Heart, Lung and Circulation (2016) 25, 1077–1086 ORIGINAL ARTICLE

1443-9506/04/$36.00
http://dx.doi.org/10.1016/j.hlc.2016.02.023

Monocyte to HDL Cholesterol Ratio

Predicts Coronary Artery Disease Severity
and Future Major Cardiovascular Adverse
Events in Acute Coronary Syndrome
Mehmet Serkan Cetin, MD, Elif Hande Ozcan Cetin, MD *,
Erol Kalender, MD, Selahattin Aydin, MD, Serkan Topaloglu, MD,
Halil Lutfi Kisacik, MD, Ahmet Temizhan, MD
Türkiye Yuksek Ihtisas Education and Research Hospital, Cardiology Department, Ankara Turkey

Received 20 October 2015; received in revised form 22 February 2016; accepted 24 February 2016; online published-ahead-of-print 12 April 2016

Background We aimed to investigate the usefulness of monocyte to HDL cholesterol ratio (MHR) in predicting coronary
artery disease severity and future major adverse cardiovascular events (MACE) in patients with acute
coronary syndrome (ACS).
Methods 2661 patient with ACS were enrolled and followed up during median 31.6 months.

Results MHR were significantly positively correlated with neutrophil to lymphocyte ratio (r = 0.438), CRP
(r = 0.394), Gensini (r = 0.407), and SYNTAX score (r = 0.333). During in-hospital and long-term follow-
up, MACE, stent thrombosis, non-fatal MI, and mortality occurred more frequently in the third tertile group.
Kaplan-Meier analysis revealed the higher occurrence of MACE in the third tertile group compared with
other tertiles. Adjusting for other factors, a MHR value in the third tertile group was determined as an
independent predictor of in-hospital and long-term MACE.
Conclusions MHR as a novel inflammation-based marker seemed to be an independent predictor of severity of coronary
artery disease and future cardiovascular events in patients with ACS. MHR may utilise the identification of
patients who are at higher risk for MACE and individualisation of targeted therapy.
Keywords Monocyte to HDL ratio  Acute coronary syndrome  Inflammation  Gensini score  SYNTAX score

oxidative stress, and endothelial dysfunction in the initiation

Introduction
Despite the improvements in antithrombotic therapy and
innovations in reperfusion strategies, the outcome of the
patients with acute coronary syndrome (ACS) still remains
unsatisfactory. Mounting interest focusses on the identifica-
tion of new prognostic markers better enabling the catego-
risation of patients who are at higher risk for future
cardiovascular events. Considering the role of inflammation,
and progression of atherosclerotic process, various inflam-
matory biomarkers including C-reactive protein, and inter-
leukin-6 have been reported to be associated with severity of
coronary artery disease and prognosis.
Circulating monocytes as a source of various cytokines and
molecules, interact primarily with platelets and endothelial
cells leading to aggravation of inflammatory, pro-thrombotic
pathways [1]. On the contrary, high-density lipoprotein

