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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 9  |  Issue : 2  |  Page : 51-55

Utility of neutrophil-to-lymphocyte ratio, triglycerides, and high-density lipoprotein cholesterol in assessing the severity of coronary artery disease


1 Department of Pathology, Army College of Medical Sciences and Base Hospital, New Delhi, India
2 Department of Cardiology, Army College of Medical Sciences and Base Hospital, New Delhi, India

Date of Submission26-Feb-2020
Date of Decision26-Mar-2020
Date of Acceptance04-Apr-2020
Date of Web Publication01-Aug-2020

Correspondence Address:
Dr. Sharmila Dudani
7/41, Vikram Vihar, 3rd Floor, Lajpat Nagar-4, New Delhi - 110 024
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JCPC.JCPC_7_20

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  Abstract 


Context: Coronary artery disease (CAD) occurs as a consequence of dyslipidemia and chronic inflammation. Cardiovascular disease mortality is on the rise in India. Aims: Explore the utility of simple markers such as neutrophil-to-lymphocyte ratio (NLR) and triglyceride/high-density lipoprotein cholesterol (TG/HDLc) ratio, to study the extent of coronary lesions as seen on angiography. Settings and Design: Observational study in a tertiary-care hospital in North-India. Methodology: Coronary angiograms of 126 outpatients were graded as per Friesinger Index. Lipid profile was analyzed for each patient, along with complete blood count parameters, including total leukocyte count (TLC), absolute neutrophil, and lymphocyte counts and mean platelet volume (MPV). Statistical Analysis Used:Comparison of groups was done using a Mann–Whitney U test, of continuous variables using a correlation coefficient, and of categorical variables using a Chi-square test, and odds ratios were estimated. Receiver operator characteristic curves were constructed, and cutoffs were obtained. Results: TG/HDLc-ratio was associated with severe coronary lesions (Friesinger-Index ≥5) [odds ratio (OR): 3.46; 95% confidence interval (CI): 1.32–9.10], which was stronger than the association of TG [OR: 3.15; 95%CI: 1.33–7.42] or HDLc [OR: 1.86; 95%CI: 0.81–3.82] alone. No association existed for total or low-density lipoprotein cholesterol. NLR was significantly higher among patients with severe lesions. NLR and MPV were significantly correlated with TG/HDLc ratio. Area under curve for TG/HDLc ratio and NLR was 73.7 and 60.8. Cutoff values were 2.53 (Sensitivity (SN) = 83.1%, Specificity (SP) = 56.7%) and 1.84 (SN = 61.0%, SP = 49.3%), respectively. Conclusions: TG/HDLc ratio and NLR are associated with CAD severity, more so than TG or HDLc alone, or TLC. They are easily accessible and inexpensive markers that may be utilized in identifying patients at risk for heart disease.

Keywords: Angiography, dyslipidemias, inflammation, mean platelet volume


How to cite this article:
Mangalesh S, Yadav P, Dudani S, Mahesh NK. Utility of neutrophil-to-lymphocyte ratio, triglycerides, and high-density lipoprotein cholesterol in assessing the severity of coronary artery disease. J Clin Prev Cardiol 2020;9:51-5

How to cite this URL:
Mangalesh S, Yadav P, Dudani S, Mahesh NK. Utility of neutrophil-to-lymphocyte ratio, triglycerides, and high-density lipoprotein cholesterol in assessing the severity of coronary artery disease. J Clin Prev Cardiol [serial online] 2020 [cited 2020 Oct 28];9:51-5. Available from: https://www.jcpconline.org/text.asp?2020/9/2/51/291231




  Introduction Top


Cardiovascular disease (CVD) is the leading cause of mortality worldwide, with an estimated 17.9 million deaths in 2016, amounting to 31% of global mortality.[1] Notably, higher case fatality rates for CVDs are being observed in India, compared to middle- and high-income countries.[2] Substantial effort is being directed towards its prevention and control. In India, CVD is seen to affect the urban and rural populations alike, and the prevalence of ischemic heart disease has more than quadrupled in India since 1970.[3] Endothelial dysfunction is an early sign of atherosclerosis, appearing even before plaques become apparent on angiography.[4] The Asian-Indian population is particularly considered to be at a significantly greater risk for coronary artery disease (CAD).[5],[6]

“Atherogenic dyslipidemia” is an important entity seen commonly in Asian-Indians, and comprises increased triglycerides (TGs), decreased high-density lipoprotein cholesterol (HDLc) and an increased fraction of small dense low-density lipoprotein cholesterol (sdLDLc) particles.[7] Furthermore, Asian Indians are observed to have similar or lower total cholesterol (Tc) levels than their Caucasian counterparts but have significant atherogenic dyslipidemia.[8]

