a b s t r a c t

Background: Monocyte count to high-density lipoprotein ratio (MHR) has recently emerged as an indicator of in- flammation and oxidative stress in the literature. We aimed to investigate the prognostic value of MHR in pa- tients with ST-segment elevation myocardial infarction treated with Primary percutaneous coronary intervention .

Methods: A total of 513 patients who were hospitalized with diagnosis of Acute ST-segment elevation myocardial infarction and treated with Primary PCI were retrospectively enrolled in the study. Demographic and clinical data, admission laboratory parameters, and MHR values were recorded. Inhospital Major adverse cardiac events and mortality were reported as the clinical outcomes.

Results: Twenty-six patients (5%) died, and MACE was observed in 86 patients (17%) during hospital follow-up. Patients were categorized in 3 groups according to tertiles of admission MHR. The rates of Inhospital mortality and MACE were significantly higher in tertile 3 group compared to tertile 1 group (10% vs 1%, 27% vs 11%; P b

and P b .01). In multivariate regression analysis, age, sex, presence of Killip 3 or 4, left ventricular ejection frac-

tion, troponin I, C-reactive protein, and increased MHR levels (odds ratio, 1.03; 95% confidence interval, 1.01- 1.05; P b .01) independently predicted inhospital mortality; age, presence of Killip 3 or 4, troponin I, and in- creased MHR levels (odds ratio, 1.02; 95% confidence interval, 1.01-1.04; P b .01) independently predicted MACE. Conclusion: Admission MHR values were found to be independently correlated with inhospital MACE and mortal- ity after primary PCI.

(C) 2015

Introduction

Inflammation plays a substantial role in atherothrombosis and ath- erosclerotic plaque rupture which are the main mechanisms in the pathophysiology of acute ST-segment elevation myocardial infarction \(STEMI\) [1,2]. The important role of inflammation in atherothrombosis has focused attention on the immune system. Development of athero- sclerosis and its several complications are influenced by innate and adaptive immune responses [3]. Monocytes are one of the most impor- tant essential components of the immune system. They are involved in various phases of coronary artery disease process and associated with

* Corresponding author at: Siyami Ersek Training and Research Hospital, Istanbul, Turkey. Tel.: +90 5054841777.

E-mail address: [email protected] (B. Gungor).

the inflammatory response at the vulnerable plaque sites in patients with STEMI [4].

In addition, monocyte counts have been postulated as predictor of coronary events [5]. On the other hand, several trials have shown that lower levels of high-density lipoprotein (HDL) levels may also lead to worse prognosis in critically ill patients and Infective endocarditis [6,7]. In a recent study, lower levels of Low-density lipoprotein cholesterol and HDL cholesterol have emerged as predictors of short- term mortality after myocardial infarction (MI) [8]. Monocyte counts to HDL ratio (MHR) is a novel parameter predicting worse cardiovascu- lar outcome in chronic kidney disease and Atrial fibrillation recur- rence after cryoballoon-based Catheter ablation in patients with AF [9,10]. However, short-term prognostic significance of MHR has not been yet studied in STEMI patients treated with primary percutaneous coronary intervention . The aim of this study was to investigate

http://dx.doi.org/10.1016/j.ajem.2015.10.049

0735-6757/(C) 2015

the association of admission MHR levels with inhospital mortality and major adverse cardiac events in patients with STEMI.

Methods

Study population

Medical records of patients, who were admitted to the emergency department of Dr Siyami Ersek Training and Research Hospital, with the diagnosis of STEMI and underwent primary PCI between January 2010 and January 2013 were retrospectively collected. Patients were enrolled in the study if they fulfilled the following criteria: (1) presented within 12 hours of the onset of symptoms (typical chest pain lasting for N 30 minutes) and (2) ST-segment elevation of greater than or equal to 1 mm in at least 2 consecutive leads. Patients with clinical evidence of active cancer, hematological proliferative disorders, active hepatobiliary diseases, chronic antihyperlipidemic treatment, active infection, chronic inflammatory disease, receiving Steroid therapy for autoimmune dis- ease, and patients without a recorded measurement of admission labo- ratory parameters including cholesterol levels before primary PCI were excluded from this study. In addition, 40 patients who were under statin therapy were excluded from the study. Finally, 513 patients were in- cluded in the study.