*Corresponding author at: Yuksek Ihtisas Education and Research Hospital, Cardiology Department, Kızılay Street, Ankara, 06100, Turkey.
Tel.: +90 555 720 3753, Email: dr.elifhande@gmail.com
© 2016 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V.
All rights reserved.
1078
cholesterol (HDL-C) counteracts these proinflammatory and
prooxidant effects of monocytes by hindering the migration
of macrophages and oxidation of LDL molecules as well as
promoting the efflux of cholesterol from these cells [2]. In
addition to the HDL-C particles’ well-known anti-inflamma-
tory and antioxidant actions, recently these molecules have
been claimed to have a suppressive role in controlling mono-
cyte activations and proliferation-differentiation of the pro-
genitor cells of monocytes [3,4].
As a recently emerged inflammation-based marker, the
monocyte count to HDL-C ratio (MHR) has been reported
as a new predictor and prognostic indicator of cardiovascular
diseases [5–7]. In the STEMI patient population, MHR has
been represented to be a predictor of stent thrombosis and in-
hospital MACE as well as mortality [8,9]. However, there is
no data on the association of this parameter with the severity
of coronary artery disease and long-term outcomes in
patients with ACS.
In this prospective study, we aimed to investigate the
usefulness of MHR in predicting coronary artery disease
severity and future major adverse cardiovascular events in
patients with ACS.
Materials and Methods
Study Population
A total of 3269 consecutive patients who were admitted to
our tertiary, heart-specialist hospital with ACS and under-
went primary percutaneous coronary intervention (pPCI)
between 2009-2015, were enrolled. Consistent with the Dec-
laration of Helsinki, this study was approved by the Institu-
tional Ethics Committee. Informed consent was obtained
from all participants. Acute coronary syndrome was diag-
nosed based on the criteria recommended by the current
American College of Cardiology and European Society of
Cardiology guidelines.[10–13]
Patients who had a previous history of coronary revascu-
larisation either CABG or PCI, active infection, haematolog-
ical (including anaemia), oncological or inflammatory
disease, renal or hepatic insufficiency, severe valvular dis-
ease, hypo- and hyperthyroidism, treatment with fibrinolytic
agents (only or before referral for pPCI) were excluded. After
elimination according to the exclusion criteria, the remaining
2661 patients were included and followed-up for median 31.6
months (Range 1-63 months). The patient population was
assigned into tertiles based on the admission MHR level. The
33rd and 66th percentile were determined as cut-off points.
Hypertension was defined as receiving antihypertensive
therapy and/or having an arterial blood pressure (BP)
>140 mmHg for systolic and/or 90 mmHg for diastolic BP.
Diabetes mellitus was diagnosed with the use of an antidia-
betic drug and a fasting blood glucose >126 mg/dl. Hyper-
lipidaemia was considered as total cholesterol >200 mg/dl,
low density lipoprotein-cholesterol (LDL-C) >130 mg/dl, tri-
glyceride (TRG) >150 mg/dl or receiving lipid-lowering
medication. Patients, who were smoking or quit smoking
M.S. Cetin et al.
within the last year, were classified as smokers. A family
history of premature CAD was defined as CAD in a parent or
sibling diagnosed under the age of 55 for men and 65 years
for women.
Laboratory Parameters
Blood samples were collected during the emergency room
admission before any medical therapy and pPCI. Dry tubes
for biochemical tests and tubes with EDTA for the haemato-
logical test were used. Erythrocyte count, haemoglobin, hae-
matocrit, and white blood cell (WBC) count were measured
using an automated haematology analyser XE-1200 (Sysmex,
Kobe, Japan). The biochemical measurements were deter-
mined by using a molecular analyser (Roche Diagnostics,
Mannheim, Germany). Baseline MHR was calculated by
dividing the monocyte count by the HDL cholesterol count.
Echocardiography
Baseline 2D and Doppler echocardiographic examination
was performed by experienced echocardiographers in the
intensive coronary care unit to assess left ventricular ejection
fraction (LVEF), left ventricular diameters and mechanical
complications within the first 48 hours by using the same
commercially available system (GE Vivid 7 Pro, Horten,
Norway) with a 1.5–3.6 MHz multi-frequency phased array
probe.
Coronary Angiography and Percutaneous
Coronary Intervention
Our hospital is a high volume tertiary, heart-specialised
hospital with the facility to perform PCI 24 hours, seven days
a week. Every patient who is admitted with chest pain to our
emergency department is assessed initially by a cardiology
specialist. Premedication (intravenous unfractionated hepa-
rin 100 IU/kg, 600 mg clopidogrel and 300 mg aspirin) is
given immediately in the emergency room, and the patients
are admitted to the catheterisation laboratory. Average door-
to-balloon time is under 30 minutes. Coronary angiography
followed by pPCI via femoral approach with the conven-
tional technique was performed to achieve adequate blood
flow for the infarct-related artery. Procedural decisions, such
as the size and type of diagnostic or guiding catheter, direct
stenting or predilatation, the necessity of thrombus aspira-
tion and device selection (stent type (drug-eluting stent
[DES] or bare metal stent [BMS]), size, length) as well as
usage of adjunctive pharmacotherapy (including glycopro-
teinIIb/ IIIa receptor antagonists) were made at the discre-
tion of the individual interventional cardiologist for the
procedure. Cobalt chromium BMS (CommanderTM, Alvi-
medica and TangoTM, MicroPort) and everolimus and pac-
litaxel-eluting stents (XienceV Everolimus Eluting Coronary
Stent System, Abbott Vascular and TAXUS Paclitaxel-Eluting
Coronary Stent System, Boston Scientific Corporation) were
used. After stent implantation, angiographic optimisation
