Summary
Aim
We aimed to explore the value of peripheral blood neutrophil-to-lymphocyte ratio (NLR) for the clinical diagnosis and prognosis of elderly patients with chronic heart failure (CHF) and atrial fibrillation (AF).
Methods
A total of 248 eligible patients were followed up for five years, and divided into major adverse cardiovascular event (MACE) and non-MACE groups. The independent predictive factors for MACE were explored by multivariate logistic regression analysis. Based on quartile of NLR, they were divided into groups A to D. The duration of MACE was analysed using Kaplan–Meier survival curves. The diagnostic value of NLR for MACE
Results
Higher age, low-density lipoprotein cholesterol and NLR, lower left ventricular ejection fraction, diabetes and NYHA heart function class III and IV were independent predictive factors for MACE. The incidence of MACE rose with increasing NLR. Groups A to D had significantly different rates of acute myocardial infarction, severe arrhythmia and cardiac death (p < 0.05). The average duration of MACE in groups A to D were 49.31, 45.27, 43.63 and 40.34 months, respectively.
Conclusion
The sensitivity and specificity of NLR for diagnosis of MACE were 72.39 and 86.18%, respectively. NLR was an independent predictive factor for MACE in these elderly patients with CHF and AF.
Keywords: neutrophil-to-lymphocyte ratio, chronic heart failure, atrial fibrillation, prognosis
Chronic heart failure (CHF) refers to changes in cardiac structure and function due to various pathogenic factors, leading to ventricular filling, or impairment of the ejection function, pulmonary oedema, cardiogenic shock and other symptoms. Patients are prone to cardiovascular lesions during prognosis.1 With increasing age, the incidence of cardiovascular disease rises significantly, so elderly people are a high-risk group of HF patients. The incidence of HF in elderly patients above 65 years of age is five to 10 times that in younger adults, therefore seriously threatening the life and health of the elderly.2
The incidence of atrial fibrillation (AF) is significantly elevated with increasing severity of HF. AF then further reduces stroke volume and cardiac output in patients with CHF, significantly increasing the risk of major adverse cardiovascular events (MACE). Therefore, early diagnosis and therapeutic measures have important clinical significance for patients with CHF and AF.
Neutrophil-to-lymphocyte ratio (NLR) can directly reflect the inflammatory state and immune level of the patient, and it rises with myocardial ischaemia.3 In recent years, NLR has been widely used in the diagnosis of cardiovascular diseases, and when it is elevated, it has been confirmed in many studies to be an independent risk factor for coronary heart disease.4 However, the association between NLR and the prognosis of patients with CHF and AF is rarely reported. Therefore, this study aimed to explore the value of NLR in evaluation of disease risk and prognosis in patients with CHF and AF.
Methods
A total of 248 patients with CHF and AF, admitted to our hospital from October 2013 to June 2014, were selected. According to the New York Heart Association (NYHA) functional classification,5 there were 58 cases in class I, 62 in class II, 68 in class III, and 60 in class IV. Among the patients, there were 156 males (62.90%) and 92 females (37.10%), aged on average 72.04 ± 10.87 years (65–88).
Inclusion criteria were: (1) patients aged ≥ 65 years, (2) those meeting the relevant criteria in the Guideline for the Management of Heart Failure (2014) developed by the Society of Cardiology, Chinese Medical Association, and (3) those accompanied by paroxysmal, persistent or permanent AF based on the relevant standards in the Guideline for the Management of Atrial Fibrillation (2014). All patients gave informed consent to this study, and the study was approved by the hospital ethics committee.
Exclusion criteria were: (1) patients with cardiac dysfunction caused by congenital heart disease, pulmonary heart disease, primary valvular heart disease, or acute myocardial infarction, (2) those with malignant tumours, (3) those with severe hepatic or renal dysfunction, (4) those who failed to complete the study as required due to mental disorders, or (5) those whose condition of disease became stable for less than one week after the acute phase of CHF.
The basic clinical parameters such as gender, age, smoking history, body mass index, blood pressure, diabetes history and hypertension history were collected. In addition, 5 ml of fasting venous blood was drawn from each patient in the morning, the day after percutaneous coronary intervention. It was anticoagulated with EDTA and centrifuged at 3 000 rpm and 4°C for 15 minutes.
The serum was examined using a fully automatic biochemical analyser (Hitachi Labospect 008) to determine creatinine (Cr), total cholesterol (TC), low-density lipoprotein cholesterol (LDLC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), fasting plasma glucose (FPG), and blood urea nitrogen (BUN) levels. Neutrophils and lymphocytes were counted using a haematology analyser (Sysmex XE2100). Within 24 hours of admission, left ventricular ejection fraction (LVEF) was determined using a DW-F3 Doppler ultrasonic diagnostic system (DAWEI).