Data regarding clinical and demographic properties and laboratory parameters were collected from medical records. Inhospital MACE and mortality were reported as the clinical outcomes. For evaluation of events, hospital records and state-wide death registry database were used. The study protocol was approved by the local ethics committee.

Definitions

Hypertension (HT) was defined as use of Antihypertensive drugs or systolic blood pressure (SBP) greater than or equal to 140 mm Hg and/or diastolic blood pressure greater than or equal to 90 mm Hg; dia- betes mellitus (DM) was defined as use of antidiabetic drugs or fasting plasma glucose levels of greater than 126 mg/dL. Smoking status was de- fined as current Tobacco use. Inhospital mortality was defined as all- cause mortality during hospitalization. Ventricular arrhythmia (ventric- ular fibrillation, ventricular tachycardia), reinfarction, cardiopulmonary resuscitation, target vessel revascularization, and death during index hospitalization were regarded as MACE. Postprocedural Thrombolysis in Myocardial Infarction flow 3 was defined as complete filling of the distal vessel with normal flow [10]. Reinfarction was defined as an acute MI that occurs within 28 days of an incident or recurrent MI [1].

Revascularization procedure and medications

All patients received a loading dose of 600 mg clopidogrel, 300 mg aspirin at admission, and 100 U/kg Bolus injection of enoxaparin after coronary anatomy was defined. Primary PCI was achieved with stan- dard techniques according to established guidelines. Selection of the type of stent (bare metal or drug eluting) and the decision of using gly- coprotein IIb/IIIa antagonist (tirofiban) or an intraaortic balloon pump were left to the discretion of the operator. In addition, the use of predilation or postdilation and Thrombus aspiration was left to the dis- cretion of the physician. The infarct-related artery was graded according to the TIMI classification after procedure. During hospitalization and follow-up period, ?-blocker, angiotensin-converting enzyme inhibitor, and statin were administered to all patients unless contraindicated. A 75 mg clopidogrel daily dose was given for at least 12 months after the primary PCI, and 100 mg aspirin was used indefinitely.

Laboratory analysis and echocardiog”>Laboratory analysis and echocardiography

According to the hospital protocol, venous blood samples were taken from antecubital vein and collected in calcium EDTA tubes during

the emergency admission. Blood counts were studied by an autoanalyzer (Cell-dyn 3700; Abbott, Wiesbaden, Germany) within 30 minutes after blood sampling. Total cholesterol, HDL cholesterol and triglyceride levels were measured enzymatically (Architec c-Systems; Abbott). Low-density lipoprotein cholesterol levels were measured from these lipid parameters with Friedewald formula. C-reactive pro- tein (CRP) measurements were conducted on Cobas Integra analyzer (Roche Diagnostics, Istanbul, Turkey) using turbidimetric method. The results of laboratory parameters were collected by using electronic database of the hospital. Monocyte to high density lipoprotein ratio was calculated by dividing monocyte count to HDL level from the same blood sample obtained before primary PCI.

Left ventricular ejection fraction (LVEF) measured in accordance with the American Society of Echocardiography guidelines after primary PCI was recorded (Vivid 3 system; General Electric Company, Milwaukee, WI).

Statistical analyses

All data were presented as a mean +- SD or a median (interquartile range) for parametric variables and as percentages for categorical vari- ables. Continuous variables were checked for the normal distribution assumption using Kolmogorov-Smirnov statistics. Differences between tertile groups were evaluated using the Kolmogorov-Smirnov test or analysis of variance with the Tukey post hoc test as appropriate. Differ- ences between MACE(+) patients and MACE(-) patients were evalu- ated using the Mann-Whitney U test or the Student t test when appropriate. Categorical variables were tested by Pearson ?² test and Fisher exact test. Receiver operating curves were generated to define the cutoff values of MHR for inhospital mortality and MACE. Univariate and multivariate binary logistic regression analyses were performed to identify the independent predictors of inhospital mortality and MACE separately. Forward stepwise multivariable regression models using pa- rameters with P b .10 were created in logistic regression analyses. P values were 2 sided, and P b .05 was considered statistically significant. All statistical studies were carried out using SPSS software (SPSS 16.0 for Windows; SPSS, Inc, Chicago, IL).

