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

cholesterol (HDL-C) counteracts these proinflammatory and within the last year, were classified as smokers. A family
prooxidant effects of monocytes by hindering the migration history of premature CAD was defined as CAD in a parent or
of macrophages and oxidation of LDL molecules as well as sibling diagnosed under the age of 55 for men and 65 years
promoting the efflux of cholesterol from these cells [2]. In for women.
addition to the HDL-C particles’ well-known anti-inflamma-
tory and antioxidant actions, recently these molecules have Laboratory Parameters
been claimed to have a suppressive role in controlling mono- Blood samples were collected during the emergency room
cyte activations and proliferation-differentiation of the pro- admission before any medical therapy and pPCI. Dry tubes
genitor cells of monocytes [3,4]. for biochemical tests and tubes with EDTA for the haemato-
As a recently emerged inflammation-based marker, the logical test were used. Erythrocyte count, haemoglobin, hae-
monocyte count to HDL-C ratio (MHR) has been reported matocrit, and white blood cell (WBC) count were measured
as a new predictor and prognostic indicator of cardiovascular using an automated haematology analyser XE-1200 (Sysmex,
diseases [5–7]. In the STEMI patient population, MHR has Kobe, Japan). The biochemical measurements were deter-
been represented to be a predictor of stent thrombosis and in- mined by using a molecular analyser (Roche Diagnostics,
hospital MACE as well as mortality [8,9]. However, there is Mannheim, Germany). Baseline MHR was calculated by
no data on the association of this parameter with the severity dividing the monocyte count by the HDL cholesterol count.
of coronary artery disease and long-term outcomes in
patients with ACS. Echocardiography
In this prospective study, we aimed to investigate the
Baseline 2D and Doppler echocardiographic examination
usefulness of MHR in predicting coronary artery disease
was performed by experienced echocardiographers in the
severity and future major adverse cardiovascular events in
intensive coronary care unit to assess left ventricular ejection
patients with ACS.
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,
Materials and Methods Norway) with a 1.5–3.6 MHz multi-frequency phased array
Study Population probe.
A total of 3269 consecutive patients who were admitted to
our tertiary, heart-specialist hospital with ACS and under- Coronary Angiography and Percutaneous
went primary percutaneous coronary intervention (pPCI) Coronary Intervention
between 2009-2015, were enrolled. Consistent with the Dec- Our hospital is a high volume tertiary, heart-specialised
laration of Helsinki, this study was approved by the Institu- hospital with the facility to perform PCI 24 hours, seven days
tional Ethics Committee. Informed consent was obtained a week. Every patient who is admitted with chest pain to our
from all participants. Acute coronary syndrome was diag- emergency department is assessed initially by a cardiology
nosed based on the criteria recommended by the current specialist. Premedication (intravenous unfractionated hepa-
American College of Cardiology and European Society of rin 100 IU/kg, 600 mg clopidogrel and 300 mg aspirin) is
Cardiology guidelines.[10–13] given immediately in the emergency room, and the patients
Patients who had a previous history of coronary revascu- are admitted to the catheterisation laboratory. Average door-
larisation either CABG or PCI, active infection, haematolog- to-balloon time is under 30 minutes. Coronary angiography
ical (including anaemia), oncological or inflammatory followed by pPCI via femoral approach with the conven-
disease, renal or hepatic insufficiency, severe valvular dis- tional technique was performed to achieve adequate blood
ease, hypo- and hyperthyroidism, treatment with fibrinolytic flow for the infarct-related artery. Procedural decisions, such
agents (only or before referral for pPCI) were excluded. After as the size and type of diagnostic or guiding catheter, direct
elimination according to the exclusion criteria, the remaining stenting or predilatation, the necessity of thrombus aspira-
2661 patients were included and followed-up for median 31.6 tion and device selection (stent type (drug-eluting stent
months (Range 1-63 months). The patient population was [DES] or bare metal stent [BMS]), size, length) as well as