All patients enrolled were followed up for five years through the out-patient clinic, by re-examination, re-hospitalisation and telephone. The occurrence of MACE was taken as the end point of follow up. MACE include acute myocardial infarction, congestive HF, ischaemic stroke, peripheral arterial occlusion, recurrent angina, severe arrhythmia (persistent ventricular tachycardia, ventricular fibrillation, new-onset haemodynamically unstable AF or atrial flutter, high-grade atrioventricular block, excluding reperfusion arrhythmia during PCI), and cardiac death.6
Statistical analysis
SPSS20.0 software (SPSS Inc, Chicago, IL, USA, 2011) was used for statistical analysis. Quantitative data in line with normal distribution are expressed as means ± standard deviation, and one-way analysis of variance was performed for comparison between groups. Numerical data are expressed as percentages, and the chi-squared test was performed for intergroup comparison. Factors related to MACE were analysed through multivariate logistic regression models.
The diagnostic value of NLR for MACE was analysed using the receiver operating characteristic (ROC) curves. Survival curves were plotted using GraphPad 5 software, survival analysis was conducted using the Kaplan–Meier method, and the difference in survival curves was detected using the log-rank test. A p-value < 0.05 was considered statistically significant. The corrected test level α = 0.0206 was used in the pairwise comparison among groups.
Results
All 248 patients were divided into MACE and non-MACE groups according to whether MACE occurred during the follow-up period. Compared with the non-MACE group, the MACE group had a higher age, higher proportion of cases with a history of smoking and diabetes, LDL-C and FPG level, NLR and NYHA functional class (III + IV), and lower LVEF. The differences were statistically significant (p < 0.05) (Table 1).
With the presence or absence of MACE during the follow-up period as the dependent variable, and the statistically significant factors in univariate analysis as the independent variables, multivariate logistic regression analysis was performed. The results showed that higher age, LDL-C level and NLR, and lower LVEF and diabetes, and NYHA class III and IV were independent predictive factors for MACE (p < 0.05) (Table 2).
Based on the quartile of NLR, the patients were divided into group A (NLR < 1.98), group B (1.98 ≤ NLR < 2.85), group C (2.85 ≤ NLR < 4.62) and group D (NLR ≥ 4.62). The incidence of MACE during follow up in each group is shown in Table 3. It was found that the incidence of MACE rose with increased NLR and the differences were statistically significant between groups (p < 0.05). There were statistically significant differences in the incidence of acute myocardial infarction, severe arrhythmia and cardiac death among the four groups (p < 0.05), but the incidence of other MACE showed no statistically significant differences (p > 0.05).
Table 1. Baseline clinical data of MACE and non-MACE groups [mean ± standard deviation/number (%)].
| Index | Non-MACE group (n = 152) | MACE group (n = 96) | t/x² | p-value |
| Age (year) | 53.97 + 10.19 | 67.24 + 10.12 | 10.016 | < 0.001 |
| Male | 92 (60.53) | 64 (66.67) | 0.951 | 0.33 |
| BMI (kg/m²) | 24.42 + 2.11 | 24.67 + 2.01 | 0.926 | 0.356 |
| Smoking history | 70 (46.05) | 62 (64.58) | 8.116 | 0.004 |
| Systolic pressure (mmHg) | 134.37 + 12.89 | 135.18 + 13.33 | 0.476 | 0.635 |
| Diastolic pressure (mmHg) | 84.25 + 7.63 | 85.34 + 8.17 | 1.066 | 0.287 |
| Diabetes mellitus | 60 (39.47) | 55 (57.29) | 7.512 | 0.006 |
| Hypertension | 87 (57.24) | 58 (60.42) | 0.245 | 0.621 |
| LVEF (%) | 58.07 + 6.18 | 39.42 + 3.98 | 26.312 | < 0.001 |
| Cr (umol/l) | 75.91 + 22.54 | 74.45 + 20.32 | 0.516 | 0.606 |
| TC (mmol/l) | 4.21 + 0.51 | 4.22 + 0.49 | 0.153 | 0.879 |
| TG (mmol/l) | 1.50 + 0.06 | 1.51 + 0.10 | 0.984 | 0.326 |
| LDL-C (mmol/l) | 2.84 + 0.12 | 2.96 + 0.15 | 6.953 | < 0.001 |
| HDL-C (mmol/l) | 1.27 + 0.19 | 1.26 + 0.15 | 0.437 | 0.663 |
| FPG (mmol/l) | 6.93 + 0.65 | 7.63 + 0.96 | 6.846 | < 0.001 |
| BUN (mmol/l) | 5.44 + 1.39 | 5.46 + 1.33 | 0.112 | 0.911 |
| NLR | 2.38 + 0.21 | 4.32 + 0.38 | 32.38 | < 0.001 |
| NYHA functional class | 47.616 | < 0.001 | ||
| I + II | 100 (65.79) | 20 (20.83) | ||
| III + IV | 52 (34.21) | 76 (79.17) |
BMI: body mass index; BUN: blood urea nitrogen; Cr: creatinine; FPG: fasting plasma glucose; HDL-C: high-density lipoprotein cholesterol; LDL-C: lowdensity lipoprotein cholesterol; LVEF: left ventricular ejection fraction; MACE: major adverse cardiovascular event; NLR: neutrophil-to-lymphocyte ratio; NYHA: New York Heart Association; TC: total cholesterol; TG: triglycerides.
