https://orcid.org/0000-0001-5367-8884
Abstract
Introduction
Cardiovascular diseases (CVDs) are major global health problem and are the third leading cause of death in the world. Most studies found the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were correlated with myocardial infarction and heart failure. Previous studies reported a higher risk of CVD among physicians but no study concerns NLR and the PLR to predict coronary artery disease (CAD) among the physicians.
Purpose
This study aimed to evaluate the role of blood features in the CBC, with a particular focus on NLR and PLR levels, in predicting the presence of CAD.
Patients and Methods
Data of Thai physicians who participated in the “Save Doctors’ Heart” project which was conducted between February 14 and October 31, 2022, were collected from personal information, work and health habits, physical examination, white blood cell (WBC), laboratory, cardiac testing, and presence of CAD. Prior to studying their association with CAD, optimal values of age and each blood parameter, NLR, and PLR were determined.
Results
Of 1161 physicians mean age was 47.7 ± 10.16 years. By cardiac tests, CAD was identified in 11.3%. Significantly higher levels of WBC, neutrophils, NLR, and lower platelets were found in physicians with CAD. Except for lymphocytes and platelets which exhibited a reverse association with CAD, other factors were found as significant risk factors for CAD by univariate analysis. By multivariate analysis, the independent risk factors for CAD in order of their adjusted odds ratio (aOR) were age ≥50 years (aOR 9.34), NLR ≥ 1.87 (aOR 2.75), CAC score > 1 (aOR 2.39), and PLR ≥ 161.66 (aOR 2.32).
Conclusion
NLR and PLR, older age and CAC score were found as independent factors predicting CAD. The findings of this study could potentially provide valuable insights into the relationship between blood parameters and CAD risk among physicians.
Introduction
Cardiovascular diseases (CVDs) pose a major global health problem, presenting a considerable threat to the worldwide population with high mortality rates.Citation1 Coronary artery disease (CAD) is one important type of CVD, ranking as the third leading cause of death, accounting for approximately 17.8 million deaths annually worldwide.Citation2 The symptoms of CAD include chest pain, discomfort, dizziness, fainting, fatigue, etc. However, some individuals have non-specific symptoms. Hence, it is crucial for the early detection of CAD in at-risk individuals for early detection, especially among those who are at risk. Complete blood count (CBC) is the most common test for providing crucial hematologic information. Abnormal CBC may indicate underlying health disorders, such as infection or inflammation.Citation3 The relationship between the inflammatory response, hematologic markers, and CVDs has been a subject of research. Increasing evidence suggests inflammation develops and progresses atherosclerosis, endothelial lesions, plaque formation, and disruption,Citation4 which lead to acute coronary syndrome (ACS), including myocardial infarction (MI) and unstable angina.Citation5 Fewer studies showed an association between white blood cell (WBC) count and cardiovascular event parameters, both as prognostic markers for predicting myocardial damage, severity, and mortality from CVD.Citation6–8 Most studies found that higher WBC counts, especially neutrophils, increase the risk of CAD and heart failure (HF).Citation9–11 Additionally, changes in the neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) levels are correlated with MI and HF.Citation12–17
Physicians, who bear significant responsibility for the health of the population, may also face health risks of their own. Previous studies reported a higher risk of CVD among physicians.Citation18–20 This can attribute to occupation-related stress, poor lifestyle and habits, and lack of exercise leading to high blood pressure (BP) and obesity, consequent to CVD.Citation19,Citation20 Our hospital conducted the corporate social responsibility (CSR) project, “Save Doctors’ Heart”, to assess the cardiac health of Thai physicians, specifically CAD through cardiac tests. This study aimed to evaluate the role of blood features in the CBC, with a particular focus on NLR and PLR levels, in predicting the presence of CAD.