Results

A total number of 513 patients were included in the study. Major ad- verse cardiac events were observed in 86 patients (17%) in the study population. Of the observed events, 28 (5.5%) had Ventricular tachycardia and/or ventricular fibrillation, 15 (3%) had reinfarction, 13 (2.5%) had cardiopulmonary arrest, 15 (3%) had target vessel revascularization, and 26 (5%) died in hospital follow-up. Patients were categorized in 3 groups according to tertiles of admission MHR: MHR was less than 13.9 in tertile 1 (n = 171), MHR was between 13.9 and 22.9 in tertile 2 (n = 171), and MHR was greater than 22.9 in tertile 3 (n = 171). Comparison of the de- mographic, clinical, and laboratory characteristics between tertile groups are summarized in Table 1. Serum levels of white blood cell (WBC), monocyte, and MHR values were significantly higher in tertile 3 com- pared to tertile 1 group (P b .01 for all comparisons). Serum cholesterol levels were significantly lower in tertile 3 compared to tertile 1 group except triglyceride levels which were similar between groups. Although the frequency of patients with postprocedural TIMI 3 flow was signifi- cantly lower in tertile 3 group, frequency of patients with Killip 3 or 4 was significantly higher in tertile 3 compared to tertile 1 group (75% vs 88%, 16% vs 6%; P b .01 and P b .01). Patients in tertile 3 group had lower values of LVEF compared to tertile 1 group (P = .01). The rates of inhospital mortality and MACE were significantly higher in tertile 3 group compared to tertile 1 group (10% vs 1%, 27% vs 11%; P b .01 and P b .01). Other parameters were similar among tertiles. When we evaluated MHR between patients with MACE and without MACE, we have observed higher MHR levels in MACE(+) group compared to MACE(-) group (23.3 [18.5] vs 17.2 [12.6]; P b .01).

Table 1

Demographic, clinical, and laboratory properties of the groups according to the tertiles of MHR

Table 2

Independent predictors of inhospital mortality and MACE according to the univariate and multivariate regression analyses in the study population

Characteristics	Tertile 1, MHR b13.9	Tertile 2, MHR of 13.9-22.9 (n	Tertile 3, MHR N 22.9	P1a	P2b		Variables	Unadjusted, OR (95% CI)	P	Adjusted, OR (95% CI)a	P
	(n = 171)	= 171)	(n = 171)				Mortality
Age, y	56.9 +- 12.5	55.7 +- 12.1	56.7 +- 12.9	.26	.49	Age		1.05 (1.02-1.09)	b.01	1.04 (1.01-1.08)	.04
Male, n (%)	115 (67)	114 (67)	114 (67)	.99	.90	Male sex		0.28 (0.12-0.64)	b.01	0.27 (0.10-0.73)	.01
HT (%)	74 (43)	68 (40)	71 (42)	.80	.72	Killip class 3 or 4		5.62 (2.36-13.38)	b.01	3.06 (1.03-9.09)	.04
DM, n (%)	32 (19)	22 (13)	36 (21)	.12	.59	LVEF		0.96 (0.93-0.98)	b.01	0.96 (0.93-0.99)	.03
Smoking, n (%)	82 (48)	84 (49)	86 (50)	.91	.67	Troponin I		1.03 (1.02-1.04)	b.01	1.02 (1.01-1.04)	b.01
Duration of	3 (2)	3 (2.2)	3.1 (2.2)	.23	.31	CRP		1.02 (1.01-1.04)	b.01	1.02 (1.01-1.03)	.04
angina, h							MHR tertilesb
SBP, mm Hg	123 +- 20	120 +- 19	119 +- 24	.26	.37	Tertile 1		Reference	-	-	-
Killip class 3 or 4, n	11 (6)	12 (7)	28 (16)	b.01	b.01	Tertile 2		8.34 (1.03-67.4)	.04	14.27 (1.56-130.0)	.02

