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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).
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).
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
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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.
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2.2. Specific objectives
The study will be carried out at Al-Thawra General Hospital in Sana'a city.
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
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).
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.
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4. Methods
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.
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.
Five ml of venous blood will be collected from each selected patient and healthy
control divided into 2 tubes as follow:
Complete blood cell examinations include; total white blood cells (WBC) and its
subtypes including neutrophil, lymphocyte, monocytes, eosinophil and basophils will
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be determined by using an automated Sysmex XS1000 hematology analyzer (Sysmex
Corporation, Kobe, Japan).
The NLR will be calculated as the ratio of neutrophil cell count to lymphocyte
cell count, obtained of complete blood counts.
The MLR will be calculated as the ratio of monocyte cell count to lymphocyte
cell count, obtained of complete blood counts.
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).
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
Field work and Lab. Work 21: April: 2018 01: August:2018
7. Budget
Details Amount
(US $)
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