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Research Article | DOI: https://doi.org/10.31579/2692-9759/038
1 Department of Internal Medicine, Faculty of Medicine and Health Sciences, Alneelain University, Khartoum, Sudan
2 Interventional cardiology, Ahmad Gasim Cardiac Centre, Ahmad Gasim Hospital, Khartoum North, Sudan
3 Sudan Medical Specialization Board (S.M.S.B), Internal Medicine Council
4 Medical Biochemistry and Molecular Biology, Khartoum, Sudan.
*Corresponding Author: Hayder A Giha, Medical Biochemistry and Molecular Biology, Khartoum, Sudan.
Citation: Osman Al-Sayed Osman Alamin, Sara Osman AbdAllah Hassan, Hayder A Giha (2022) Disparity of risk factors and concordance of NLR with Gensini score in acute coronary syndrome in an Afro-Arab multiethnic nation J. Cardiology Research and Reports 4(2); DOI: 10.31579/2692-9759/038
Copyright: © 2022, Hayder A Giha, This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received: 11 December 2021 | Accepted: 25 December 2021 | Published: 05 February 2022
Keywords: ACS; ECG; angiography; gensini score; NLR
Background: Acute coronary syndrome (ACS), is ischemic heart disease of varying risk factors and clinical pattern and with immense health burden worldwide. Inflammation is believed to be an etiological factor in ACS, and neutrophil to lymphocyte ratio (NLR), to be a biomarker.
Objectives: To describe the clinical pattern and risk factors of ACS in Afro-Arabs of Sudan and to evaluate the NLR as a severity marker.
Method: In a total population, cross-sectional study, conducted in Al-Shaab Hospital- Sudan, clinical, laboratory and ECG data were used for ACS grouping into unstable angina (UA), non-ST-segment elevation myocardial infarction (NSTEMI) and STEMI. All patients underwent coronary angiography (CAG) and their Gensini score and NLR were calculated.
Results: A total of 130 patients (62.3% men) of a median age of 58.0, 50.0-65.0 yrs., (range 32.0-82.0), were diagnosed with ACS; 44.6% STEMI, 37.7% NSTEMI and 17.7% UA. The median Gensini score was higher in STEMI (42.5, 12.0-71.0) and NSTEMI (40.0, 15.8-60.5) compared with UA (10.0, 5.0-23.0), p 0.002, similarly, was the NLR; 3.5, 1.6-4.6; 2.9, 1.5-3.8 and 0.9, 0.8-1.1, respectively p<0.001. Furthermore, the NLR in concordance with CAG findings p<0.001. Finally, hypertension, diabetes mellitus and dyslipidemia, respectively, were stronger ACS risk factors in women than in men unlike smoking, and family history imposed the least risk.
Conclusion: While the ACS clinical pattern was in-line with literature, the risk factors order was different, and it was different between sexes. Importantly, the NLR strongly associated with ACS severity, but failed to distinguish between NSTEMI and STEMI.
ACS Acute coronary syndrome
MI Myocardial infarction
CAD Coronary artery disease
CAG Coronary angiography
CVD Cardiovascular disease
DM Diabetes mellitus
HDL High density lipoprotein
HTN Hypertension
LDL Low density lipoprotein
NLR Neutrohil lymphocyte ratio
NSTEMI Non-ST-segment elevation myocardial infarction
STEMI ST-segment elevation myocardial infarction
UA Unstable angina
Cardiovascular diseases (CVD) are one of the major causes of death worldwide. The World Health Organization declared that CVD are responsible of about 17.9 million death/year, which was 31% of the world deaths in 2016, of which 7.5 million are due to ischemic heart disease (IHD), mainly acute coronary syndrome (ACS) and sudden death [1]. The incidence of IHD increases with age, and it is responsible for more than half of all CVD in the ages < 75>
The ACS refers to a spectrum of clinical presentation ranging from ST-segment elevation myocardial infarction (STEMI) to non–STEMI (NSTEMI) and unstable angina (UA) according to the presence or absence of ST-segment elevation on initial ECG, in addition to measurement of myocardial biomarkers, such as troponin or creatine kinase, however in both condition there is myocardial necrosis [4, 5]. The UA is different from stable angina, which develops during physical activity or stress and resolves at rest, still there is no myocardial necrosis in UA [4, 6].
