control group. A significant increase in fasting glucose, Hb1Ac, and insulin by 58%, 53%, and 44% was observed in the CAD group. Moreover, CRP level also showed a significant increase of 39% in the CAD group compared with control individuals. The WBC count revealed a significant increase in total WBC, neutrophils, and lymphocytes. The NLR was significantly (P < 0.001) elevated by 110% in CAD patients compared with controls. This study suggested that NLR could be used as a predictive biomarker of CAD as it is a simple, inexpensive, and could be performed as a routine blood investigation. Most observations made in this study were in agreement with our study except the presence of a control group or age and gender-matched group of patients without CAD.
| Conclusion|| |
- Inflammatory markers such as NLR, CRP, and WBC counts are significantly elevated in severe coronary stenosis and correlate well with CAD stenosis as measured by Syntax and Gensini scores
- The level of cardiac markers such as troponin T and CPK-MB needs further evaluation in relation to NLR
- Patients with significant coronary artery stenosis had remarkably higher NLR. NLR of 2.15 or higher was an independent predictor of CAD.
The shortcomings of the present study were an absence of a control group to compare the results, a non-randomized study design, and adding to a selection bias. There were only limited number of study participants, and participants were from one center rather than multiple centers. We suggest a multicenter, cross-sectional study with large sample size and studies with intravascular ultrasound and coronary computerized tomography may provide more accurate information on the amount of coronary atherosclerosis. In conclusion, NLR seems to be a simple and cheap parameter which could be used as a part of cardiovascular risk stratification before CAG.
We acknowledge all the authors for their valuable correlation as well as the department of statistics for helping us formulate our data into relevant results.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Mallige Medical Centre, 31/32, Crescent Road, Madhava Nagar, Gandhi Nagar, Bengaluru - 560 001, Karnataka
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13], [Figure 14], [Figure 15], [Figure 16], [Figure 17], [Figure 18]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]