(%)

					Tertile 3	18.7 (2.46-122.7)	b.01	19.15 (2.26-161.8)	b.01
13.7 +- 1.7	14.1 +- 1.6	14.0 +- 1.8	.16	.28	MHRb	1.04 (1.02-1.25)	b.01	1.03 (1.01-1.05)	b.01

Hemoglobin, g/dL

WBC, 10³/uL 11.3 +- 3.5 11.9 +- 3.2 14.2 +- 4.3 b.01 b.01

MACE

Monocyte, 109/L	400 (192)	640 (200)	910 (400)	b.01	b.01	Age	1.04 (1.02-1.06)	b.01	1.03 (1.01-1.05)	.04
HDL, mg/dL	43.3 +- 11.9	37.3 +- 9.5	31.9 +- 8.2	b.01	b.01	Killip class 3 or 4	5.74 (3.11-10.57)	b.01	3.24 (1.57-6.66)	b.01
MHR	10.4 (4.5)	17.8 (4.2)	30.7 (13.2)	b.01	b.01	Troponin-I	1.012 (1.004-1.020)	b.01	1.010 (1.001-1.019)	.03
Total cholesterol,	195.2 +- 42.4	189.3 +- 41.0	175 +- 40.3	b.01	b.01	MHR tertilesb
mg/dL Tertile 1 Reference								-	-	-

Triglyceride, mg/ dL

128 (85)	140 (90)	138 (98)	.22	.16	Tertile 2	1.12 (0.58-2.17)	.74	1.32 (0.66-2.66)	.43
					Tertile 3	2.94 (1.64-5.28)	b.01	2.81 (1.48-5.32)	b.01
123.1 +- 37.2	121.2 +- 34.0	112 +- 31.6	b.01	b.01	MHRb	1.03 (1.01-1.05)	b.01	1.02 (1.01-1.04)	b.01

LDL, mg/dL

Creatinine, mg/dL	0.9 +- 0.5	0.9 +- 0.2	1 +- 0.4	.04	.20
Admission	143 (74)	126 (55)	128 (63)	.06	.20
glucose, mg/dL Troponin I, ng/mL	8.1 (40.7)	5.4 (40.4)	6.4 (49.2)	.73	.93
CRP, mg/L	2.3 (11.2)	3.1 (15.8)	3.3 (28.6)	.27	.14
culprit artery
LAD, n (%)	66 (38)	71 (41)	77 (45)	.48	.23
CX, n (%)	34 (20)	35 (21)	33 (19)	.52	.89
RCA, n (%)	66 (38)	62 (36)	59 (34)	.73	.43
N 1-vessel	78 (46)	76 (44)	82 (48)	.80	.66
disease, n (%)
Postprocedural 150 (88)		143 (83)	129 (75)	.01	b.01
TIMI 3, n (%)
LVEF, %	45.4 +- 11.1	43.9 +- 11.7	41.7 +- 13.6	.02	.01
Mortality, n (%)	1 (1)	8 (5)	17 (10)	b.01	b.01
MACE, n (%)	19 (11)	21 (12)	46 (27)	b.01	b.01

Abbreviations: CAD, coronary artery disease; CAG, coronary angiography; CX, Circumflex artery; LAD, left anterior descending artery; PTCA, percutaneous transluminal coronary angioplasty; RCA, right coronary artery.

^a P₁ is the P value obtained from comparison of 3 groups.

^b P₂ is the P value obtained from comparison of tertile 1 with tertile 3.