was performed by high-pressure dilatation to provide a
satisfactory angiographic result. Procedural success was
MHR and Acute Coronary Syndrome
defined as a residual stenosis of <20% without major com-
plications (i.e., stent thrombosis, need for emergent CABG or
repeat PCI, coronary dissection or rupture, and death).
Unless cardiogenic shock emerged, the other stenotic lesions
in coronary arteries were not targeted for any intervention in
the index procedure.
The evaluation of coronary angiograms and determination
of Gensini and SYNTAX score were made by two interven-
tional cardiologists who were blinded to the laboratory and
clinical follow-up data of the patients. In the case of disagree-
ment, a third interventional cardiologist who was blinded to
the other interpretations evaluated the coronary angiograms.
Endpoints
The primary composite endpoint was determined as MACE
including stent thrombosis, non-fatal MI, cardiovascular
mortality during in-hospital and long-term follow-up period.
According to the Academic Research Consortium ‘definite
ST’ criteria, ‘definite’ ST was defined as angiographic confir-
mation of a thrombus originating from the stent or 5 mm
proximal or distal to the stent, with total or partial vessel
occlusion leading to MI [14]. Non-fatal MI was considered as
the recurrence of chest pain and/or new ECG changes with a
new dynamic change (>20% rise from baseline) in cardiac
biomarkers (CKMB and troponin I levels) [10,11]. ‘Cardio-
vascular mortality’ was diagnosed as death because of
life-threatening arrhythmias, MI, congestive heart failure,
cardiac arrest, death attributed to cardiac events.
Follow-up
The post-intervention antiplatelet medication based on
current guidelines included lifelong acetylsalicylic acid
(75-150 mg/day) and clopidogrel (75 mg/day) for at least
12 months.
All patients were scheduled for an elective clinical follow-
up at one, six and 12-months as well as for every six months
thereafter and earlier if they developed any symptoms. We
clinically monitored the patients for cardiovascular events
and DAPT adherence. As well, follow-up data were docu-
mented from the hospital records, telephone calls with the
patients, their relatives, and/or their general practitioners, as
well as from the pharmacy databases and hospital records.
The follow-up data were verified with the Ministry of Health
records and Turkish National Population Register. The cause
of death was determined based on medical records or death
certificates.
Statistical Analysis
The continuous variables were reported as mean  standard
deviation (SD) and the categorical variables were expressed
as the number of patients and percentages. The comparisons
between MHR tertiles were performed with one-way
ANOVA (for continuous variables), Kruskal-Wallis tests
(for non-parametric variables) and chi-square test or Fisher’s
exact test for the categorical variables. Pearson correlation
analysis was performed to assess the correlation of MHR
with neutrophil to lymphocyte ratio, CRP, Gensini, and
1079
SYNTAX score. Cox proportional multivariate hazards
regression model was used to determine the risk ratio of
the MHR tertiles (comparing the third tertile versus others)
for occurrence of MACE, non-fatal MI, cardiovascular death
and ST during both in-hospital and long-term follow-up.
The effects of different variables on the occurrence of in-
hospital and long-term MACE in univariate analysis were
analysed, and the variables whose unadjusted p-value was
<0.05 were specified as potential risk markers and included
in the full model. The model was constituted by using for-
ward elimination at multivariate regression analyses, and
potential risk markers were eliminated by using likelihood
ratio tests. Receiver operating characteristic analysis was
used to determine the cut-off values of MHR to predict in-
hospital and long-term MACE.
Kaplan-Meier analysis was applied to evaluate the MACE-
free survival, free survival between MHR tertiles. A p < 0.05
(two-sided) was considered significant. Data were analysed by
using SPSS 20.0 software.
Results
A total of 2661 patients (1766 male, 66.4%; mean age 59.818.2)
with the diagnosis of ACS were enrolled and followed-up
during median 31.6 months (range 1-63 months).
Comparison of the Tertile Groups
Baseline characteristics, laboratory parameters, and coronary
angiographic findings of the patient groups according to the
MHR tertile groups are demonstrated in Table 1. Peak CKMB,
Gensini and SYNTAX scores were higher and also the neces-
sity of GIIb/IIIa inhibitors, multivessel disease, and no-reflow
phenomenon were more prevalent in the third tertile group.
In correlation analysis, admission MHR were significantly
positively correlated with neutrophil to lymphocyte ratio
(r = 0.438, p < 0.001), CRP (r = 0.394, p < 0.001), Gensini
(r = 0.407, p < 0.001), and SYNTAX score (r = 0.333,
p < 0.001) (Figure 1).
Comparison of Clinical Outcomes
The median follow-up duration was not different between
tertile groups (p=0.722). The in-hospital and long-term
MACE (with the events composing MACE) were represented
comparing MHR tertile groups (Table 2). During in-hospital
and long-term follow-up, MACE, the prevalence of stent
thrombosis, non-fatal MI, and mortality occurred more fre-
quently in the third tertile group. The results of Cox regres-
sion analysis for in-hospital and long-term clinical outcomes
are also shown in Table 2. Having a MHR in the third tertile
was associated with a 1.4-fold increased risk of in-hospital
and long-term MACE.
In ROC analysis, a MHR cut-off of 144.3 had 80.2% sensitiv-
ity and 69.8% specificity for prediction of in-hospital MACE
(AUC = 0.770, 95CI%: 0.745-0.795, p < 0.001) (Figure 1). Also, a
MHR cut-off value of 142.9 had 81.5% sensitivity and 71.2%
specificity for prediction of long-term MACE (AUC =0.806,
95CI%: 0.785-0.827, p<0.001) (Figure 2).
1080 M.S. Cetin et al.