Atherosclerosis is a product of dyslipidemia and chronic low-grade inflammation; the latter eventually leading to the evolution of coronary vascular occlusion and ischemic damage. Several pro-inflammatory responses due to lipotoxicity mediate endothelial dysfunction, as dyslipidemia and inflammation go hand in hand. The endothelial injury also produces larger, reactive platelets that have procoagulant activity. Inflammation at the systemic and local levels plays an important role in the destabilization of plaques, resulting in cardiovascular events. Several systemic inflammatory markers, including C-reactive protein (CRP), Interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor (TNF)-α have been studied to this effect.[9] However, these assays are not easily available, expensive, and difficult to perform as well as standardize in most developing countries. Meaningful interpretation of more routinely available diagnostic resources is required in poor- and middle-income countries to tackle the burgeoning burden of CAD.

This study was conducted amongst Indian patients undergoing coronary angiography. We aimed to analyze the extent of coronary lesions and their association with lipid-profile variables and inflammatory markers from complete blood count parameters, as both these tests are easily available in peripheral health centers. The association of inflammatory markers with lipid variables is also explored.


  Methodology Top


Study design

This was an observational study comprising outpatients referred for coronary angiography in a tertiary care hospital in North India. The study was conducted from May 2018 to November 2019. The prevalence of coronary heart disease in an urban Indian population was taken to be 10% for the sample size calculation. With a 95% confidence interval (CI) and precision taken to be 6%, the sample size required was 96. The sample size for comparison of continuous measures in two independent samples was calculated taking neutrophil-to-lymphocyte ratio (NLR) to be the test variable. The effect size was taken to be 0.5, with α = 0.05 and β = 0.2, and the required sample size was 126. This study included 126 participants. Informed consent was obtained from all participants. The study was conducted as per the tenets of the declaration of Helsinki and approval was taken from the Institutional Medical Ethics Committee.

Inclusion criteria

All patients above the age of 18 years of either sex, referred for coronary angiography for any indication, were included.

Exclusion criteria

Patients with a prior history of myocardial infarction, prior coronary angiography, and history of intake of statins for >6 months were excluded from the analysis.

Sample collection and analysis

Coronary angiography was performed through a percutaneous radial puncture using the Judkin technique. Coronary lesions were visualized and angiograms were graded as per the Friesinger Index by an interventional cardiologist blind to the hematological parameters of the study participant. The Friesinger Index is a scoring system that assigns a score from zero to five depending on the severity of stenosis, to the left anterior descending artery, right coronary artery, and the left circumflex artery each. A total score ranging from 0 to 15 is thus obtained.[10] Participants with normal angiograms receive a score of zero, and the vessels are scored individually according to stenosis severity.[11],[12]

Venous blood samples were drawn from all patients prior to angiography and analyzed. Lipid profile variables such as Tc, HDLc, and TG were measured using a fully automated biochemistry analyzer, EM360– Transasia. LDLc and very-LDLc levels were calculated using Friedwald's equation. TG/HDLc ratio was calculated for all individuals. A Tc of >200 mg/dL, TG of >150 mg/dL, LDLc of >130 mg/dL, and HDLc of <40 mg/dL were taken to be abnormal. TG/HDLc ratio of above four was considered abnormal.[12] Apolipoprotein A (apoA), apolipoprotein B (apoB), lipoprotein a (Lp (a)), and CRP levels were not assayed due to technical limitations.

A complete blood count was performed on an automated hematology cell counter, Sysmex KX-21 (Sysmex Corporation, Kobe, Japan). Total leukocyte count (TLC), differential leukocyte counts, and platelet count were obtained, and absolute neutrophil and lymphocyte counts (ANC and ALC) were calculated. The mean platelet volume (MPV) was also determined. NLR and platelet-to-lymphocyte ratio (PLR) were calculated.

Statistical analysis

Statistical analysis was performed using SPSS version 21.0 for Windows (Armonk, NY, USA: IBM Corp). Categorical variables are expressed as a percentage and continuous variables as mean ± standard deviation or median ± interquartile range. A Chi-square test was applied to test the relationship between categorical variables, and odds ratios with 95% CI were estimated. The normality of continuous data was assessed using the Shapiro–Wilk test. A t-test or Mann–Whitney U-test was used as appropriate to compare groups. A Pearson or Spearman correlation coefficient was calculated as appropriate to determine the correlation between continuous variables.