For ACS patients, coronary angiography (CAG) is usually conducted and assessed by specialized cardiologists. Significant CAD is assumed as a lumen diameter stenosis of ≥50% in the major coronary arteries e.g. left main, anterior descending or circumflex artery coronary arteries, right coronary artery, or one of their major branches [7].
The IHD is caused by atherosclerosis of the coronary arteries, which leads to development of unstable plaque as a result of chronic inflammatory mechanism [8, 9]. The rupture of the plaque is accompanied by a cascade of platelet reactions culminating in formation of thrombus, followed by occlusion of the affected coronary artery then ischemia/necrosis of the underlying myocardial tissue, leading to ACS [9]. Thus, inflammation plays is an important factor in both initiation and progression of atherosclerotic process [10], and increased neutrophil count is known to be associated with the development and severity of coronary atherosclerosis [11]. Neutrophil to lymphocyte ratio (NLR), is a combination of inflammatory markers in which the neutrophils are nonspecific markers of inflammation and lymphocytes are regulatory cells [12]. The association between NLR and various CVD, is well documented, thus there is propensity of the former to evolve into an accurate, inexpensive, and independent prognostic marker for diagnosis of ACS and predictor for its short and long-term mortalities [13]. In a recent study, NLR was found to be associated with severity and plaque morphology in patients with CHD [14], and the high NLR compared to low NLR at admission was found to be associated with higher mortality in STEMI and NSTEMI patients [15]. Furthermore, the NLR is significantly elevated in patients with low HDL-cholesterol and negatively correlated with high-density lipoprotein (HDL) which has anti-inflammatory activity [16]. However, which NLR value is correlated with a higher risk for developing atherosclerosis, which cut-off value will differentiate normal from abnormal results are still debatable. Different values of NLR, with different methods, in different populations are cited, with no universal value is currently available [17].
There is an extreme need for a reliable, accessible, less invasive prognostic marker in ACS that would help in early identifications of patients with high cardiovascular risk. The goal of this study is to describe the ACS risk factors and clinical spectrum in the biggest cardiology center in Sudan and included subjects with different ethnic decent (Afro-Arabs) to evaluate the potential use of NLR as a quick, reliable and affordable biomarker for grading the ACS severity in a country with limited resources. Moreover, the NLR have racial differences, thus it’s a necessity that data to be collated from all over the world.
Study design: Total-population, cross-sectional hospital-based study.
Study area. The study was conducted in Alshaab Teaching Hospital (ATH) in Khartoum, the main cardiac center in Sudan.
Study population: All patients with ACS admitted to ATH in the period from September to December 2020, with confirmed ACS and underwent coronary angiography, were included while active inflammation, infection, malignancy, hematological disorder, autoimmune disease, and immunosuppressive treatments, were the exclusion criteria. The patients were derived from different ethnic backgrounds of varying degrees of African and Arab race crossing.
Data collection: The personal, demographic, clinical and laboratory investigation data were collected from each participant with inclusion of information about potential cardiovascular risk factors e.g. hypertension (HTN), diabetes mellitus (DM), smoking history, dyslipidemia and family history of CAD.
Blood test: Hemoglobin (Hb), total and differential white blood cells (WBC), and platelets count were done using Sysmex XP 300 machine
Neutrophil / lymphocytes Ratios (NLR): The absolute neutrophil count was divided by the absolute lymphocyte count to calculate the NLR.
The ACS diagnosis:
The following investigations were doneto patients on arrival in the emergency room i. Electrocardiogram (ECG); the resting 12-lead ECG, ii. Cardiac biomarkers: measurement of cardiac troponin (cTn) T or I.
iii. Coronary angiography was done by expert interventional cardiologists.
Based on the clinical data in addition to the cardiac markers and ECG, patient were grouped into, STEMI, NSTEMI and UA [4]. The STEMI is suspected in patients presented with a consistent clinical history and ECG showed persistent (>20 minutes) ST-segment elevation (measured at the J-point) in at least two contiguous leads of ≥ 2.5mm in men < 40>
Assessment of coronary angiography
Coronary angiography (CAG) was conducted and assessed by experienced specialized cardiologists. Significant vessel disease (stenosis) was defined as a lumen diameter narrowing of ≥50% in the major coronary arteries; left main coronary artery, left anterior descending artery, left circumflex artery, right coronary artery, or one of their major branches. The CAD results categorized as; one-vessel disease (1-VD), two-vessel disease (2-VD; or left main trunk disease without right coronary artery stenosis) or three-vessel disease (3-VD; or left main trunk disease with right coronary artery stenosis).