Table 1 Comparison of the baseline characteristics and laboratory parameters among the tertiles of Monocyte to HDL ratio

Variables Tertile 1 Tertile 2 Tertile 3 P Value

(n=887) (n=887) (n=887)
(62.5-121.6) (122.1-158.2) (158.4-247.7)

Demographics
Age (years) 59.618.4 59.818.2 60.018.2 0.486
Male gender, n (%) 578 (65.2%) 587 (66.2%) 601 (67.8%) 0.507
Diabetes mellitus, n (%) 229 (25.8%) 200 (22.5%) 241 (27.2%) 0.070
Smoking, n (%) 298 (33.6%) 307 (34.6%) 315 (35.5%) 0.697
Family history of CAD, n (%) 195 (22.0%) 174 (19.6%) 211 (23.8%) 0.103
Hypertension, n (%) 307 (34.6%) 292 (32.9%) 281 (31.7%) 0.420
Hyperlipidaemia, n (%) 408 (46.0%) 393 (44.3%) 395 (44.5%) 0.739
BMI, kg/m2 24.03.1 23.93.2 24.13.4 0.722
Previous Medication
ASA, n (%) 238 (26.8%) 272 (30.7%) 248 (28.0%) 0.185
ACE inh, n (%) 396 (44.6%) 365 (41.1%) 355 (40.0%) 0.121
Beta blocker, n (%) 336 (37.9%) 346 (39.0%) 320 (36.1%) 0.438
Diuretic, n (%) 136 (15.3%) 104 (11.7%) 121 (13.6%) 0.085
Statin, n (%) 230 (25.9%) 204 (23.0%) 201 (22.7%) 0.206
Laboratory Parameters
LVEF on admission (%) 42.07.7 41.67.0 41.97.2 0.513
Haemoglobin (mg/dl) 14.41.3 14.21.5 14.31.3 0.548
Platelet (/mm3) 259.445.6 257.744.1 26249.4 0.318
WBC (103 mL) 12.04.8 12.14.4 12.24.9 0.554
Neutrophil (103 mL) 6.91.3 6.71.5 6.81.4 0.607
Lymphocyte(103 mL) 2.31.2 2.71.3 2.81.5 0.185
Monocyte (103 mL) 0.450.14 0.580.16 0.790.18 <0.001
Total cholesterol (mg/dl) 181.234.5 184.835.3 185.533.6 0.084
LDL-C (mg/dl) 111.730.5 118.528.3 113.530.2 0.304
On-treatment LDL-C (mg/dl) 82.427.6 83.7 27.5 82.828.0 0.181
HDL-C (mg/dl) 42.812.7 41.510.9 39.510.1 0.070
Triglyceride (mg/dl) 162.159.9 164.866.4 166.465.8 0.470
Glucose (mg/dl) 104.936.4 106.531.4 108.335.2 0.131
Urea (mg/dl) 33.87.7 34.17.4 34.47.9 0.418
Serum creatinine (mg/dl) 0.880.22 0.920.23 0.900.21 0.102
Albumin (g/dL) 4.50.2 4.40.3 4.50.4 0.203
Peak CK-MB, IU/L 65.726.4 68.828.1 74.229.3 0.002
Angiographic Characteristics
Use of GpIIb/IIIa inhibitor, n (%) 125 (14.1%) 144 (16.2%) 167 (18.8%) 0.026
No reflow, n (%) 70 (7.9%) 87 (9.8%) 105 (11.8) 0.020
Total number of stents 1.50.6 1.60.4 1.50.4 0.149
Mean stent diameter* (mm) 3.10.5 3.00.4 3.10.7 0.389
Total stent length (mm) 23.94.7 24.15.1 24.54.9 0.059
Pain to balloon (hours) 4.22.8 4.42.1 4.32.6 0.617
Multivessel disease (n,%) 222 (25.0%) 234 (26.4%) 269 (30.3%) 0.034
SYNTAX score 36.511.5 38.012.2 38.913.4 0.001
Gensini score 40.713.8 42.114.2 44.715.4 <0.001
DES (n,%) 173 (19.5%) 213 (24.0%) 197 (22.2%) 0.069
Hospitalisation (days) 7.12.9 7.23.4 7.23.6 0.168
Killip class >II(n,%) 226 (25.5%) 232 (26.2%) 261 (29.4%) 0.135
DAPT interruption <30 days (n,%) 29 (3.3%) 35 (3.9%) 32 (3.6%) 0.747
DAPT interruption <180 days (n,%) 79 (8.9%) 87 (9.8%) 97 (10.9%) 0.357
Adherence to DAPT for 1 year (n,%) 751 (84.7%) 743 (83.8%) 748 (84.3%) 0.870