Materials and Methods
Our hospital conducted the “Save Doctors’ Heart” project between February 14 and October 31, 2022, among Thai physicians aged 35–75 without congenital heart diseases. The inclusion criteria were physicians who were available to measure personal health, blood tests, and cardiac testing. Exclusion criteria were those who had a history or current autoimmune/hematologic/bone marrow disease, infection, inflammatory bowel disease, active cancer, steroid or inflammatory drug use, inadequate cardiac investigations, or only suspicious CAD without definite confirmation. Data were collected from personal health information including age, gender, BMI, personal history (hypertension, diabetes mellitus, dyslipidemia), work and health habits (weekly work hours, fiber in the diet, smoking, exercise, stress), physical examination (weight, height, BP, cardiovascular system), laboratory (WBC count, absolute neutrophils, absolute lymphocytes, platelet count, BP, blood sugar, lipid profiles), cardiac testing, and presence of CAD.
Cardiac testing is based on abnormal basic testing results and the cardiologist’s discretion. Non-invasive cardiac investigations included a 12-lead electrocardiogram (EKG), coronary artery calcium (CAC) scanning, exercise stress tests and/or echocardiogram, or stress echocardiogram. Additionally, coronary computed tomography angiography (CCTA) or coronary angiogram (CAG) may be performed. The CAC score obtained from the CAC scanning measures the amount of calcified plaque in the coronary arteries. This score provides valuable information about the extent of atherosclerosis and the risk of developing CAD. The collected blood was transferred to a test tube containing EDTA as an anticoagulant and sent to the laboratory unit to be assessed within one hour after venipuncture and analyzed by a Sysmex XN-1500 analyzer. The hospital conducted daily internal quality assessments of the laboratory, and annual external quality assessments of the laboratory were performed annually.
Ethics
The study received approval from the MedPark Institutional Review Board (COA-MPIRB 003/2023). A waiver of informed consent was obtained due to being a retrospective study. The data were collected from the archive of the CSR project (February to October 2022) between March 31 and May 31, 2023. The confidentiality of information was protected according to the Helsinki Declaration and was used only for research purposes. The individual identifiers were removed during data collection and were replaced with serial code numbers.
Statistic
Statistical analyses were performed using IBM SPSS Statistics for Windows, Version 26.0 (IBM Corporation, Armonk, NY, USA). Continuous variables were presented as mean ± standard deviation (SD) for normally distributed data or median and ranges for non-normally distributed data. Categorical variables were presented as frequency and percentage. For clinical data, BMI was categorized as underweight/normal (<25 kg/m2) or overweight/obese (≥ 25 kg/m2). Personal history of hypertension, diabetes mellitus, and dyslipidemia, and/or abnormal values identified in the project for the respective disorders were categorized as having such disorders. The CAC score was classified as “no evidence” (score 0–1) or “evidence of CAD” (score > 1).
The diagnostic performance, mean or median values of each blood component, NLR, and PLR to predict CAD were compared with the Area Under Curve (AUC). The optimal cut-off values of age and each blood feature were determined using Receiver Operating Curve (ROC) analysis to categorize them into 2 groups to assess their risk of CAD. Except for NLR and PLR, each value of the blood feature was rounded to the nearest whole number.
Group comparisons by univariable analysis were made using Student’s t-test or Mann–Whitney U-test for continuous variables and chi-square or Fisher’s exact test for categorical variables, as appropriate. Clinical important features or significant by univariate analysis were included for a multivariate analysis by logistic regression to explore independent factors or risk for CAD. Only blood features of NLR and PLR, significant clinical features, and cardiac testing were included in the multivariate analysis. A p-value <0.05 was considered statistically significant.
Results
Of 1244 physicians who participated in “Save Doctors’ Heart” project, 83 were excluded due to no CBC results/had it done elsewhere, CAD not confirmed, and history of the disease. A total of 1161 physicians were included in the study, the mean age was 47.7 ± 10.16 years, and 55.6% were female. Among the 1153 physicians with available data, 28.7% were overweight/obese, 46.1% had high BP, 29.7% had high blood sugar, and 77.0% had dyslipidemia. The echocardiogram, stress echocardiogram, exercise stress test, and CAC score evaluation were performed on different numbers of physicians. For CCTA/CAG was conducted as indicated. Our details about cardiac testing were presented elsewhere. The presence of CAD was confirmed in 11.3% of physicians.
shows the overall median values of each blood feature according to the presence of CAD. It was observed that physicians with CAD had significantly higher levels of WBC, neutrophils, and NLR. Each increase of 1000 cells/mm3 in WBC or neutrophils was associated with a 1.02-fold and 1.30-fold risk of CAD, respectively. On the other hand, the number of lymphocytes, platelets, and PLR was found to be lower among physicians with CAD, with platelets and PLR showing statistical significance. Each decrease of 1000 cells/mm3 of lymphocytes or platelets reduced the risk of CAD by 0.86 folds and 0.99 folds, respectively.