Gensini score: Calculation of the Gensini score was initiated by giving a severity score to each coronary stenosis as follows: It defined narrowing of the lumen of the coronary arteries as 1 for 1 to 25% stenosis, 2 for 26 to 50%, 4 for 51 to 75%, 8 for 76 to 90%, 16 for 91 to 99%, and 32 for total occlusion. The score was then multiplied by a factor representing the importance of the lesion location in the coronary artery system. For the location scores, 5 points were given for a left main lesion; 2.5 for the proximal left anterior descending (LAD) or left circumflex (LCX) artery; 1.5 for the mid-segment LAD and LCX; 1 for the distal segment of the LAD and LCX, first diagonal branch, first obtuse marginal branch, right coronary artery, posterior descending artery, and intermediate artery; and 0.5 for the second diagonal and second obtuse marginal branches [18]. Finally, Gensini score of >25 was used to draw a cutoff point for the NLR atherogenic risk, using Receiver Operating Characteristics (ROC) program.
Ethical consideration
Ethical clearance was obtained from the research ethics committee at Sudan medical specialization board. Permission was obtained from A-Shaab Hospital management staff as a site for the study. Written and verbal consents were obtained from study participants. Confidentiality and anonymity of individual identity is maintained.
Statistical analysis
Sigma-Stat software was used for statistical analysis. T-test and One Way of Analysis of variance (ANOVA) were used for comparisons of normally distributed data (mean ± SD), while Mann-Whitney Rank Sum Test (MW) and Kruskal-Wallis One Way Analysis of Variance on Ranks (KW) were used for analysis of the data which was not normally distributed. The rates and proportions were analyzed by Chi-square test (χ2). The Pearson Product Moment Correlation was used for running the correlations.
Description of the study subjects
As shown in (Table 1), the total study subjects were 130 patients with ACS, of whom 81 were males and 49 females, aged between 32 and 82 years with a median age of 58.0 (50.0 - 65.0) years. As risk factors, the frequency of diseases associated ACS were as follows; hypertension (HTN) 49.2%, diabetes mellitus (DM) 43.8%, HTN/DM, 25.4% (33/130) and dyslipidemia 11.5%. While frequency of family history of ACS was 7.7% and of smoking was 24.6%. The average hematological indices for all subjects were; hemoglobin (Hb), 13.4 ± 1.5 g/dl, total white blood cells count (TWBC), 7.75, 6.4 - 10.0 x 109/L and platelets 282.2 ± 84.8 x 109/L. However, the female patients had significantly lower Hb (p<0>p 0.037) compared to males, but had comparable TWBC (p 0.379), (Table 2).
Acute coronary syndrome pattern:
The frequencies of the three clinical types of ACS, the unstable angina (UA), non-ST-segment elevation myocardial infarction (NSTEMI), and STEMI, were 17.7%, 37.7%, and 44.6%, respectively (Table 1). While the vast majority of the STEMI were males (72.4%), majority of the UA were females 56.5% and of the NSTEMI were males (59.2%). Although the NSTEMI patients were slightly older, the 3 groups of patients were comparable in age, p 0.388, KW. Notably, all the UA patients were ≥ 45 yrs. Furthermore the Hb and platelet count were comparable between the three groups with slightly lower Hb in UA and platelet in STEMI, p 0.089 and p 0.255, respectively, however, the TWBC was significantly higher in STEMI, followed NSTEMI compared to UA, p <0>
Acute coronary syndrome risk factors and sex:
The potential risk factors, HTN, DM, combined HTN/DM, dyslipidemia and family history of ACS were comparable between the 3 clinical groups, UA, NSTEMI and STEMI except for cigarette smoking which was significantly higher in STEMI, followed by NSTEMI compared to UA, p 0.028, as shown in (Table 1). However, most of the risk factors were significantly different between the male and females patients. Females compared to males had significantly more frequent HTN (p 0.021), DM (p 0.011), HTN/DM (p 0.035) and dyslipidemia (p 0.006), on the contrary males were significantly more frequent smokers (p<0>
Concordance of the coronary angiography (CAG) findings, Gensini score and the neutrophils/ lymphocytes ratio (NLR)
The Gensini score is a numerical estimation of the overall degree of ischemia and thus ACS severity, which was worked out from the visible angiographic findings, it was calculated based on the numbers and locations of stenosis in coronary arteries. The CAG showed, single vessel disease in 43 (33.1%) patients, three vessels disease in 38 (29.2%) patients, two vessels disease in 26 (20%) patients and non-significant CHD in 23 (17.7%) patients (data not shown).