assigned into tertiles based on the admission MHR level. The usage of adjunctive pharmacotherapy (including glycopro-
33rd and 66th percentile were determined as cut-off points. teinIIb/ IIIa receptor antagonists) were made at the discre-
Hypertension was defined as receiving antihypertensive tion of the individual interventional cardiologist for the
therapy and/or having an arterial blood pressure (BP) procedure. Cobalt chromium BMS (CommanderTM, Alvi-
>140 mmHg for systolic and/or 90 mmHg for diastolic BP. medica and TangoTM, MicroPort) and everolimus and pac-
Diabetes mellitus was diagnosed with the use of an antidia- litaxel-eluting stents (XienceV Everolimus Eluting Coronary
betic drug and a fasting blood glucose >126 mg/dl. Hyper- Stent System, Abbott Vascular and TAXUS Paclitaxel-Eluting
lipidaemia was considered as total cholesterol >200 mg/dl, Coronary Stent System, Boston Scientific Corporation) were
low density lipoprotein-cholesterol (LDL-C) >130 mg/dl, tri- used. After stent implantation, angiographic optimisation
glyceride (TRG) >150 mg/dl or receiving lipid-lowering was performed by high-pressure dilatation to provide a
medication. Patients, who were smoking or quit smoking satisfactory angiographic result. Procedural success was
MHR and Acute Coronary Syndrome 1079

defined as a residual stenosis of <20% without major com- SYNTAX score. Cox proportional multivariate hazards
plications (i.e., stent thrombosis, need for emergent CABG or regression model was used to determine the risk ratio of
repeat PCI, coronary dissection or rupture, and death). the MHR tertiles (comparing the third tertile versus others)
Unless cardiogenic shock emerged, the other stenotic lesions for occurrence of MACE, non-fatal MI, cardiovascular death
in coronary arteries were not targeted for any intervention in and ST during both in-hospital and long-term follow-up.
the index procedure. The effects of different variables on the occurrence of in-
The evaluation of coronary angiograms and determination hospital and long-term MACE in univariate analysis were
of Gensini and SYNTAX score were made by two interven- analysed, and the variables whose unadjusted p-value was
tional cardiologists who were blinded to the laboratory and <0.05 were specified as potential risk markers and included
clinical follow-up data of the patients. In the case of disagree- in the full model. The model was constituted by using for-
ment, a third interventional cardiologist who was blinded to ward elimination at multivariate regression analyses, and
the other interpretations evaluated the coronary angiograms. potential risk markers were eliminated by using likelihood
ratio tests. Receiver operating characteristic analysis was
Endpoints used to determine the cut-off values of MHR to predict in-
The primary composite endpoint was determined as MACE hospital and long-term MACE.
including stent thrombosis, non-fatal MI, cardiovascular Kaplan-Meier analysis was applied to evaluate the MACE-
mortality during in-hospital and long-term follow-up period. free survival, free survival between MHR tertiles. A p < 0.05
According to the Academic Research Consortium ‘definite (two-sided) was considered significant. Data were analysed by
ST’ criteria, ‘definite’ ST was defined as angiographic confir- using SPSS 20.0 software.
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 Results
the recurrence of chest pain and/or new ECG changes with a A total of 2661 patients (1766 male, 66.4%; mean age 59.818.2)
new dynamic change (>20% rise from baseline) in cardiac with the diagnosis of ACS were enrolled and followed-up
biomarkers (CKMB and troponin I levels) [10,11]. ‘Cardio- during median 31.6 months (range 1-63 months).
vascular mortality’ was diagnosed as death because of
life-threatening arrhythmias, MI, congestive heart failure, Comparison of the Tertile Groups
cardiac arrest, death attributed to cardiac events. Baseline characteristics, laboratory parameters, and coronary
angiographic findings of the patient groups according to the
Follow-up MHR tertile groups are demonstrated in Table 1. Peak CKMB,
The post-intervention antiplatelet medication based on Gensini and SYNTAX scores were higher and also the neces-
current guidelines included lifelong acetylsalicylic acid sity of GIIb/IIIa inhibitors, multivessel disease, and no-reflow
(75-150 mg/day) and clopidogrel (75 mg/day) for at least phenomenon were more prevalent in the third tertile group.