Table 1 Median Values of Blood Features According to the Presence of Coronary Artery Diseases
We evaluated the diagnostic performance of each blood component, NLR, and PLR in predicting CAD. Among these features, NLR, neutrophils, and total WBC count demonstrated higher AUC values compared to the other features ( Optimal thresholds for predicting the risk of CAD were determined for age and various blood features. The cut-off values for these thresholds were as follows: age (50 years), WBC (6350 cells/mm3), neutrophils (3570 cells/mm3), lymphocytes (1476 cells/mm3), platelets (239,500 cells/mm3), NLR (1.86), and PLR (161.66).
Table 2 Diagnostic Performance of Each Blood Component, Neutrophil to Lymphocyte Ratio and Platelets to Lymphocyte Ratio to Predict Coronary Artery Disease
The association between age, gender, personal illnesses, BMI, blood features, cardiac testing, and risk for CAD. Except for lymphocytes and platelets, which exhibited a reverse association with CAD, all others were at significant risk for CAD by univariate analysis. In the multivariate analysis, the risk factors for CAD in order of their adjusted odds ratio (aOR) were age ≥ 50 years (aOR 9.34), NLR ≥ 1.87 (aOR 2.75), CAC scores > 1 (aOR 2.39), and PLR ≥ 161.66 (aOR 2.32).
Table 3 Personal Characteristics, Blood Features, and Cardiac Testing to Predict Coronary Artery Disease
Discussion
Although the WHO Health Evidence Network reported that population screening for CVDs does not result in a reduction of morbidity and mortality,Citation1 it remains crucial to recognize the potential benefits of screening for individuals who are at risk. Therefore, it is necessary to carefully weigh the benefits and costs when considering an appropriate cardiac screening test, especially in countries with limited resources. The use of CBC as a tool for assessing the inflammatory response in the development and progression of atherosclerosis and cardiovascular events should yield potential benefits.Citation9
Our study discovered a significant association between CAD and increased WBC count, neutrophils, and NLR, along with a decrease in platelets and PLR. Although lower lymphocyte was found among the physicians with CAD, the difference was not statistically significant. Among these factors, elevated NLR, WBC count, and neutrophils had superior predictive performance for CAD compared to other parameters. When considering blood features and other clinical characteristics, independent risk factors for CAD included age ≥ 50 years, NLR ≥ 1.87, PLR ≥ 161.66, and a moderate to extensive CAC score. Age ≥ 50 years carried the highest risk of CAD (9.34-fold) compared younger group. Our study discovered that the risk for CAD of NLR (2.75-fold) and PLR (2.32-fold) was comparable with the risk associated with a CAC score >1 (2.39-fold). These findings are consistent with previous studies linking NLR and PLR to CVDs such as MI, heart failure, and death.Citation8,Citation12–14,Citation17
Several studies showed an association between an elevated WBC and neutrophil count with an increased risk of cardiovascular events. Citation6–11 A cohort study conducted in healthy young men reported an elevated WBC > 6900 cells/mm3 was associated with a 2.17-fold increase in the risk for CAD compared to elevated lipids or family history of CAD. It was found that each increment of 1000 cells/mm3 in WBC count led to a 1.17-fold increased risk for CAD.Citation11 Their results were consistent with this study which found a 1.02-fold risk of CAD with an increase of 1000 cells/mm3 in WBC count or a 2.13-fold risk with WBC ≥ 6500 cells/mm3. Previous studies found a direct association between high neutrophil or low lymphocyte counts with CAD, HF, and death.Citation21–24 For neutrophils, one study reported that a high (>6600/μL) or low (<1560 /μL) neutrophil had better function than total CBC for independently predicting death or MI in patients with high risk for CAD.Citation10 Our results, similar to previous study, also reported a 1.68-fold risk of CAD with neutrophils count ≥3500 cells/mm3 or 1.3-fold for an increase of every 1000 neutrophils/mm3.
