1.

Introduction
Cardiovascular diseases (CVDs) refer to conditions that involve narrowed or
blocked blood vessels. CVDs are on the top of the list of causes of death globally,
where more people die annually from CVDs than from any other cause. An estimated
17.7 million people died from CVDs in 2015, representing 31% of all global deaths
(WHO, 2015). In the Eastern Mediterranean Region (EMR), an estimated 1.4 million
CVD deaths occurred in 2015, representing 34.1% of all deaths in the region. Over
three quarters of CVD deaths take place in low- and middle-income countries
(LMICs). CVDs were the principal causes of death in the Middle East and North
Africa in 2013. Death rates attributable to CVDs ranged from 145 per 100 000 (in
Qatar, which was the lowest) to 548 per 100 000 (in Yemen, which was the highest)
(Roth et al., 2015, Tehrani-Banihashemi et al., 2017).

Ischemic heart disease (IHD) is usually acute event and is mainly caused by a
blockage that prevents blood from flowing to the heart. IHD also known as coronary
heart disease (CHD) is the most common form of heart disease. Out of 17.7 million
CVDs deaths, an estimated 7.4 million were due to IHD (WHO, 2015). IHD was the
leading cause of death in the Middle East and North Africa in 2013. Out of 1.4 million
CVDs deaths occurred in 2015 in the EMR, about 58.4% were due to IHD. There
were 637,640 additional CVDs deaths in 2015 compared to 1990, out of which 62.5%
was contributed by IHD (Tehrani-Banihashemi et al., 2017, Roth et al., 2015). CHD
is almost always due to atherosclerosis.

Acute coronary syndrome (ACS) is increasing in Yemen in recent years and in-
hospital mortality was (8.6%), which a highest among overall mortality in the Gulf
states, and long-term mortality was high at 1 month follow-up (14.9%) and was even
higher at 1 year follow-up (17.4%). This was higher than the mortality rate in the Gulf
in 1 month and 1 year follow-up (7.2 and 9.4%) respectively (Al-Motarreb et al.,
2013). Therefore, a marker that could improve risk stratification and identify ACS at
an early stage would be beneficial to decreasing the morbidity and mortality of this
disease.

The effect of inflammation in ACS has been established. It has a major role in
the development and progression of atherosclerosis, the underlying process in the
blood vessels that result in ACS. To show this inflammatory effect, numerous markers
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such as high sensitive C-reactive protein (hs CRP), erythrocyte sedimentation rate
(ESR), white blood cell (WBC) count and its subtypes and interleukins have been
used to understand the effect of inflammation (Ross, 1999, Hansson, 2005).

In consideration of the important role that inflammatory processes play in ACS,

work has been focused on whether biomarkers of inflammation may help to improve
risk stratification and identify patient groups who might benefit from particular
treatment strategies. Of these biomarkers, C-reactive protein (CRP) has emerged as
one of the most important inflammatory markers. CRP, an acute phase protein, is
synthesized by hepatocytes in response to pro-inflammatory cytokines, in particular
interleukin-6 (IL-6). It has proven that CRP strongly and independently predicts
adverse cardiovascular events, including myocardial infarction, ischemic stroke, and
sudden cardiac death in individuals both with and without overt CHD (Shrivastava et
al., 2015).

High sensitive C-reactive protein (hs-CRP) can be used as a risk-marker for IHD.
In clinical scenario, hs-CRP estimation can be employed as a screening tool in the
prediction of future coronary artery events (Sabatine et al., 2007, Davis et al., 2012)
hs-CRP can be used as prognostic marker in patients with ACS and is a strong
independent predictor of future coronary events in apparently healthy subjects (Rifai
and Ridker, 2001). In additional, hs-CRP can probably be used as a surrogate marker
of chronic inflammation in patients with metabolic syndrome (Gowdaiah et al., 2016).
Elevated serum CRP levels is predictive of worse cardiovascular prognosis in patients
with resistant hypertension (Cortez et al., 2016).

IL‐6, an upstream inflammatory marker which increase in response to infections

or tissue injuries. After IL-6 is synthesized in a local lesion in the initial stage of
inflammation, it moves to the liver through the bloodstream. It induces hepatocytes to
produce acute phase proteins such as CRP (Tanaka et al., 2014). IL-6 was
independently associated with the risk of major adverse cardiovascular events and all‐
causes of mortality, myocardial infarction, heart failure, and cancer mortality in
patients with stable coronary heart disease. IL‐6 might reflect a pathophysiological
process involved in the development of these events (Held et al., 2017). However, hs
CRP and IL-6 laboratory tests are expensive and not available in contemporary
practice, particular in developing countries.
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 Recently, neutrophil to lymphocyte ratio (NLR) and monocyte to lymphocyte
(MLR) has emerged as one of the most important novel widely available, inexpensive
and robust inflammatory markers which can aid in the risk stratification of patients
with various CVDs (Bhat et al., 2013, Ji et al., 2017, Küçük et al., 2016, Sharma et
al., 2017).