12 months. In correlation analysis, admission MHR were significantly
All patients were scheduled for an elective clinical follow- positively correlated with neutrophil to lymphocyte ratio
up at one, six and 12-months as well as for every six months (r = 0.438, p < 0.001), CRP (r = 0.394, p < 0.001), Gensini
thereafter and earlier if they developed any symptoms. We (r = 0.407, p < 0.001), and SYNTAX score (r = 0.333,
clinically monitored the patients for cardiovascular events p < 0.001) (Figure 1).
and DAPT adherence. As well, follow-up data were docu-
mented from the hospital records, telephone calls with the Comparison of Clinical Outcomes
patients, their relatives, and/or their general practitioners, as The median follow-up duration was not different between
well as from the pharmacy databases and hospital records. tertile groups (p=0.722). The in-hospital and long-term
The follow-up data were verified with the Ministry of Health MACE (with the events composing MACE) were represented
records and Turkish National Population Register. The cause comparing MHR tertile groups (Table 2). During in-hospital
of death was determined based on medical records or death and long-term follow-up, MACE, the prevalence of stent
certificates. thrombosis, non-fatal MI, and mortality occurred more fre-
quently in the third tertile group. The results of Cox regres-
Statistical Analysis sion analysis for in-hospital and long-term clinical outcomes
The continuous variables were reported as mean  standard are also shown in Table 2. Having a MHR in the third tertile
deviation (SD) and the categorical variables were expressed was associated with a 1.4-fold increased risk of in-hospital
as the number of patients and percentages. The comparisons and long-term MACE.
between MHR tertiles were performed with one-way In ROC analysis, a MHR cut-off of 144.3 had 80.2% sensitiv-
ANOVA (for continuous variables), Kruskal-Wallis tests ity and 69.8% specificity for prediction of in-hospital MACE
(for non-parametric variables) and chi-square test or Fisher’s (AUC = 0.770, 95CI%: 0.745-0.795, p < 0.001) (Figure 1). Also, a
exact test for the categorical variables. Pearson correlation MHR cut-off value of 142.9 had 81.5% sensitivity and 71.2%
analysis was performed to assess the correlation of MHR specificity for prediction of long-term MACE (AUC =0.806,
with neutrophil to lymphocyte ratio, CRP, Gensini, and 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- In the multivariate logistic regression model for long-term
free survival revealed the higher occurrence of MACE in the MACE, diabetes mellitus, smoking, LVEF, peak CK-MB lev-
third tertile group compared with first (p=0.001) and second els, no-reflow phenomenon, multivessel disease, Gensini
tertile (p=0.010) (Figure 3). score, Killip class >II, DAPT interruption <30 days, DAPT
The association of different variables with in-hospital interruption <180 days and MHR were included. Adjusting
(Table 3) and long-term MACE (Table 4) were evaluated for other factors, a MHR value in the third tertile group
by univariate and multivariate analysis. The variables whose (HR:1.303, 95%CI: 1.119-1.516, p = 0.001) was determined
p-value <0.05 in univariate analysis were specified as poten- as an independent predictor of long-term MACE (Table 4).
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.