As shown in (Fig. 1A), the Gensini score was markedly significantly different between patients with no (5.0, 2.25-6.75) or with single, (16.0, 7.25-30.0) double (44.0, 36.0-54.0) or triple (75.5, 62.0-99.0) coronary artery lesion regardless of the degree or location of stenosis, or the affected artery, p<0>
Figures legends:
Figure 1. Grouping of patients with acute coronary syndrome (ACS), based on cardiac angiography (CAG), into patients with; no significant stenosis (No), single vessel disease (SVD), double vessel disease (DVD) and three vessel disease (TVD). A. Comparison of the median Gensini score showed marked difference between the four CAG groups, p<0>p<0>p<0>
Interestingly, the NLR was similarly markedly significantly different between the patients in the same above 4 angiographic groups, patients with no stenosis (0.8, 0.78-1.08), single (1.5, 1.13-2.05), double (4.0, 2.9-4.9) or triple (3.9, 3.6-6.2) coronary artery lesion, p<0>
Finally, the ROC curve defined NLR cut-off value of atherosclerosis to be 2.2, with 88.89% sensitivity, and 91.38% specificity (data not shown).
The association of the NLR with the acute coronary syndrome types
The median NLR values were significantly different between the ACS clinical types, it was highest in STEMI (3.5, 1.6-4.6), followed by NSTEMI (2.9, 1.48-3.8) and lowest in UA (0.9, 0.8-1.1), p<0>p<0>p 0.255 (Table 1).
The correlations of Gensini score with NLR and individual hematological parameters
As shown in (Fig. 2) there was statistically significant positive correlation between the NLR and Gensini score, i.e., as the Gensini score increased the NLR was equivalently increased, CC 0.671, p<0>p<0> p<0>p<0>p 0.368 - data not shown).
in the main cardiac center in Sudan, and furthermore to evaluate the NLR as simple affordable non-invasive indicator for disease severity as compared to Gensini score.
Age and sex are two important variables in ACS, in this study most of the patients (62.3%) were males, with an overall average age of presentation of 58 years, nevertheless, 53.8% of the patients were aged between 40-60 years, an age related to structural changes in arteries [19]. As expected, women present earlier (median age of 56 yrs.), compared to men (60 yrs.), and as small as 32 yrs. old patients were seen among both men and women (Table 2), as noticed somewhere else [20]. Unexpectedly, while the median age for NSTEMI was 60 yrs., the median age in both STEMI and UA was 57 yrs., but a large sample study was previously declared that older people are more likely to develop NSTEMI than STEMI [21].
This study disclosed the fact that the vast majority (82.3%) of patients diagnosed with ACS were had myocardial infarction (USTEMI and STEMI) i.e., cardiac necrosis, while the remainders had myocardial ischemia due to UA. Additionally, the more sever MI, the STEMI, was the more frequent (45%), which was consistent with what was reported before [22]. Furthermore, all patient were underwent cardiac angiography (CAG), almost half of the patients had 2 or more coronary arteries with significant stenosis. As seen in (Fig. 1A), the Gensini score of 5.0, 16.0, 44.0 and 75.5, was reflecting angiographic classification; no significant stenosis, single (SVD), double (DVD) and three (TVD) vessel diseases, respectively, p<0>p 0.002, the Gensini score failed to distinguish between NSTEMI and STEMI, p 0.639, (Table 1).
The role of inflammation in atherosclerosis pathology and CVDs, and characterization of the latter as a chronic low-grade inflammatory conditions are now largely accepted [23, 24]. Of the markers of inflammation, the leukocytes (WBCs), namely neutrophils and lymphocytes [14]. In this study we noticed increased numbers of circulating TWBC and neutrophils on the contrary decreased lymphocytes, in patients with severe ACS (Table 1), as well as there were positive correlations of the TWBC and neutrophils and negative correlation of the lymphocytes with Gensini score, the ACS severity marker (Fig. 2). The NLR, which integrates the neutrophils and lymphocytes into a single biomarker, was found to be strong predictor for the ECG-dependent ACS clinical severity, in the present study. The NLR increment was more pronounced in the STEMI followed by NSTEMI compared to UA, in line with previous studies [13, 14). The NLR like the Gensini score, was also failed to distinguish between the NSTEMI and STEMI, p 0.154, (Table 1). However, the NLR was markedly positively correlated with the Gensini score (Fig. 2D), as reported before [11, 25]. The parallel increase of both markers as indicators for increased ACS severity was recognized in different sites [26, 27]. Although healthy control subject were not included in the present study, a previous study showed that, NLR was significantly higher in CVD patients than in normal subjects, as well as it varied according to ethnicity [28].
