1

Introduction

Patients with acute coronary syndrome due to left main and/or three-vessel disease (LM/3VD) are at the highest risk of short- and long-term adverse cardiovascular events . In contrast to the well-defined indication for an emergent coronary angiography in ST elevation myocardial infarction (STEMI) population, there is still an uncertainty regarding the optimal timing of angiography in non-ST-elevation myocardial infarction (NSTEMI) patients, and ischemia-guided strategy is an appropriate strategy for selected low-risk patients . Indeed, only 60% of the patients with NSTEMI underwent coronary angiography during the index hospitalization according to large registry data . According to the current guidelines, LM/3VD is an indication for revascularization to improve survival, and patients with LM/3VD will likely benefit from coronary angiography and revascularization . Therefore, knowing the severity of coronary artery disease (CAD) burden upon presentation can help guide the management with respect to the timing of coronary angiogram and revascularization.

In this context, driven by the clinical importance of early identification of patients with LM/3VD, various clinical variables and electrocardiographic findings have been investigated and shown to predict LM/3VD, including advanced age, heart failure on admission, ST-segment depression, and ST-segment elevation in lead aVR . In addition to these well-recognized predictors, neutrophil-to-lymphocyte ratio (NLR) has recently been recognized as a predictor of CAD severity assessed by the number of diseased vessels , the SYNTAX score , and the Gensini score . However, there is a paucity of data validating the predictive value of NLR in assessing the severity of CAD specifically in NSTEMI patients. In addition, the independent predictive value of NLR for severity of CAD burden from other well-known predictors including electrocardiographic findings has not been investigated. A simple blood test that carries an independent predictive value for LM/3VD would be of significant clinical value.

The purpose of the present study is to evaluate the independent predictive value of NLR for LM/3VD in patients with NSTEMI.

2

Materials and methods

A retrospective analysis was performed on all patients who underwent coronary angiography from January 2013 to June 2014 at our institution. Two researchers independently reviewed the emergency department records, in-hospital admission records and cardiac catheterization procedure records to identify patients with NSTEMI. Myocardial infarction (MI) was diagnosed according to the European Society of Cardiology and American College of Cardiology criteria .

Inclusion criteria were 1) cardiac troponin I value greater than the 99th percentile reference value before cardiac catheterization; 2) chest pain (or anginal equivalent) or ischemic changes on the electrocardiogram including horizontal or down-sloping ST-segment depression (≥ 0.05 mV) or T-wave inversion (≥ 0.1 mV) in two or more contiguous leads; and 3) absence of ST elevation and new left bundle branch block on the electrocardiogram. Exclusion criteria were; 1) cardiac catheterization more than 5 days after presentation (n = 143); 2) previous coronary artery bypass grafting (n = 60); 3) severe aortic stenosis, hypertrophic cardiomyopathy, cocaine use within 5 days, cardiac arrest on presentation, ventricular tachycardia, supraventricular tachycardia with heart rate greater than 150 beats per minute, implantable cardioverter defibrillator shock, and blood pressure on presentation > 230/130 mmHg (n = 49); 4) subsequent documented diagnosis of Takotsubo cardiomyopathy, myocarditis, and pulmonary embolism (n = 15); 5) clinically suspected infection, chronic autoimmune disease, steroid use, cancer not in remission, and hematologic proliferative disorder (n = 25); and 6) insufficient data for analysis (n = 40).

The present study complied with the Declaration of Helsinki and was approved by the institutional review board of our institution. Patients’ demographic data and risk factors along with admission characteristics including hemodynamic parameters such as blood pressure, heart rate, and Killip class on admission were obtained.

Peripheral venous blood samples were drawn in the emergency department at the time of presentation. Baseline laboratory data including white blood cell count with differential, hemoglobin, creatinine, and troponin I were recorded. The levels of total and differential blood cell counts were analyzed using an automated blood cell counter, the Beckman Coulter LH 750® (Beckman Coulter Inc., CA, USA). NLR was calculated as the ratio of neutrophil to lymphocyte. Troponin I was measured serially at approximately 6-h intervals before and after catheterization, as clinically indicated. Estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease Study formula . Transthoracic echocardiography was performed during hospitalization, and left ventricular ejection fraction was calculated using either the Teichholz or biplane Simpson’s method.