Discussion
Patients in the third MHR tertile group had a hazard ratio To the best of our knowledge, this is the first study demon-
of 1.406 (95%CI: 1.144-1.727 p=0.001) for in-hospital MACE strating the association of MHR with the severity of coronary
(Table 3). artery disease and the prognostic importance of this
1082 M.S. Cetin et al.

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 inflammation based indicator, the MHR had a significantly
adverse cardiovascular events in patients with ACS. In the positive correlation with CRP levels, and NLR levels. As a
detailed analysis of the impact of MHR on in-hospital and secondary aim, we determined that MHR has been also
long-term MACE, the stent thrombosis, non-fatal MI, and associated with severity of coronary artery disease in the
cardiovascular mortality occurred more frequently in the context of Gensini and SYNTAX score.
third MHR tertile. Confirming this ratio as a novel 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%
Figure 3 Kaplan-Meier survival curve demonstrating
compared with the control group [19]. Considering mono-
long-term MACE among Monocyte to HDL ratio tertiles.
Abbreviations: MACE: Major adverse cardiovascular cytes to be the primary source of tissue factor in thrombo-
events. 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 1085

On the other hand, HDL-cholesterol represents well- Limitations

known anti-inflammatory and antioxidant as well as We could not assess all potential factors that might involve
antithrombotic effects; these activities have been shown in the interaction between monocytes and HDL particles.
accordance with both the quality and quantity of HDL-C [20]. Monocytes are not homogenous in behavioural response
As well, HDL-cholesterol has a close interaction with mono- and have various types demonstrating different activities
cytes through suppressing monocyte activities, interrupting [17]. The classification of different monocyte subgroups
differentiation of monocytes to macrophages which results in may strengthen our results. The same situation also exists
a restricted inflammatory response [21]. in HDL particles. Beyond the quantity of HDL particles, HDL
Ongoing studies focus on a new aspect of anti-inflammatory particles can be classified based on size such as small, inter-
properties of HDL with newly defined haematopoietic effects. mediate and large HDL subtypes [24]. The evaluation of
Elevation in HDL particles acts within the haematopoietic atherogenic properties of these subtypes may have a contrib-
system by suppressing haematopoietic stem-cell and multipo- uted to our study. Determination of Apo A1 level and Apo E,
tential progenitor cell proliferation, mobilisation and mono- which are major components of HDL’s anti- inflammatory
cyte production leading to diminishing inflammation [3,4]. properties, may give our results greater precision[25]. In
Leuschner et al’s. study on the monocyte activity in ACS addition, our study was a single centre study and also we
demonstrated that the monocytes exist in tissue with a short assessed only MHR on admission. Evaluation of the temporal
life span, but the sustained release of new monocytes from trend of MHR in ACS and during the follow-up period may
spleen, produced by extramedullary monocytepoiesis pro- provide a different point-of-view. The evaluation of the pro-
vides the presence of monocytes during days after initiation cedural success with optical coherence tomography would
of inflammation. The spleen was attributed as a major source enpower our study.
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-
Conclusions
stituted HDL infusion suppress the production of various In conclusion, MHR as a novel inflammation-based marker is
chemokines including IL-23 and granulocyte-CSF and inter- indicated to be an independent predictor of severity of coro-
rupts the monocyte production and differentiation process in nary artery disease and future cardiovascular events in
the extramedullary haematopoiesis[3]. patients with ACS. This parameter was determined to be
MHR is a recently emerging indicator of inflammatory closely correlated with well-known inflammatory markers
status. The pioneering study of Kanbay et al. reported that and coronary artery disease severity indexes. MHR may
higher MHR has been associated with worse cardiovascular utilise the identification of patients who are at higher risk
prognosis in chronic kidney disease [5]. Following this study, for MACE and individualisation of targeted therapy.
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, Funding
MHR has been found to be associated with CSFP [7]. MHR has
This research received no grant from any funding agency in
been determined to be a predictor of stent thrombosis and in-
the public, commercial or not-for-profit sectors.
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-
Conflicts of Interest
nostic marker in cardiovascular diseases. Consistent with The authors declare that there is no conflict of interest.
these studies, we found close correlations between MHR
and conventional inflammatory markers including CRP and
NLR. Acknowledgments
Clinical Implications None.
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
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