Table 2. Multivariate logistic regression analysis of independent predictive factors for MACE.
| ß | SE | Wald | p-value | OR (95% CI) | |
| Age < 60 | 1.000 | ||||
| 60 | 2.304 | 0.467 | 22.657 | 0.008 | 10.291 (3.789-24.315) |
| Smoking history No | 1.000 | ||||
| Yes | 2.644 | 0.854 | 0.212 | 0.323 | 2.32 (0.021-6.544) |
| Diabetes mellitus | |||||
| No | 1.000 | ||||
| Yes | 0.542 | 0.343 | 1.743 | 0.001 | 1.622 (1.311-3.245) |
| LDL-C | |||||
| < 2.30 mmol/l > 2.30 mmol/l NLR | 0.020 | 0.010 | 2.6987 | 0.001 | 1.000 2.022 (1.987-2.056) |
| < 3.50 | 1.000 | ||||
| > 3.50 | 1.501 | 0.341 | 19.412 | < 0.001 | 4.159 (2.378-8.814) |
| LVEF | |||||
| < 50% > 50% FPG | -0.432 | 0.308 | 58.802 | < 0.001 | 1.000 0.657(0.365-0.802) |
| < 7.1 mmol/l > 7.1 mmol/l | 0.759 | 0.218 | 11.242 | 0.014 | 1.000 2.142 (1.391-3.132) |
| NYHA heart function class | |||||
| I + II | 1.000 | ||||
| III + IV | 0.987 | 0.458 | 0.102 | 0.005 | 1.854 (2.654-4.654) |
FPG: fasting plasma glucose; LDL-C: low-density lipoprotein cholesterol; LVEF: left ventricular ejection fraction; MACE: major adverse cardiovascular event; NLR: neutrophil-to-lymphocyte ratio; NYHA: New York Heart Association.
Table 3. Prognosis of patients with different NLR values.
| Group A | Group B | Group C | Group D | |||
| (n = 62) | 'n = 62) | (n = 62) | (n = 62) | x² | p-value | |
| Acute myocardial | 1 | 5 | 8 | 10 | 8.488 | 0.037 |
| infarction | ||||||
| Congestive heart failure | 1 | 3 | 2 | 2 | 1.033 | 0.793 |
| Ischaemic stroke | 1 | 1 | 1 | 1 | 0.000 | 1.000 |
| Peripheral artery occlusion | 2 | 2 | 1 | 1 | 0.683 | 0.877 |
| Recurrent angina | 3 | 3 | 1 | 1 | 2.067 | 0.559 |
| Severe arrhythmia | 2 | 3 | 6 | 10 | 8.064 | 0.045 |
| Cardiac death | 2 | 4 | 8 | 11 | 8.674 | 0.034 |
| Total | 12 | 21 | 27 | 36 | 20.803 | < 0.001 |
NLR: neutrophil-to-lymphocyte ratio.
According to the Kaplan–Meier curves of patients with CHF and AF, the average duration of MACE was 49.31 months in group A, 45.27 months in group B, 43.63 months in group C and 40.34 months in group D. It was confirmed using the log-rank test that the survival curves of patients with MACE showed statistically significant differences among the four groups (p < 0.05; group A vs group B; p = 0.006, group A vs group C; p = 0.002, group A vs group D; p = 0.001, group B vs group C; p = 0.009, group B vs group D; p = 0.011, group C vs group D; p = 0.018) (Fig. 1).
Fig. 1.
Survival analysis of patients with different NLR values undergoing MACE. MACE: major adverse cardiovascular event; NLR: neutrophil-to-lymphocyte ratio.