Data are expressed as mean  standard deviation for normally distributed parametric variables and percentage for categorical variables. The DAPT(dual
antiplatelet therapy) interruption was defined as the cessation of either aspirin or/and clopidogrel for at least 1 day within 1 year from PCI. The timing of
interruption was determined as the first interruption day.
Abbreviations: ASA, acetylsalicylic acid; ACE angiotensin converting enzyme; BMI, body mass index; CAD, coronary artery disease; DAPT, dual antiplatelet
therapy; DES, drug eluting stent; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; LVEF, left ventricular ejection fraction;
MI, myocardial infarction; PCI, percutaneous coronary intervention; WBC, white blood cell.
MHR and Acute Coronary Syndrome 1081

Figure 1 Correlation of monocyte to HDL ratio with Gensini score (Figure 1a) and SYNTAX score (Figure 1b). Each dot
represents one patient; the straight line represents the best fit line obtained by linear regression analysis.

Table 2 In-hospital and long-term major adverse cardiac events stratified by monocyte to HDL ratio tertile groups and
Cox regression analysis

Variable Monocyte to HDL ratio Cox regression analysis

(Third Tertile vs Others)

Tertile 1 Tertile 2 Tertile 3 P value HR (95%CI) P value

In-hospital MACE (n,%) 35 (3.9%) 50 (5.6%) 67 (7.6%) 0.005 1.406 (1.144-1.727) 0.001
Stent thrombosis (n,%) 13 (1.5%) 25 (2.8%) 34 (3.8%) 0.009 1.592 (1.177-2.152) 0.003
Non-fatal myocardial infarction (n,%) 23 (2.6%) 38 (4.3%) 49 (5.5%) 0.008 1.605 (1.185-2.011) 0.001
In-hospital CV mortality (n,%) 12 (1.4%) 22 (3.5%) 34 (3.8%) 0.004 1.835 (1.328-2.535) <0.001
Long term MACE (n,%) 63 (7.1%) 99 (11.2%) 124 (14.0%) <0.001 1.440 (1.234-1.681) <0.001
Stent thrombosis (n,%) 22 (2.5%) 41 (4.6%) 52 (5.9%) 0.002 1.522 (1.199-1.931) 0.001
Non-fatal myocardial infarction (n,%) 40 (4.5%) 47 (5.3%) 69 (7.8%) 0.009 1.350 (1.103-1.652) 0.004
Long-term CV mortality (n,%) 24 (2.7%) 32 (3.6%) 53 (6.0%) 0.002 1.5347 (1.201-1.959) 0.001
All-cause mortality (n,%) 28 (3.2%) 44 (5.0%) 64 (7.2%) 0.001 1.637 (1.233-2.112) <0.001

Abbreviations: CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MACE, major adverse cardiovascular events.