Among the various inflammatory markers, NLR has emerged as a strongest

predictor of coronary artery disease (CAD) that could be useful as biomarker to
predict the future cardiovascular risk (Sharma et al., 2017). A high NLR has been
independent predictor of mortality and adverse outcomes in patients with ACS (Bhat
et al., 2013, Kounis et al., 2015, Tamhane et al., 2008). A high NLR has been
independent predictor of both in- hospital and long-term adverse outcomes that could
be used for risk stratification in patients with ST-elevation myocardial infarction
(STEMI) (Park et al., 2013). A high NLR has been closely correlated with lower
ejection fraction and higher long-term mortality in STEMIs patients (Arbel et al.,
2014).

The role of NLR seems to begin even before the occurrence of any target organ
damage, as was demonstrated in a cohort study a higher NLR significantly correlated
with an increased risk of developing hypertension compared to participants with lower
levels (Liu et al., 2015). In other studies in hypertension, patients with non-dipper
pattern (that is associated with cardiovascular mortality) presented significantly
higher mean NLR than those with dipper pattern (Demir, 2013). NLR is also
associated with resistant hypertension (Belen et al., 2015) and other risk factors for
atherosclerosis such as metabolic syndrome and diabetes (Buyukkaya et al., 2014,
Yilmaz et al., 2015).

MLR has been independent risk factor of the presence and severity of CAD and
compared to NLR, MLR has better performance to reflect the severity of coronary
lesion (Ji et al., 2017). MLR has been a strong and independent predictor of all-causes
of mortality and cardiovascular mortality (myocardial infarction, heart failure, cardiac
arrest, cerebrovascular accident, or peripheral vascular disease) among hemodialysis
patients (Xiang et al., 2017). A higher MLR has been independent risk factor of thin
cap fibrous atheroma in patients with stable angina (Fan et al., 2017). MLR is
strongly related to heart failure markers and predicts heart failure hospitalizations

3
during follow-up in patients with CAD (Gijsberts et al., 2017). MLR is correlated
with psycho-neuro-inflammatory factors in patients with stable CAD (Serfőző et al.,
2016).

The reference values in an adult, population in good health are between 0.78 and
3.53 at 95% CI for NLR (Forget et al., 2017). And for MLR the reference intervals
were 0.12 to 0.35 in male and 0.10 to 0.32 in female (Meng et al., 2018). This value
can be used as a cut-off to differentiate patients that are in the range of a population in
good health or not. However, the reference values of NLR and MLR vary with age,
ethnicity and environment. Therefore the use of arbitrary cut off points for risk
stratification will be inherently misleading. Suggesting that a tailored cut-off value
according to race would provide more precise prognostic information (Alexander,
2016, Misumida et al., 2015, Meng et al., 2018). Here in our comparative cross-
sectional study, we will use healthy individuals as control to distinguish between a
normal NLR and MLR values from abnormal.

Since most CVDs deaths occur in LMICs (including Yemen) with limited
resources and technical facilities, inflammatory markers and other cardiovascular
imaging modalities for risk assessment of ACS are rarely used in daily practice.
Therefore, there is a need for cheap and easily obtainable, widely available marker of
inflammation, that can be used in daily practice.

Since it has been hypothesized that the NLR and MLR may reflect ongoing
inflammation in various CVDs. Therefore, in our developing country a comparative
cross-sectional study will be design to investigate the association between NLR and
MLR as inflammatory markers and ACS.

2. Aims of the study

2.1. General objective

The study will be aimed to evaluate an association of neutrophil to lymphocyte ratio

(NLR) and monocyte to lymphocyte ratio (MLR) with acute coronary syndrome
(ACS).

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2.2. Specific objectives

This study will be done to:

1. Determine the sensitivity, specificity, predictive values and suitable cut-off of

NLR and MLR as potential biomarkers of ACS.
2. Highlight the potential application of these inflammatory markers (NLR &
MLR) as predictive biomarkers for patients with ACS.

3. Study design and subjects

3.1. Study design

A comparative cross-sectional study will be carried out.

3.2. Study area

The study will be carried out at Al-Thawra General Hospital in Sana'a city.

3.3. Sample size

Sample size at confidence level 95% is 80 participants with ACS calculated by

using Epi Info 6 version based on population size 1000000 patients and frequency of
CHD of 5.5% (Aljefree and Ahmed, 2015).

3.4. Study population

Study will include 200 participants. Based on electrocardiographic (ECG),

troponin and CK-MB results, as gold standard, the study population will be divided
into two groups:

1. Study group: This group will include 100 patients who admitted to the
cardiac center at Al-Thawra General Hospital and confirmed to have ACS by a
cardiologist after clinical examinations, cardiac enzymes and ECG findings.
2. Control group: This group will include 100 healthy individuals matched for
age and sex. These individual controls are confirmed to not have ACS by a
cardiologist after clinical examinations, cardiac enzymes and ECG findings.

