Introduction to CHD occur in low- and middle-income


Cardiovascular disease (CVD), a leading
cause of morbidity and mortality worldwide, is accounting for 17.3 million
deaths per year and this number is expected to grow to be more than 23.6
million in 2030 1. In 2008, World Health Organization (WHO) reported that CVD
mortality was about 30% of total global deaths. Of those, approximately 7.4
million deaths were caused by coronary heart disease (CHD) 1, 2. CHD causes a
high morbidity rate ranges from 81 per 100.000 population in China to 718 per
100.000 population in Finland 3. Atherosclerosis of coronary arteries, the
main cause of CHD, is a complex inflammatory disorder, changes the cells of the
artery wall and the blood components 4, 5. Several inflammatory markers such
as troponin, C reactive protein (CRP), and B-type natriuretic peptide (BNP) or
pro-BNP are now used to identify the risk stratification and therefore to
identify patients at higher risk 6. A high-sensitivity CRP (hs-CRP), for example,
is one of the commonest predictor being used in predicting recurrent events, myocardial
infarction, or restenosis after percutaneous coronary intervention 7.
However, its usage in developing country is not routine due to the cost. In fact,
most of deaths due to CHD occur in low- and middle-income countries 1, 2.

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It has been hypothesized that the injury
of the vascular wall leads to an inflammatory response involving complex
interactions between endothelial and smooth muscle cells, leukocytes, and
platelets. Elevated leukocyte count, a marker of inflammation, has been
identified for a long time as an independent predictor of an increased risk for
long-term mortality and myocardial infarction both in individuals without CVD
at baseline and in patients with established CHD 8. Studies found that
leukocyte count was associated with aortic arch plaque thickness 9, progression
of aortic atheroma in patients with stroke 10, and it increased risk of
stroke andvascular death in patients with symptomatic intracranial
atherosclerotic disease 11. Another study revealed that neutrophil count was
prognostic marker for major adverse cardiac events in acute coronary syndrome
12. In addition, other components of the complete blood count, such as
hematocrit, platelet count, and erythrocyte sedimentation rate are also
associated with CHD. Combination of leukocyte count with other components of
the complete blood count could improve the ability to predict the risk of CHD
13, 14. Assessment of these blood components is inexpensive and widely
available. Therefore, the aim of this study was to investigate the possibility
of complete blood count as predictor of CHD.



designs and patients

A retrospective study was conducted in
Aisyiyah Hospital, Malang, Indonesia. The target population was all CHD
patients treated in Aisyiyah Hospital during January 2011 to December 2015 (610
patients – updated January 7th 2016). The inclusion criteria were (1) suffered
from CHD and (2) aged over 18 years. Patients with one of these clinical
conditions (renal dysfunction (creatinine ? 1.5 mg/dL), hepatic disorder,
concomitant inflammatory disease, neoplastic disease, systemic disorder, acute
or chronic infectious disease, haematological disorder, and on medications
which could affect complete blood count) were excluded. Information related to
gender, age, diagnosis, body mass index, mean arterial blood pressure, the
level of blood glucose, low-density lipoprotein (LDL), ureum and creatinin and
complete blood count was extracted from medical record. A simple random
sampling method was used to select 610 CHD patients (population size). The
sample of this study was 133 CHD patients and 50 controls as theminimum sample
size. Controls were obtained from healthy and or non-CHDindividualswith age-and
gender-matchedrecorded in Aisyiyah Hospital.



The response variable in this study was
the incidence of CHD. The explanatory variables in this study were hematocrit
(%), concentration of haemoglobin (g/dl), and the levels of erythrocytes,
leukocytes, thrombocytes, eosinophils, basophils, neutrophils, monocytes, and
lymphocytes (cell/µl). Those variable measurements, measured using XS – 800i
Hematology Analyzer (Sysmex Europe GmbH, Norderstedt, Germany), were retrieved
from medical record.



Association between complete blood count
and the risk of CHD were analyzed using double logistic regression. All
significance tests were two tailed and P-value of less than 0.05 was considered
to be statistically significant. All analysis were performed using the
Statistical Package of Social Sciences 17.0 software (SPSS Inc., Chicago, IL).



A meta-analysis was also performed to evaluate
the association between complete blood count and the risk of CHD. The approach
of meta-analysis was adapted from the previous studies 15-18. Briefly,
articles related to the association between complete blood count and the risk
of CHD were collected for calculating combined ORs 95% CI and assessed using
fixed or random effect model.


criteria and data extraction for meta-analysis

The inclusion criteria for this study were:
(1) retrospective studies; (2) prospective studies; (3) cross-sectional
studies; (4) randomized-controlled trials (RCTs); (5) controlled
before-and-after studies; (6) cross-over studies; (7) investigating the
association between complete blood count and the risk of CHD; and (8) providing
sufficient data for calculating OR 95% CI. The following information were extracted
from each study: (1) name of the first author; (2) year of publication; (3)
country of origin; (4) sample sizes of cases and controls, and (5) levels of
blood cells count.


strategy and literature for meta-analysis

We searched published articles up to
June 20th, 2016 in PubMed and Embase with no language restrictions. For searching
stategy, we used the combination of the following key words: (complete blood
count or CBC or hematocrit or haemoglobin or erythrocytes or leukocytes or
thrombocytes or eosinophils or basophils or neutrophils or monocytes or
lymphocytes) and (coronary disease or coronary heart disease or coronary artery
disease or myocardial infarct or ischemic heart disease or CHD or IHD or MI or
cardiovascular disease or heart disease OR angina). The publication languages
were limited to English.


analysis for meta-analysis

The correlation between complete blood
count and the risk of CHD was determined by calculating pooled ORs and 95% CIs.
The significance of pooled ORs was estimated by Z-tests (P value of less than 0.05
was considered statistically significant). A Q-test was conducted to evaluate
whether heterogeneity existed. A random effects model was used to calculate the
OR 95% CI if heterogeneity existed (P0.05). Forest
plots the association between leukocyte, eosinophil, and monocyte and the
risk of CHD are presented in Fig 2A-D.



Atherosclerosis, the main cause of CHD,
is a multifactoral disease that involve chronic inflammation at every stage
50. The inflammation process in atherosclerosis is a complex, and consist of
several steps 51. Complete blood count has been proven to be associated with
inflammation 52 and here we reported the correlation between complete blood
count and CHD. To the best of our knowledge, this report is the first study
conducted to assess the association between complete blood count and CHD in
Indonesia. The first was conducted in Japan 19. Basically, the concept of
this study is similar with previous studies and therefore the results of this
study are expected to be able to be used as the comparison.


Some studies have shown that
leukocytosis to be an independent risk factors of cardiovascular events 8,
42. There are several theories that explain the role of leukocytes in CHD.
Leukocytes cause vascular injury through several ways, including damage to the
endothelial cells caused by proteolytic and oxidative 53, 54, 55, plug the
microvasculature through binding to the ischemicendothelium via the leukocyte
integrin CD 11b/CD18 54, 56, induce hypercoagulability by increased
expression of tissue factor on leukocyte 54, 57, promote infarct expansion by
releasing pro-inflammatory cytokines 54, 57, 58, and destabilize of coronary
artery plaques 54.       Our study
revealed that leukocytes count increased the risk of CHD by 1.01. Although this
result indicates very small impact, our meta-analysis reveled that elevated
leukocyte increased the odds of having CHD by 3.5 times (OR 95%CI = 3.57 1.84
– 6.93, P