Kaplan-Meier analysis according to the long-term event-
free survival revealed the higher occurrence of MACE in the
third tertile group compared with first (p=0.001) and second
tertile (p=0.010) (Figure 3).
The association of different variables with in-hospital
(Table 3) and long-term MACE (Table 4) were evaluated
by univariate and multivariate analysis. The variables whose
p-value <0.05 in univariate analysis were specified as poten-
tial risk markers and included in the full model. Multivariate
logistic regression analysis for in-hospital MACE consisted of
diabetes mellitus, LVEF, peak CK-MB levels, no-reflow, mul-
tivessel disease, Gensini score, Killip class >II and MHR.
Patients in the third MHR tertile group had a hazard ratio
of 1.406 (95%CI: 1.144-1.727 p=0.001) for in-hospital MACE
(Table 3).
In the multivariate logistic regression model for long-term
MACE, diabetes mellitus, smoking, LVEF, peak CK-MB lev-
els, no-reflow phenomenon, multivessel disease, Gensini
score, Killip class >II, DAPT interruption <30 days, DAPT
interruption <180 days and MHR were included. Adjusting
for other factors, a MHR value in the third tertile group
(HR:1.303, 95%CI: 1.119-1.516, p = 0.001) was determined
as an independent predictor of long-term MACE (Table 4).
Discussion
To the best of our knowledge, this is the first study demon-
strating the association of MHR with the severity of coronary
artery disease and the prognostic importance of this
1082
Figure 2 ROC curve analysis showing the predictive cut-off value of MHR for in-hospital (Figure 2a) and long-term MACE
(Figure 2b). Abbreviations: AUC: area under the curve; MACE: Major adverse cardiovascular events; MHR: Monocyte to
HDL ratio; ROC: receiver operating curve.
parameter in predicting in-hospital and long-term major
adverse cardiovascular events in patients with ACS. In the
detailed analysis of the impact of MHR on in-hospital and
long-term MACE, the stent thrombosis, non-fatal MI, and
cardiovascular mortality occurred more frequently in the
third MHR tertile. Confirming this ratio as a novel
Figure 3 Kaplan-Meier survival curve demonstrating
long-term MACE among Monocyte to HDL ratio tertiles.
Abbreviations: MACE: Major adverse cardiovascular
events.
M.S. Cetin et al.
inflammation based indicator, the MHR had a significantly
positive correlation with CRP levels, and NLR levels. As a
secondary aim, we determined that MHR has been also
associated with severity of coronary artery disease in the
context of Gensini and SYNTAX score.
Inflammation and oxidative stress cross-linked each other
and have been proposed as the main constituents of the
pathophysiology of atherosclerosis. Baseline pro-inflamma-
tory and pro-oxidant status have been represented as impor-
tant predictors of adverse clinical outcomes in ACS. Not only
inside the arterial wall but also in circulation, monocyte
activation is involved in the inflammatory process and
cardiovascular disease in which monocytes and differenti-
ated macrophages can modulate the inflammatory
response [15]. Circulating monocytes account for the major
source of various proinflammatory and prooxidant factors
and interact with endothelial cells and platelets leading to
inflammation, thrombosis and endothelial dysfunction
[16,17]. The association of monocyte count with the extent
of atherosclerosis has been demonstrated in animal studies.
Qiao et al. who investigated atherosclerosis in macrophage
colony-stimulating factor deficient mice, reported a gene
dosage–related reduction in atherosclerosis correlated with
a decrease in blood monocyte counts [18]. Palmerini et al.
reported that there was a significant increase in monocyte
tissue factor expression with stent implantation procedure.
Also, they determined that when monocytes are extracted
from the milieu, fibrin deposition is diminished by approx-
imately 45% and tissue factor level of thrombus by 83%
compared with the control group [19]. Considering mono-
cytes to be the primary source of tissue factor in thrombo-
sis, monocytes can be a pivotal player in future thrombotic
events in ACS.
MHR and Acute Coronary Syndrome 1083

Table 3 Effects of variables on in-hospital MACE in univariate and multivariate logistic regression analysis

Variables Univariate logistic regression analysis Multivariate logistic regression analysis

OR 95% CI P value OR 95% CI P value

Age 0.997 0.968-1.027 0.849

Male gender 0.990 0.678-1.445 0.958
Diabetes mellitus 1.813 1.227-2.679 0.003 1.428 1.102-2.135 0.009
Smoking 0.709 0.492-1.022 0.065
Family history of CAD 0.962 0.812-1.139 0.652
Hypertension 1.266 0.903-1.775 0.171
Hyperlipidaemia 1.140 0.822-1.583 0.432
BMI 1.018 0.981-1.056 0.342
ASA 0.739 0.502-1.089 0.126
Beta blocker 0.924 0.662-1.290 0.642
ACE inh 0.880 0.624-1.240 0.466
Diuretic 0.951 0.693-1.305 0.757
Statin 1.277 0.887-1.840 0.188
LVEF on admission 0.988 0.979-0.997 0.010 0.979 0.970-0.992 0.020
Haemoglobin 1.012 0.953-1.074 0.703
Haematocrit 0.932 0.818-1.062 0.292
Platelet 0.997 0.993-1.001 0.089
WBC 1.042 0.925-1.174 0.497
Neutrophil 1.134 0.995-1.292 0.060
Lymphocyte 0.833 0.672-1.033 0.096
Total cholesterol 1.002 0.997-1.007 0.483
LDL-C 1.009 0.991-1.018 0.359
HDL-C 1.014 1.001-1.026 0.030
Triglyceride 0.998 0.995-1.001 0.134
Glucose 0.996 0.990-1.001 0.114
Urea 1.000 0.994-1.006 0.929
Serum creatinine 1.759 0.807-3.833 0.155
Total protein 0.941 0.815-1.023 0.207
Albumin 0.715 0.526-1.008 0.314
Peak CK-MB 1.326 1.019-1.875 0.008 1.113 1.112-1.125 0.026
Use of GpIIb/IIIa inhibitor 0.976 0.844-1.033 0.184
No reflow 1.478 1.107-2.410 0.001 1.236 1.102-1.733 0.009
Total number of stents 0.994 0.982-1.015 0.276
Mean stent diameter 0.724 0.441-1.012 0.158
Total stent length 1.121 0.982-1.066 0.195
Pain to balloon 0.987 0.974-1.001 0.056
Anterior MI 0.889 0.640-1.235 0.492
Number of diseased artery >1 1.250 1.116-2.260 <0.001 1.096 1.027-1.639 <0.001
Gensini score 1.779 1.281-2.469 0.001 1.421 1.119-2.256 0.006
DES 1.209 0.848-1.724 0.295
Hospitalisation (days) 1.020 1.001-1.038 0.035 1.004 0.996-1.011 0.334
Killip class >II 2.489 1.335-4.640 0.004 2.083 1.499-2.894 <0.001
MHR (Third tertile vs. others) 1.641 1.287-2.362 <0.001 1.406 1.144-1.727 0.001