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3.4.1. Definitions

Acute Coronary Syndrome

The World Health Organization (WHO) criteria for the diagnosis of ACS
require at least two of the following three elements to be present:
1. AMI with ST elevation (typical symptoms or ECG with segment ST elevation
and raised serum cardiac enzymes (CK-MB or troponin).
2. AMI without ST elevation (typical symptoms or ECG without ST-segment
elevation and raised CK-MB or troponin).
3. unstable angina (symptoms or ECG indicative of ischemia, with normal
enzymes) (Gomes et al., 2005).

3.5. Inclusion criteria

All the following patients will be included:

 Male and female patients were diagnosed to have ACS according to WHO
criteria for the diagnosis of ACS and their age equals to 18 years old or over.
 ACS patients with or without hypertension or diabetes mellitus.

3.6. Exclusion criteria

All the following patients will be excluded:

 Patients with ACS less than 18-years old

 Patients with CVDs other than ACS.
 Patients with ACS who had coronary artery bypass grafting (CABG).
 Patients with medical conditions or treatments known to effect the white blood
cell count, such as hematopoietic stem cell disorders, malignancies, chronic
renal failure, hepatic diseases, chronic infections and autoimmune diseases
such as systemic lupus erythematous and rheumatoid arthritis.

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4. Methods

4.1 Data collection

Data such as age, sex, smoking, clinical examinations and cardiac investigations
including ECG and cardiac enzymes (CK-MB and troponin) will be recorded into a
predesigned questionnaire.

4.2. Body mass index and blood pressure measurement

Body mass index (BMI) and hypertension will be evaluated for each patient and
control as following: -

 BMI will be evaluated by using balance and height meter to measure weight
and height, respectively. Then BMI will be calculated as weight (kg) over
length (m2).
 Hypertension will be evaluated by using simple mercury sphygmomanometer
to measure of systolic and diastolic blood pressure.

4.3. Sample collection

Five ml of venous blood will be collected from each selected patient and healthy
control divided into 2 tubes as follow:

 3 ml of whole blood will be placed into EDTA tube for hematological

parameters examinations.
 2 ml of whole blood will be placed in plain tube, and leaving it at room
temperature to allow blood to clot. Clotted blood sample will be centrifuged at
200g for 5 min. Then serum will be separated and pipetted into eppendorf tube
labeled with the name and serial number of each participant and stored at 2-8
ºC until further analysis. .

4.4. Complete blood cell examinations

Complete blood cell examinations include; total white blood cells (WBC) and its
subtypes including neutrophil, lymphocyte, monocytes, eosinophil and basophils will

7
be determined by using an automated Sysmex XS1000 hematology analyzer (Sysmex
Corporation, Kobe, Japan).

4.5. Neutrophil to lymphocyte ratio calculation

The NLR will be calculated as the ratio of neutrophil cell count to lymphocyte
cell count, obtained of complete blood counts.

4.6. Monocyte to lymphocyte ratio calculation

The MLR will be calculated as the ratio of monocyte cell count to lymphocyte
cell count, obtained of complete blood counts.

4.7. Erythrocytes sedimentation rate evaluation

EDTA blood samples will be diluted (1:4) with sodium citrate (Na3C6H5
O7.2H2O) for evaluation of erythrocytes sedimentation rate (ESR) by Westergren
method. The International Council for Standardization in Hematology recommends
the use of Westergren method as the standard method for measuring ESR (Jou et al.,
2011).

4.8. High sensitive C- reactive protein evaluation

Serum samples well be obtained for determination of CRP concentration by a

high-sensitivity immunoturbidimetry assay using CRP hs (BioSystems S.A). The
minimum detectable concentration of the CRP by this method estimated to be 0.06
mg/L.

4.9. Statistical Analysis

All statistical analysis will be carried out using Statistical Package for Social
Sciences (SPSS) program version 20.

5. Ethical consideration

The study will initiate after approval of postgraduate studies and scientific
research council of Sana'a University, written or verbal consent will be taken from all
participants to be included into the study, and they will be informed that participation
will be voluntary and they can free to withdraw from the research.
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6. Milestone

Plan Start date End date

Proposal 20: March: 2018 20: April: 2018

Field work and Lab. Work 21: April: 2018 01: August:2018

Data analysis 02:August: 2018 29: September 2018

Final report 01: October 2018 29: November: 2018

7. Budget

Details Amount
(US $)

For blood sample collection requirements (Needles 5ml, K3 EDTA tubes

(3-ml volume), plane tubes, eppendorf tubes, vacutainer holder, tourniquets, 100
disinfection swabs, adhesive dressing, rubber gloves, separate stoppers for
opened vacuum tubes and non-vacuum tubes and needle disposal box).

For blood pressure measurements requirements (simple mercury 100

sphygmomanometer, stethoscope, cuffs and non-elastic measuring tape).

For weight & height measurements requirements (balanced beam 50

scale and calibrated length rods of 150 cm and 200 cm).

For CBC examination requirements (CBC- solution). 300

For ESR evaluation requirements (sodium citrate

(Na3C6H5O7.2H2O), westergren pipettes, stainless steel rack for holding 50

pipette and timer).

For hs CRP evaluation requirements (C-reactive protein-hs (CRP-hs) 200
(BioSystems S.A ) and cuvettes).
Transportation 100

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