In receiver operating characteristic curve analysis, admission MHR levels higher than 17.1 predicted inhospital mortality with a sensitivity of 88.5% and a specificity of 49.5% (area under the curve, 0.756; P b .01), levels higher than 20.4 predicted inhospital MACE with sensitivity of 60.5% and a specificity of 65.6% (area under the curve, 0.639; P b .01).

Univariate and multivariate regression analyses were performed to investigate the possible predictors of inhospital mortality in the study population. In univariate regression analysis, age, sex, presence of HT, Killip 3 or 4, post-TIMI 3 flow, troponin I, CRP, creatinine, MHR, duration of angina, and LVEF were correlated with inhospital mortality. In multi- variate regression analysis, using model adjusted for aforementioned parameters, age, sex, presence of Killip 3 or 4, LVEF, troponin I, CRP, and increased MHR levels (odds ratio [OR], 1.03; 95% confidence inter- val [CI], 1.01-1.05; P b .01) independently predicted inhospital mortality (Table 2). The patients in tertile 3 had 19.15 times higher risk of mortal- ity compared to patients in tertile 1 (P b .01).

Univariate and multivariate regression analyses were also per- formed to investigate the possible predictors of MACE in the study pop- ulation. In univariate regression analysis, age, sex, presence of HT, Killip 3 or 4, post-TIMI 3 flow, systolic blood pressure, troponin I, creatinine, hemoglobin, duration of angina, LVEF, and MHR levels were correlated with MACE. In multivariate regression analysis, using model adjusted for aforementioned parameters, age, presence of Killip 3 or 4, troponin I, and increased MHR levels (OR 1.02, 95% CI 1.01-1.04, P b .01)

^a Parameters with P b .10 in univariate model were entered to the multivariate re- gression analysis.

^b Monocyte to HDL ratio (tertiles and as a continuous variable) was entered to the multivariate model separately to prevent multicollinearity.

independently predicted MACE (Table 2). The patients in tertile 3 had

2.81 times higher risk of MACE compared to patients in tertile 1 (P b

.01).

Discussion

The main findings of our study were that age, female sex, presence of Killip class 3 or 4, LVEF, increased serum troponin I, CRP levels, and MHR values were independently associated with inhospital mortality in pa- tients with STEMI treated with primary PCI. In addition, advance age, presence of Killip 3 or 4, increased troponin I, and MHR levels indepen- dently predicted MACE in STEMI patients.

Atherosclerosis and atherosclerotic plaque rupture are the main causes of STEMI. Inflammation plays a pivotal role in formation of ath- erosclerosis and may lead to plaque rupture in the presence of several risk factors. In addition, inflammation is related with adverse cardiac events and Life-threatening complications of STEMI which is the leading cause of mortality and morbidity in general population [11,12]. Primary PCI is the preferred Treatment modality of the STEMI in the worldwide. Inhospital mortality rates of STEMI patients treated with primary PCI range from 3% to 14% [12]. In our study, inhospital mortality rate was 5% compatible with prior studies.

Various easily applicable laboratory parameters associated with in- flammation were investigated in patients with cardiovascular disease and demonstrated to be the predictors of short- or long-term mortality [1,12]. White blood cell count, elevated peripheral blood platelet count, low lymphocyte count, Neutrophil to lymphocyte ratio, CRP, and platelet to lymphocyte ratio [13-18] are some of these markers that attracted the attention of researchers in recent years who have an interest about the role of inflammation in the atherosclerotic process. In addi- tion, admission troponin I level is known as predictor of adverse cardio- vascular outcomes [1]. We found higher levels of admission CRP and troponin I to be independently correlated with inhospital mortality.