Despite the well established relationship between NLR and atherosclerosis, the association between NLR and complexity of the coronary arteries stenosis is rarely investigated [29]. In this study, the NLR was also varied significantly with the CAG findings, as the NLR was almost 4 times higher in patients with double (DVD) or three (TVD) coronary arteries stenosis/disease as compared to patients with non-significant arterial stenosis, and around three times higher compared to patients with single artery stenosis (SVD), Fig. (1B). Similar results were reported before [29, 30], although another study, debated this relationship [31].
However, of the limitations of the NLR use as a biomarker for ACS is the versatile non-specific nature of the inflammatory markers in general. A systematic review and meta-analysis showed that high NLR was significantly associated with all CVD outcomes including CAD, ACS, stroke, and composite CVEs [32]. Thus, for use in ACS the NLR need to be coupled with other investigations and suggestive clinical evidences.
In the present study seven risk factors for IHD, including sex were tested. The higher incidence of ACS in men compared with women over the study period was evident (Table 2), which is a well-known testimonial [33]. In this study, HTH was found to be the most common risk factor (49.2%) followed by DM (43.8%), smoking (24.6%), then dyslipidemia (11.5%) and finally family history of IHD (7.7%). However, in a large European study dyslipidemia was found to be the highest risk factor followed by HTN [22], however, in another study, smoking was found to be the commonest risk factor [33]. Chronically, HTN is implicated in atherosclerosis by damaging the blood vessel walls and possibility of plaque deposition. Alternatively, the high prevalence of HTN in general population in different regions including Sudan [34, 35], which is by far overweighing the ACS prevalence, gives false impression that HTN is the predominant IDH risk factor. Although, the above variables are well established risk factors for ACS [36], in the present study the frequency of these factors, except smoking, were not significantly different between the clinical types of ACS, the UA, NSTEMI and STEMI (Table 1). Interestingly, when splitting the patient into males and females, the above factors, except the family history, were found to show differential frequencies between men and women and probably being stronger risk factors for ACS in one sex more than the other (Table 2). Thus, HTN, DM, HTN/DM and dyslipidemia were likely to derive towards ACS in women more than in men, while smoking derive oppositely. As it stand, men probably bears an unidentified stronger risk factor/s than the mentioned ones since the prevalence of the IHD is significantly higher in men.
Finally, in the present study, the calculated NLR cut-off point for atherosclerosis was found to be >2.2. However there are several different approaches e.g. Interactive Dot Plot, were used to define the cu-off points for different goals with different values [11, 37]. In this setting, the NLR cut-off value of 2.2 was set to be used as a predictor of severity of atherosclerosis. Of the limitations of this study, the relatively small sample size and lack of healthy controls, as well as, other acute inflammation markers such as CRP, hs-CT, serum amyloid A, were not tested.
In conclusion, this study described the clinical pattern of ACS and highlighted the differences of the order of the traditional risk factors of IHD between the local and global orders and between sexes. The vast majority of patients had STEMI and NSTEMI, most of them were males with a median age for ACS of 58 years. HTN, DM and dyslipidemia, in this order, were more strongly associated with ACS in women while smoking was the main risk factor in men. The NLR was in strong concordance with the ECG-dependent clinical diagnosis, CAG findings and Gensini score, and proved to be a reliable indicator for ACS severity. The NLR cutoff value for ACS severity was found to be 2.2.
The authors highly appreciate the willingness of all patients and their families in participation and collaboration in this study. Many thanks are extended to the medical doctors, nurses and chemistry labs managers in Al-Shaab Teaching Hospital - Khartoum, for the unlimited assistance
Funding: No fund
Conflicts of interest/Competing interests: No conflict of interest for all authors to declare
Availability of data and material: The data is available upon genuine request
Code availability: 'Not applicable'
Authors' contributions (optional): 'Not applicable'
Ethics approval: The studies were ethically approved by the ethical committee of Sudanese medical speciation board (no reference number).
Consent to participate: An informed consent was obtained from each patient before inclusion in the study. The data was confidentially maintained
Consent for publication: Consent for publication was obtained.
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