The ROC curves showed that the area under the curve, optimal cut-off value, sensitivity and specificity of NLR for MACE in patients with CHF and AF were 0.879 (95% CI: 0.801–0.978, p < 0.001), 3.12, 72.39% and 86.18%, respectively (Fig. 2).
Fig. 2.
Predictive value of NLR for MACE. MACE: major adverse cardiovascular event; NLR: neutrophil-tolymphocyte ratio.
Discussion
CHF is a clinically common and frequently occurring disease. The proportion of patients with HF in the total population is as high as 2–3%, even in developed countries.7 AF is a common type of arrhythmia and also has a high rate of incidence. HF and AF often co-exist, and the rate of incidence of AF in patients with HF is up to 54%. There is a positive correlation between the degree of HF and the rate of incidence of AF, and the rate of incidence of AF in HF patients in NYHA class IV is 10 times that in patients in class I.8
There has been a consensus in multiple studies that the long-term prognosis of patients with HF and AF is poor. Both chronic diseases seriously affect the quality of life of patients and impose a heavy burden on the medical system.9 However, there are no reliable methods for predicting the prognosis of patients with CHF and AF. Therefore, we urgently need to find new markers to improve the early identification of adverse prognostic events and improve the quality of life of such patients.
AF leads to a decline and even disappearance of atrial systolic function in patients with HF, it causes irreversible embolism and a systemic inflammatory response, and reduces lymphocyte counts in patients, ultimately resulting in a steady increase in NLR in the blood.10 It has been confirmed in a large number of studies and clinical practice that NLR serves as an evaluation index for diagnosis and prognosis of patients with cardiac insufficiency.11 Determining NLR in plasma in patients with CHF and AF has been a subject of study in recent years. It is currently believed that NLR is an ideal marker of myocardial injury, and the level has a significant positive correlation with the degree of myocardial injury.12
NLR has predictive value for the prognosis of a variety of cardiovascular diseases.13 Patients with coronary heart disease have a higher NLR in plasma.14 Furthermore, NLR in plasma is higher in patients with acute myocardial infarction than that in patients with unstable angina, while it is also higher in the latter than that in patients with stable angina. After correcting for a variety of traditional cardiovascular risk factors, NLR can be used as a predictor for major adverse events of AF.15 In our study, the results of logistic regression analysis showed that NLR was an independent predictive factor for MACE in patients with CHF and AF.
In our study, the patients were divided into four groups based on the quartile of NLR. It was found that the difference in incidence of MACE was statistically significant between the four groups (p < 0.05), manifesting as increased incidence of acute myocardial infarction, severe arrhythmia and cardiac death with increasing NLR. AF raises both resting heart rate and response heart rate, further reducing cardiac output and elevating cardiac filling pressure, which is the internal cause of aggravation of HF by AF and an important factor causing acute myocardial infarction.16 AF is a common type of arrhythmia, and CHF can further enhance atrial depolarisation and repolarisation dispersion and cause re-entry more easily, thereby leading to severe arrhythmia.17
In this study, according to the analysis results of Kaplan–Meier survival curves, the duration of MACE in group D was significantly shorter than that in groups A and B. Yylmaz et al. demonstrated that NLR > 3.08 was an independent predictor of new-onset myocardial infarction and in-hospital death in patients with HF.18 In our study, the ROC curves showed that the optimal cut-off value and area under the curve of NLR for MACE in patients with CHF and AF were 3.12 and 0.879, respectively, confirming their high diagnostic value.
Conclusion
NLR was an independent predictive factor for MACE in these patients with CHF and AF, and it had high diagnostic value, which is of importance for adopting the appropriate therapeutic regimen and improving prognosis as early as possible.
Acknowledgments
This study was financially supported by Xintai Research and Development Project (No 2020ZC272).
Contributor Information
Qin Jie, Email: faridik92@yahoo.com.
Hua Yang, Department of Clinical Laboratory, Xingtai Third Hospital/ Xingtai Cardiovascular Hospital, Xingtai 054000, Hebei Province, PR China.
Sufang Feng, Department of Clinical Laboratory, Xingtai People’s Hospital, Xingtai 054000, Hebei Province, PR China.