Monocyte activation is a very important step in the beginning of the atherosclerotic process. The count of circulating monocytes, as the source of tissue macrophages and foam cells, was found to be a predic- tor for new plaque development [19]. endothelial dysfunction is the first stage for the subsequent development of atherosclerosis. After

endothelial cell dysfunction, mononuclear cells such as monocytes and T lymphocytes attach to the endothelium, initially loosely, and thereaf- ter, they adhere firmly to the endothelium and then migrate to the subendothelial space. After then, they mature into macrophages and differentiate into the foam cells by taking up oxidized LDL and other lipids via the scavenger receptors SR-A and CD-36 [20]. Foam cells forming the fatty streak secrete Proinflammatory cytokines that amplify the local inflammatory response in the lesion, matrix metalloprotein- ases, tissue factor into the local matrix, and growth factors that stimu- late the smooth muscle replication responsible for lesion growth. The increased activity of metalloproteinases digests the internal elastic lam- ina that yields plaque rupture [21]. Tissue factor is mostly located in macrophage-rich areas within the necrotic core of the plaque. When tis- sue factor is released and comes in contact with the circulating blood, it results in thrombus formation and acute coronary syndromes [22]. As is seen, macrophages and its precursor cell monocytes have a role in all phases of atherosclerosis from fatty streak formation to the plaque rup- ture that may lead to STEMI [20-22].

It has been evidenced that HDL cholesterol exerts anti- inflammatory, antioxidant, and antithrombotic effects [23,24]. Classical- ly known as the antiatherogenic lipoprotein, HDL promotes reverse cho- lesterol transport from the arterial wall, specifically from lipid-laden macrophages [25]. High-density lipoprotein is highly effective at inhibiting endothelial expression of adhesion molecules and preventing monocyte recruitment to the artery wall [26]. High-density lipoprotein can prevent inflammatory responses by acting directly on monocytes [27,28]. In addition, lower levels of HDL and LDL were reported as inde- pendent predictors of mortality in acute coronary syndromes and other clinical illness diseases [6-8]. In our study, serum cholesterol levels were lower in MACE(+) group but did not reveal statistical significance and also they did not correlated with mortality and MACE in the multivari- ate analyses [6-8].

As mentioned above, there is a strong correlation between elevated monocyte count and existence of atherosclerosis and its complications. Furthermore, we know that the prohibitory effect on the monocyte ac- tivation could be blunted in the evidence of low serum HDL cholesterol levels. Therefore, we hypothesized that an increased MHR may be a pre- dictor for adverse cardiovascular events in STEMI patients.

Monocyte to HDL ratio was defined as a novel potential marker to de- termine inflammation and used to predict clinical outcome in a few tri- als. The first study indicated relation of increased value of MHR with adverse cardiovascular outcomes was conducted by Kanbay et al [9] in chronic kidney disease patients. After then, increased MHR (especially MHR N 11.48) was found to be predictor of AF recurrence after cryoballoon-based catheter ablation in another study [10]. They report- ed that patients with a preprocedural MHR of greater than 11.48 had a 11.2-fold increased risk of developing AF recurrence after cryoablation. Again in a new study, MHR was found to be associated with coronary slow flow and systemic inflammation [29]. In our study, receiver oper- ating characteristic curve analysis revealed MHR greater than 17.1 as a cutoff value for mortality and MHR greater than 20.4 as a cutoff value for MACE. We also found that patients in highest tertile group had a 19.15-fold increased risk of mortality and had a 2.81-fold increased risk of developing MACE compared to lowest tertile group.

Limitations

A few limitations of our study deserve mention. This is a single- center cross-sectional retrospective study. Despite that we have found independent correlations in STEMI patients, our findings do not impli- cate a causal relationship. In addition, because of retrospective design of the study, we could not evaluate the inflammatory markers beside MHR and CRP. Additional variables which we could not include in the multivariable regression models may have interfered with our findings. In addition, use of a single blood sample in the preprocedural period does not anticipate the persistence of MHR over time.

Conclusions

In conclusion, we found that higher admission preprocedural MHR is an independent predictor of inhospital mortality and MACE in patients with STEMI treated with primary PCI. To the best of our knowledge, this is the first study to investigate the relation of MHR with inhospital MACE and mortality in patients with STEMI. Further studies are needed to confirm and to reveal clinical implications of our findings.

Funding

The authors received no financial support for the research, author- ship, and/or publication of this article.

Disclosures

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Acknowledgments

None.

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