The study of patients with chest pain found low lymphocytes (<1900 cells/mL) had a 2.45-fold increased risk for MI but high CBC or neutrophils were not.Citation25 Lymphopenia may be led by increased lymphocyte apoptosis.Citation26,Citation27 Our study was the same as their report regarding lower lymphocyte counts among the physicians who had CAD compared to the unaffected individuals. Although we found a 0.72-fold risk with lymphocytes <1500 cells/mm3 or 0.86-fold risk with a decrease of every 1000 lymphocytes/mm3, they were not statistically significant.
We found a significant association between CAD and platelet (0.99-fold risk with a decrease of every 1000 platelets/mm3 or 0.46-fold with ≥ 240,000 platelets/mm3). However, the results from the Danish population reported a high platelet count (301,000–450,000/L) was associated with an increased risk of CVD (1.32-fold) and mortality (1.43-fold).Citation28 The finding may be attributed to various influencing factors, such as the effect of heparin-induced thrombocytopenia, the use of antiplatelet drugs for hypertension or diabetes, the laboratory use of EDTA for blood test, or even diurnal variation or sleep pattern of the individuals.Citation29–31 These medications could potentially influence platelet counts and contribute to the observed differences in effect to an association between platelet counts and CAD risk.
Other studies demonstrated a direct association between higher NLR and cardiac morbidity and mortality.Citation10,Citation13,Citation15 For instance, one study found an NLR > 4.71 was associated with a higher risk of MI or death.Citation10 Others found elevated NLR was correlated with higher mortality in MI patients.Citation15 The authors who found NLR as a good predictor for 1-year mortality in MI patients undergoing surgery also supported its use as a prognostic indicator before the intervention, discharge, and long-term follow-up.Citation13
Contrary to our initial finding of a relationship between low platelet counts and CAD, our study revealed that a high PLR was associated with CAD. This suggests that the utilization of PLR may have mitigated the impact of confounding factors on platelet count. Our results regarding the higher value of PLR and CAD were in line with the previous report. The study in Chinese patients post coronary angiogram found patients with PLR > 171 had a 2.39-fold increased risk for 3-vessel CAD compared to those with PLR < 101.Citation32
Although our findings were generally consistent with previous studies regarding the higher risk of CAD or MI with high WBC count, neutrophils, NLR, and PLR, there were some differences in specific values of each blood parameter and the level of significance. These discrepancies may be attributed not only to variations in the characteristics of the participants in each study but also to differences in reported outcomes and the duration of follow-up periods. Hence, it is essential to carefully consider these factors for their clinical implications.
We were aware of some limitations in our study. Firstly, we lacked data on medications that could potentially impact blood features, particularly platelet counts. This absence of information might have influenced our findings. Secondly, our study focused solely on CAD as the outcome, without considering other CVDs, long-term outcomes, or mortality. Furthermore, the severity of CAD and long-term outcomes were not available. Expanding the scope to encompass CVDs, severity of CAD, and long-term follow-up could provide a better understanding of the relationship between blood features and cardiovascular health.
Nevertheless, our study had some strengths. Firstly, despite focusing solely on physicians, the findings were consistent with existing data, suggesting that the role of blood features can be extended to the general population. Secondly, the confirmation of CAD through cardiac testing enhanced the reliability of the study’s conclusions, as it ensured accurate identification of the condition. Thirdly, by determining the optimal values of each blood feature and their derivatives (NLR and PLR) in relation to CAD, our study should provide valuable insights into their association, contributing to the existing body of knowledge. Lastly, the incorporation of clinical features and cardiac testing in predicting NLR and PLR should have made the findings more robust. Furthermore, our findings were practical in clinical settings because CBC is a cost-effective screening test for physicians to assess their risk for CAD, even absence of symptoms. This test can serve as an initial step before considering cardiac testing.
Conclusion
NLR and PLR, along with older age and CAC score, were independent predictive features for CAD in physicians. The relationship between specific blood parameters and CAD risk among physicians may facilitate early detection and appropriate management of the disease in healthcare professionals. By improving doctors’ cardiac health, this project can have a positive impact not only on their well-being but also on the overall quality of patient care provided to the population.