Abbreviations: ASA, acetylsalicylic acid; ACE angiotensin converting enzyme; BMI, body mass index; CAD, coronary artery disease; CI: confidence interval;
DAPT, dual antiplatelet therapy; DES, drug eluting stent; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; LVEF, left
ventricular ejection fraction; MACE, major adverse cardiovascular events; MI, myocardial infarction; MHR, monocyte to HDL ratio; OR, odds ratio; PCI,
percutaneous coronary intervention; WBC, white blood cell.
1084 M.S. Cetin et al.

Table 4 Effects of variables on long-term MACE in univariate and multivariate logistic regression analysis

Variables Univariate logistic regression analysis Multivariate logistic regression analysis

OR 95% CI P value OR 95% CI P value

Age 1.007 0.993-1.022 0.320

Male gender 0.832 0.646-1.072 0.155
Diabetes mellitus 1.969 0.637-3.088 <0.001 1.449 1.089-1.927 0.011
Smoking 1.586 1.161-2.167 0.004 1.351 1.053-1.734 0.018
Family history of CAD 1.919 0.817-4.507 0.135
Hypertension 0.895 0.475-1.687 0.731
Hyperlipidaemia 1.227 0.961-1.567 0.101
BMI 1.008 0.993-1.022 0.313
ASA 1.199 0.938-1.534 0.148
Beta blocker 0.909 0.824-1.001 0.054
ACE inh 1.002 0.999-1.005 0.195
Diuretic 1.273 0.911-1.778 0.157
Statin 0.991 0925-1.062 0.805
LVEF on admission 1.219 1.082-1.425 0.001 1.196 1.024-1.469 0.010
Haemoglobin 1.012 0.953-1.074 0.703
Haematocrit 1.124 0.991-1.407 0.125
Platelet 0.998 0.995-1.001 0.226
WBC 0.930 0.850-1.016 0.108
Neutrophil 0.992 0.838-1.014 0.093
Lymphocyte 0.883 0.755-1.032 0.118
Total cholesterol 0.965 0.878-1.061 0.464
LDL-C 1.001 0.997-1.006 0.555
HDL-C 0.997 0.984-1.010 0.622
Triglyceride 0.888 0.784-1.001 0.198
Glucose 1.040 0.965-1.154 0.220
Urea 1.025 0.906-1.158 0.697
Serum creatinine 1.033 0.544-1.962 0.920
Total protein 0.933 0.984-1.001 0.103
Albumin 0.997 0.990-1.005 0.565
Peak CK-MB 1.250 1.023-1.856 0.007 1.118 1.044-1.745 0.034
Use of GpIIb/IIIa inhibitor 0.983 0.950-1.017 0.329
No reflow 1.780 1.393-2.275 <0.001 1.309 1.088-1.574 0.004
Total number of stents 0.995 0.987-1.002 0.155
Mean stent diameter 0.698 0.495-1.009 0.175
Total stent length 1.017 0.989-1.045 0.235
Pain to balloon 1.256 0.986-1.599 0.065
Anterior MI 1.008 0.986-1.031 0.483
Multivessel disease 1.680 1.393-2.275 <0.001 1.331 1.034-1.940 <0.001
Gensini score 1.753 1.349-2.278 <0.001 1.218 1.049-1.564 0.012
DES 0.998 0.983-1.013 0.789
Hospitalisation (days) 1.250 0.828-1.888 0.289
Killip class >II 2.164 1.678-2.789 <0.001 1.771 1.434-2.440 <0.001
DAPT interruption <30 days 1.601 1.191-2.153 0.002 1.411 1.099-1.813 0.007
DAPT interruption <180 days 1.521 1.134-2.775 0.007 1.376 1.074-1.762 0.011
MHR (Third tertile vs. others) 1.554 1.204-2.006 0.001 1.303 1.119-1.516 0.001