  Results Top


The study consisted of 126 participants referred for coronary angiography. The study participants were aged between 32 and 84 years, with a mean age of 61.26 ± 9.44 years. Of 126 individuals, 88 (69.8%) were male and 38 (30.2%) were female. On angiography, 67 (53.2%) had Friesinger Index scores below 5, and 59 (46.8%) were 5 or above. The mean Friesinger Index score was 4.74 ± 3.83.

A Chi-square test was used to test for association between the severity of coronary lesions (high or low, by Friesinger Index dichotomized as <5 or ≥5) and other categorical variables. Expectedly, a significant association between severe coronary lesions and male sex was observed. Significant associations were also observed for TG levels and TG/HDLc ratio. No significant associations were present for HDLc, LDLc, or Tc. Frequencies of the categorical variables and results of the analysis are summarized in [Table 1].
Table 1: Chi-square test and odds ratios for categorical variables in Friesinger index groups

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A correlation coefficient (r) was used to assess the relationship of TG, HDLc and TG/HDLc levels with platelet and leukocyte parameters. A significant positive correlation was observed for TG with NLR and MPV. HDLc showed a significant negative correlation with ANC, NLR and MPV. TG/HDLc showed significant correlations with ANC, ALC, NLR, MPV, and PLR. No significant correlation existed for TLC and platelet count with any of the three lipid parameters. All three lipid parameters were also strongly correlated with the Friesinger Index score. The results are summarized in [Table 2].
Table 2: Correlation coefficients for triglyceride, high-density lipoprotein cholesterol and triglyceride /high-density lipoprotein cholesterol versus leukocyte and platelet parameters

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A Mann–Whitney U-test (nonparametric t-test) was applied to Friesinger Index groups (high or low, dichotomized by a value of 5) to compare leukocyte and platelet parameters between these two groups. A significant difference between high and low Friesinger Index groups was observed for ALC and NLR. No significant difference existed for TLC, ANC, platelet count, MPV, or PLR. The results are summarized in [Table 3].
Table 3: Median (interquartile range) of leukocyte and platelet parameters for Friesinger Index Score groups

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A receiver operator characteristic (ROC) curve was constructed for NLR and TG/HDLc ratio for predicting severe CAD (Friesinger Index Score ≥5) [Figure 1]. Area under curve (AUC) for NLR was 0.608 and for TG/HDLc ratio was 0.737. Optimum cutoff value for TG/HDLc ratio was 2.53 (sensitivity = 83.1%, specificity = 56.7%) and for NLR was 1.84 (sensitivity = 61.0%, specificity = 49.3%).
Figure 1: Receiver operator characteristic curve of neutrophil-to-lymphocyte ratio and triglyceride/high-density lipoprotein cholesterol ratio for coronary artery disease severity

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  Discussion Top


Elevated cholesterol levels have classically been implicated in the pathogenesis of CVDs, with emphasis on reducing cholesterol either through lowered dietary intake or therapeutically. However, several studies now indicate that Tc levels may not have any effect on the development of coronary diseases.[12] Recent studies also show no association between high dietary cholesterol and risk of heart disease, as was believed earlier.[13] It is also becoming clearer that total LDLc levels are not associated with heart disease.[14] In this study, no association was observed between elevated levels of either Tc or total LDLc levels with severe coronary lesions.

Elevated TG levels and a decreased HDLc are common in the South Asian population and is associated with an increased sdLDL subfraction, with TG/HDLc established as a surrogate marker for sdLDL.[7],[15] LDLc subfractions such as large buoyant and sdLDL, though well described, are difficult to assay in resource-limited settings. Rather than total LDLc, sdLDL is emerging as the risk factor for atherosclerosis and heart disease.[16] At the cellular level, this is possibly due to more rapid infiltration into the arterial wall of sdLDL, increased oxidation, and reduced affinity for LDL receptors, leading to greater endothelial dysfunction.[17]

High TG and Low HDLc have been established in previous studies as risk factors for coronary disease.[18],[19] The study found that an elevated TG level and an elevated TG/HDLc ratio were associated with more severe coronary lesions, with TG/HDLc ratio showing a stronger association [Table 1]. A significant correlation between Friesinger Index score and TG, HDLc, and TG/HDLc ratio was also observed [Table 2]. Increased TG and decreased HDLc levels are associated with oxidative stress, correlating closely with known inflammatory markers such as CRP and TNF-α, leading to endothelial damage.[20],[21] In our study, among the inflammatory parameters namely TLC, ANC, ALC, and NLR, only NLR moderately correlated with all the three lipid parameters of TG, HDLc, and TG/HDLc. TLC did not correlate well any of these three parameters. In addition, ANC was seen to correlate weakly with HDLc levels. Atherosclerosis is fundamentally an inflammatory disease, enabled by derangement in serum lipids. TG/HDLc ratio is an effective marker for dyslipidemia in the Indian population, and can be calculated easily from the routinely estimated parameters of TG and HDLc already present in the lipid profile.