Disclosure
The authors report no conflicts of interest in this work.
Acknowledgments
This research was granted by the Research Fund of MedPark Hospital.
References
- World Health Organization (WHO). World health statistics 2021: monitoring health for the SDGs, sustainable development goals; 2021 [ Cited March 21, 2023]. Available from: https://apps.who.int/iris/handle/10665/342703. Accessed December 27, 2023.
- GBD 2017 Causes of Death Collaborators. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1736–1788. doi:10.1016/S0140-6736(18)32203-7
- Dixon LR. The complete blood count: physiologic basis and clinical usage. J Perinat Neonatal Nurs. 1997;11(3):1–18. doi:10.1097/00005237-199712000-00003
- Libby P. The changing landscape of atherosclerosis. Nature. 2021;592(7855):524–533. doi:10.1038/s41586-021-03392-8
- Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352(16):1685–1695. doi:10.1056/NEJMra043430
- Anderson JL, Ronnow BS, Horne BD, et al. Usefulness of a complete blood count-derived risk score to predict incident mortality in patients with suspected cardiovascular disease [published correction appears in Am J Cardiol. 2012 Aug 15;110(4):614]. Am J Cardiol. 2007;99(2):169–174. doi:10.1016/j.amjcard.2006.08.015
- Ates AH, Canpolat U, Yorgun H, et al. Total white blood cell count is associated with the presence, severity and extent of coronary atherosclerosis detected by dual-source multislice computed tomographic coronary angiography. Cardiol J. 2011;18(4):371–377.
- Haybar H, Pezeshki SMS, Saki N. Evaluation of complete blood count parameters in cardiovascular diseases: an early indicator of prognosis? Exp Mol Pathol. 2019;110:104267. doi:10.1016/j.yexmp.2019.104267
- Hoffman M, Blum A, Baruch R, Kaplan E, Benjamin M. Leukocytes and coronary heart disease. Atherosclerosis. 2004;172(1):1–6. doi:10.1016/S0021-9150(03)00164-3
- Horne BD, Anderson JL, John JM, et al. Which white blood cell subtypes predict increased cardiovascular risk? J Am Coll Cardiol. 2005;45(10):1638–1643. doi:10.1016/j.jacc.2005.02.054
- Twig G, Afek A, Shamiss A, et al. White blood cell count and the risk for coronary artery disease in young adults. PLoS One. 2012;7(10):e47183. doi:10.1371/journal.pone.0047183
- Caimi G, Lo Presti R, Canino B, Ferrera E, Hopps E. Behaviour of the neutrophil to lymphocyte ratio in young subjects with acute myocardial infarction. Clin Hemorheol Microcirc. 2016;62(3):239–247. doi:10.3233/CH-151968
- Zuin M, Rigatelli G, Picariello C, et al. Correlation and prognostic role of neutrophil to lymphocyte ratio and SYNTAX score in patients with acute myocardial infarction treated with percutaneous coronary intervention: a six-year experience. Cardiovasc Revasc Med. 2017;18(8):565–571. doi:10.1016/j.carrev.2017.05.007
- Tahto E, Jadric R, Pojskic L, Kicic E. 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
- Dentali F, Nigro O, Squizzato A, et al. Impact of neutrophils to lymphocytes ratio on major clinical outcomes in patients with acute coronary syndromes: a systematic review and meta-analysis of the literature. Int J Cardiol. 2018;266:31–37. doi:10.1016/j.ijcard.2018.02.116
- Yang AP, Liu JP, Tao WQ, Li HM. The diagnostic and predictive role of NLR, d-NLR and PLR in COVID-19 patients. Int Immunopharmacol. 2020;84:106504. doi:10.1016/j.intimp.2020.106504
- Liu J, Ao W, Zhou J, Luo P, Wang Q, Xiang D. The correlation between PLR-NLR and prognosis in acute myocardial infarction. Am J Transl Res. 2021;13(5):4892–4899.