Abbreviations: ASA, acetylsalicylic acid; ACE angiotensin converting enzyme; BMI, body mass index; CAD, coronary artery disease; CI: confidence interval;
DAPT, dual antiplatelet therapy; DES, drug eluting stent; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; LVEF, left
ventricular ejection fraction; MACE, major adverse cardiovascular events; MI, myocardial infarction; MHR, monocyte to HDL ratio; OR, odds ratio; PCI,
percutaneous coronary intervention; WBC, white blood cell.
MHR and Acute Coronary Syndrome
On the other hand, HDL-cholesterol represents well-
known anti-inflammatory and antioxidant as well as
antithrombotic effects; these activities have been shown in
accordance with both the quality and quantity of HDL-C [20].
As well, HDL-cholesterol has a close interaction with mono-
cytes through suppressing monocyte activities, interrupting
differentiation of monocytes to macrophages which results in
a restricted inflammatory response [21].
Ongoing studies focus on a new aspect of anti-inflammatory
properties of HDL with newly defined haematopoietic effects.
Elevation in HDL particles acts within the haematopoietic
system by suppressing haematopoietic stem-cell and multipo-
tential progenitor cell proliferation, mobilisation and mono-
cyte production leading to diminishing inflammation [3,4].
Leuschner et al’s. study on the monocyte activity in ACS
demonstrated that the monocytes exist in tissue with a short
life span, but the sustained release of new monocytes from
spleen, produced by extramedullary monocytepoiesis pro-
vides the presence of monocytes during days after initiation
of inflammation. The spleen was attributed as a major source
of monocytes in ACS [22]. Exaggerated extramedullary
monocytopoiesis interferes with conversion towards an
anti-inflammatory healing process and leads to impairment
of myocardial function [23]. Elevated HDL levels or recon-
stituted HDL infusion suppress the production of various
chemokines including IL-23 and granulocyte-CSF and inter-
rupts the monocyte production and differentiation process in
the extramedullary haematopoiesis[3].
MHR is a recently emerging indicator of inflammatory
status. The pioneering study of Kanbay et al. reported that
higher MHR has been associated with worse cardiovascular
prognosis in chronic kidney disease [5]. Following this study,
Canpolat et al. investigated this marker in AF population and
suggested elevated pre-ablation MHR as a predictor of AF
recurrence after catheter ablation [6]. Also in a recent study,
MHR has been found to be associated with CSFP [7]. MHR has
been determined to be a predictor of stent thrombosis and in-
hospital MACE as well as mortality in patients with STEMI
[8,9]. In all studies, MHR has been postulated to have an
association with systemic inflammation and endothelial dys-
function and attributed as a novel inflammation-based prog-
nostic marker in cardiovascular diseases. Consistent with
these studies, we found close correlations between MHR
and conventional inflammatory markers including CRP and
NLR.
Clinical Implications
Although requiring further evaluation in randomised con-
trolled trials, the medications targetting monocyte and HDL
particles or this interaction may provide a new approach to
preventing worse cardiovascular events. The evaluation of
this parameter may be used to categorise patients who might
benefit the most from HDL targetting therapy, intense statin
medication, longer duration of antiplatelet therapy, drugs
with anti-inflammatory, pleiotropic properties. This param-
eter may also utilise monitoring the inflammatory response
and the efficiency of therapies.
1085
Limitations
We could not assess all potential factors that might involve
the interaction between monocytes and HDL particles.
Monocytes are not homogenous in behavioural response
and have various types demonstrating different activities
[17]. The classification of different monocyte subgroups
may strengthen our results. The same situation also exists
in HDL particles. Beyond the quantity of HDL particles, HDL
particles can be classified based on size such as small, inter-
mediate and large HDL subtypes [24]. The evaluation of
atherogenic properties of these subtypes may have a contrib-
uted to our study. Determination of Apo A1 level and Apo E,
which are major components of HDL’s anti- inflammatory
properties, may give our results greater precision[25]. In
addition, our study was a single centre study and also we
assessed only MHR on admission. Evaluation of the temporal
trend of MHR in ACS and during the follow-up period may
provide a different point-of-view. The evaluation of the pro-
cedural success with optical coherence tomography would
enpower our study.
Conclusions
In conclusion, MHR as a novel inflammation-based marker is
indicated to be an independent predictor of severity of coro-
nary artery disease and future cardiovascular events in
patients with ACS. This parameter was determined to be
closely correlated with well-known inflammatory markers
and coronary artery disease severity indexes. MHR may
utilise the identification of patients who are at higher risk
for MACE and individualisation of targeted therapy.
Funding
This research received no grant from any funding agency in
the public, commercial or not-for-profit sectors.
Conflicts of Interest
The authors declare that there is no conflict of interest.
Acknowledgments
None.
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