Similarly, while several markers for systemic inflammation exist, most cannot be implemented clinically due to inaccessibility and high costs. In our study, NLR showed a stronger correlation with lipid variables, as compared to ANC, ALC, or TLC alone [Table 2]. The correlations between inflammatory and lipid variables, although significant statistically, were weak to moderate. This is perhaps attributable to the multifactorial nature of these individual variables, with a multitude of factors contributing to inflammation or dyslipidemia. We also observed that NLR was significantly higher among patients with Friesinger Index >5 compared to those with Friesinger Index <5. However, such a difference was not observed for TLC or PLR [Table 3]. As a component of the complete blood count, NLR is also an easily obtained parameter which could identify patients at risk for coronary disease. Moderate AUC values were observed in this study on ROC curve analysis of NLR and TG/HDLc for CAD severity. Optimum cutoff values were 1.84 and 2.53, respectively, for NLR and TG/HDLc ratio. TG/HDLc ratio was more sensitive than NLR, and both parameters had weak specificity.

Large studies have shown NLR to be an effective maker for CAD.[22],[23] However, the utilization of markers such as NLR or TG/HDL ratio in India is uncommon. Concerns over the rising costs of health care are at an all-time high. Epidemics such as that of CVDs are slow-growing, with the potential to become great economic burdens over time. Cost-effective diagnostic and therapeutic measures are the need of the hour, with special significance in countries like India. The study parameters assume importance as inexpensive screening tools, especially in the context of patients with multiple preexisting risk factors for CAD.

Amongst platelet parameters, MPV correlated well with TG, HDLc, and TG/HDLc ratio. Platelet size, as measured as MPV, is indicative of platelet reactivity. Endothelial injury resulting from dyslipidemia leads to an imbalance between procoagulant and anticoagulant effects of the endothelium. Larger, spherical, activated platelets are hence an indirect consequence of dyslipidemia. An elevated MPV has been shown to be associated with the risk of myocardial infarction.[24],[25] In our study, platelet count did not correlate with any lipid variables and did not vary significantly between patients of high or low Friesinger Index. PLR was also correlated with TG/HDL ratio, but this correlation was weak possibly due to no correlation between platelet count and TG/HDL ratio alone. MPV is also a relatively inexpensive test that is easily accessible, and its correlation with TG/HDLc indicates its potential utility as a screening tool.

Limitations

Prospective studies with adequately large sample size as required to suitably establish the role of various lipid and inflammatory mediators in the causation of coronary disease. The complete lipid profile including apoA, apoB, and Lp (a) could not be analyzed in this study. Furthermore, ethnic variations are expected to occur among most of the parameters in differing populations, and studies, including various ethnicities are warranted.


  Conclusions Top


The extent of coronary lesions was found to be associated with elevated TG and decreased HDLc levels, and high TG/HDLc ratio and NLR. There was no role of LDLc or Tc levels. NLR and MPV were also significantly associated with TG, HDLc, and TG/HDLc ratio, indicative of the inflammatory component of dyslipidemia. Easily accessible markers such as TG/HDLc and NLR are inexpensive and may be beneficial in monitoring patients at risk for heart disease.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Sekhri T, Kanwar RS, Wilfred R, Chugh P, Chhillar M, Aggarwal R. Prevalence of risk factors for coronary artery disease in an urban Indian population. BMJ Open 2014;4:e005346.  Back to cited text no. 6
    
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Gama R, Elfatih AB, Anderson NR. Ethnic differences in total and HDL cholesterol concentrations: Caucasians compared with predominantly Punjabi Sikh Indo-Asians. Ann Clin Biochem 2002;39:609-11.  Back to cited text no. 8
    
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Ivanova EA, Myasoedova VA, Melnichenko AA, Grechko AV, Orekhov AN. Small dense low-density lipoprotein as biomarker for atherosclerotic diseases. Oxid Med Cell Longev 2017;2017:1273042.  Back to cited text no. 16
    
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Li X, Ji Y, Kang J, Fang N. Association between blood neutrophil-to-lymphocyte ratio and severity of coronary artery disease: Evidence from 17 observational studies involving 7017 cases. Medicine (Baltimore) 2018;97:e12432.  Back to cited text no. 23
    
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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3]



 

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