- Hegde SK, Vijayakrishnan G, Sasankh AK, Venkateswaran S, Parasuraman G. Lifestyle-associated risk for cardiovascular diseases among doctors and nurses working in a medical college hospital in Tamil Nadu, India. J Family Med Prim Care. 2016;5(2):281–285. doi:10.4103/2249-4863.192355
- Ambakederemo TE, Chikezie EU. Assessment of some traditional cardiovascular risk factors in medical doctors in Southern Nigeria. Vasc Health Risk Manag. 2018;14:299–309. doi:10.2147/VHRM.S176361
- Pillay R, Rathish B, Philips GM, Kumar RA, Francis A. Cardiovascular and stroke disease risk among doctors: a cross-sectional study. Trop Doct. 2020;50(3):232–234. doi:10.1177/0049475520911233
- Acanfora D, Gheorghiade M, Trojano L, et al. Relative lymphocyte count: a prognostic indicator of mortality in elderly patients with congestive heart failure. Am Heart J. 2001;142(1):167–173. doi:10.1067/mhj.2001.115792
- Huehnergarth KV, Mozaffarian D, Sullivan MD, et al. Usefulness of relative lymphocyte count as an independent predictor of death/urgent transplant in heart failure. Am J Cardiol. 2005;95(12):1492–1495. doi:10.1016/j.amjcard.2005.02.022
- Rudiger A, Burckhardt OA, Harpes P, Müller SA, Follath F. The relative lymphocyte count on hospital admission is a risk factor for long-term mortality in patients with acute heart failure. Am J Emerg Med. 2006;24(4):451–454. doi:10.1016/j.ajem.2005.10.010
- Vaduganathan M, Ambrosy AP, Greene SJ, et al. Predictive value of low relative lymphocyte count in patients hospitalized for heart failure with reduced ejection fraction: insights from the EVEREST trial. Circ Heart Fail. 2012;5(6):750–758. doi:10.1161/CIRCHEARTFAILURE.112.970525
- Núñez J, Sanchis J, Bodí V, et al. Relationship between low lymphocyte count and major cardiac events in patients with acute chest pain, a non-diagnostic electrocardiogram and normal troponin levels. Atherosclerosis. 2009;206(1):251–257. doi:10.1016/j.atherosclerosis.2009.01.029
- Uslu AU, Deveci K, Korkmaz S, et al. Is neutrophil/lymphocyte ratio associated with subclinical inflammation and amyloidosis in patients with familial Mediterranean fever? Biomed Res Int. 2013;2013:185317. doi:10.1155/2013/185317
- Uslu AU, Küçük A, Şahin A, et al. Two new inflammatory markers associated with Disease Activity Score-28 in patients with rheumatoid arthritis: neutrophil-lymphocyte ratio and platelet-lymphocyte ratio. Int J Rheum Dis. 2015;18(7):731–735. doi:10.1111/1756-185X.12582
- Vinholt PJ, Hvas AM, Frederiksen H, Bathum L, Jørgensen MK, Nybo M. Platelet count is associated with cardiovascular disease, cancer and mortality: a population-based cohort study. Thromb Res. 2016;148:136–142. doi:10.1016/j.thromres.2016.08.012
- Gregg D, Goldschmidt-Clermont PJ. Cardiology patient page. Platelets and cardiovascular disease. Circulation. 2003;108(13):e88–e90. doi:10.1161/01.CIR.0000086897.15588.4B
- Lippi G, Plebani M. EDTA-dependent pseudothrombocytopenia: further insights and recommendations for prevention of a clinically threatening artifact. Clin Chem Lab Med. 2012;50(8):1281–1285. doi:10.1515/cclm-2012-0081
- Gao E, Hou J, Zhou Y, et al. Mediation effect of platelet indices on the association of daytime nap duration with 10-year ASCVD risk. Platelets. 2021;32(1):82–89. doi:10.1080/09537104.2020.1719055
- Zhou D, Wang G, Fan Y, Wan Z, Liu X. Platelet to lymphocyte ratio is associated with the severity of coronary artery disease and clinical outcomes of percutaneous coronary intervention in the Chinese Han population. Exp Ther Med. 2017;13(2):731–738. doi:10.3892/etm.2016.3993