References
- 1.Fontana J, Zima M, Vetvicka V. Biological markers of oxidative stress in cardiovascular diseases: after so many studies, what do we know? Immunol Invest. 2018;47(8):823–843. doi: 10.1080/08820139.2018.1523925. [DOI] [PubMed] [Google Scholar]
- 2.Ayesta A, Martinez-Selles H, de Luna AB. et al. Prediction of sudden death in elderly patients with heart failure. J Geriatr Cardiol. 2018;15(2):185–192. doi: 10.11909/j.issn.1671-5411.2018.02.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Yalcinkaya E, Yuksel UC, Celik M. et al. Relationship between neutrophil- to-lymphocyte ratio and electrocardiographic ischemia grade in STEMI. Arq Bras Cardiol. 2015;104(2):112–119. doi: 10.5935/abc.20140179. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Awad F, Assrawi E, Jumeau C. et al. Impact of human monocyte and macrophage polarization on NLR expression and NLRP3 inflammasome activation. Plos One. 2017;12(4):e0175336. doi: 10.1371/journal.pone.0175336. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Shang X, Xiao S, Dong N. et al. Assessing right ventricular function in pulmonary hypertension patients and the correlation with the New York Heart Association (NYHA) classification. Oncotarget. 2017;8(52):90421. doi: 10.18632/oncotarget.19026. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Zhu Q, Xiao W, Bai Y. et al. The prognostic value of the plasma N-terminal pro-brain natriuretic peptide level on all-cause death and major cardiovascular events in a community-based population. Clin Interv Aging. 2016;11:245–253. doi: 10.2147/CIA.S98151. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Richards AM, Troughton RW. Use of natriuretic peptides to guide and monitor heart failure therapy. Clin Chem. 2012;58(1):62–71. doi: 10.1373/clinchem.2011.165704. [DOI] [PubMed] [Google Scholar]
- 8.Guan P, Liang Y, Wang N. Fasudil alleviates pressure overload-induced heart failure by activating Nrf2-mediated antioxidant responses. J Cell Biochem. 2018;119(8):6452–6460. doi: 10.1002/jcb.26662. [DOI] [PubMed] [Google Scholar]
- 9.Tahto E, Jadric R, Pojskic L. et al. Neutrophil-to-lymphocyte ratio and its relation with markers of inflammation and myocardial necrosis in patients with acute coronary syndrome. Med Arch. 2017;71(5):312–315. doi: 10.5455/medarh.2017.71.312-315. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Yan W, Li JZ, He KL. The relationship between neutrophil-to-lymphocyte ratio and major cardiovascular events in elderly patients with chronic heart failure. J Geriatr Cardiol. 2017;14(12):780. doi: 10.11909/j.issn.1671-5411.2017.12.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Budzianowski J, Pieszko K, Burchardt P. et al. The role of hematological indices in patients with acute coronary syndrome. Dis Markers. 2017;2017:3041565. doi: 10.1155/2017/3041565. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Durmuş G, Belen E, Can MM. Increased neutrophil to lymphocyte ratio predicts myocardial injury in patients undergoing non-cardiac surgery. Heart Lung. 2018;47(3):243–247. doi: 10.1016/j.hrtlng.2018.01.005. [DOI] [PubMed] [Google Scholar]
- 13.Zhang S, Diao J, Qi CM. et al. Predictive value of neutrophil to lymphocyte ratio in patients with acute ST segment elevation myocardial infarction after percutaneous coronary intervention: a meta-analysis. BMC Cardiovasc Disord. 2018;18(1):75. doi: 10.1186/s12872-018-0812-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Wang X, Fan X, Ji S. et al. Prognostic value of neutrophil to lymphocyte ratio in heart failure patients. Clin Chim Acta. 2018;485:44–49. doi: 10.1016/j.cca.2018.06.021. [DOI] [PubMed] [Google Scholar]
- 15.Dong G, Huang A, Liu L. Platelet-to-lymphocyte ratio and prognosis in STEMI: a meta-analysis. Eur J Clin Invest. 2020;e13386 doi: 10.1111/eci.13386. [DOI] [PubMed] [Google Scholar]
- 16.Verdoia M, Barbieri L, Di Giovine G. et al. Neutrophil to lymphocyte ratio and the extent of coronary artery disease: results from a large cohort study. Angiology. 2016;67(1):75–82. doi: 10.1177/0003319715577529. [DOI] [PubMed] [Google Scholar]
- 17.Wandell P, Carlsson AC, Holzmann MJ. et al. The association between relevant co-morbidities and prevalent as well as incident heart failure in patients with atrial fibrillation. J. Cardiol. 2018;72(1):26–32. doi: 10.1016/j.jjcc.2017.12.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Yylmaz S, Canpolat U, Bater K. et al. Neutrophil-to-lymphocyte ratio predicts functionally significant coronary artery stenosis in patients with stable coronary artery disease. Arch Turk Soc Cardiol. 2018;46(2):129–135. doi: 10.5543/tkda.2017.16709. [DOI] [PubMed] [Google Scholar]