ECGs obtained on presentation were reviewed by two independent reviewers in a blinded fashion. In the event of an interpretative discrepancy, a consensus between reviewers was reached through discussion. ST-segment depression ≥ 0.05 mV in more than two contiguous leads was recorded. The cutoff of ≥ 0.05 mV for ST-segment depression was chosen in line with the current universal definition of myocardial infarction . In addition, ST-segment elevation in lead aVR ≥ 0.05 mV was recorded. The cutoff of ≥ 0.05 mV for ST-segment elevation in lead aVR was chosen in line with a previous study .

All patients underwent cardiac catheterization within 5 days after presentation. An independent cardiologist blinded to the clinical data visually interpreted all coronary angiograms, and the assessment was compared with the primary assessment by the treating cardiologist. In case of discrepancy, a third investigator made the final interpretation. In line with the standard definition of flow-limiting stenosis , obstructive CAD was defined as stenosis greater than or equal to 70% (50% for the left main coronary artery). Angiographic findings including the number of diseased vessels and revascularization procedures were recorded. Revascularization procedures including percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) were performed at the discretion of the treating physician. Three-vessel disease was present if there were obstructive CAD in all 3 major epicardial coronary arteries, namely left anterior descending, left circumflex and right coronary arteries. The primary outcome was the presence of LM/3VD on angiography. In addition, in-hospital mortality, recurrent MI, heart failure, and cardiogenic shock were recorded. Cardiogenic shock was defined as persistent low systolic pressure (< 90 mm Hg) with clinical signs of hypoperfusion, which was nonresponsive to fluid resuscitation and not attributable to other causes. Cardiac death was defined as death from any cardiac cause (lethal arrhythmia, myocardial infarction, or pump failure) or sudden unexpected death.

Receiver operating characteristic curve was constructed to determine an optimal NLR cutoff value in predicting LM/3VD. Patients were divided into two groups based on the cutoff value. Data are expressed as number (percentage) or median (interquartile range). Dichotomous variables were compared using the chi-squared test or Fisher’s exact test. For continuous variables, the Shapiro–Wilk test was used to check the normality of the distribution. Continuous variables were compared using either the Student’s t-test or Wilcoxon rank sum test, as appropriate. Univariate and multivariate analyses were performed to assess predictors of LM/3VD. The following variables were evaluated first in a univariate model: age, sex, hypertension, diabetes, hyperlipidemia, current smoking, previous MI, TIMI risk score 5–7, heart rate on presentation, Killip class > 1 on admission, eGFR < 60 mL/min/1.73 m ² , NLR, positive troponin I on presentation (> 0.034 μg/L), ST-segment depression ≥ 0.05 mV and ST-segment elevation in lead aVR ≥ 0.05 mV. Significant variables with p value < 0.25 in the univariate analysis were then entered into a multivariate logistic regression analysis using backward stepwise selection. A significance level of 0.10 was required to allow a variable to remain in the model. A 2-sided p value < 0.05 was considered statistically significant. All statistical analyses were performed with R software version 3.0.1 (The R Foundation for Statistical Computing, Vienna, Austria).

2

Materials and methods

A retrospective analysis was performed on all patients who underwent coronary angiography from January 2013 to June 2014 at our institution. Two researchers independently reviewed the emergency department records, in-hospital admission records and cardiac catheterization procedure records to identify patients with NSTEMI. Myocardial infarction (MI) was diagnosed according to the European Society of Cardiology and American College of Cardiology criteria .

Inclusion criteria were 1) cardiac troponin I value greater than the 99th percentile reference value before cardiac catheterization; 2) chest pain (or anginal equivalent) or ischemic changes on the electrocardiogram including horizontal or down-sloping ST-segment depression (≥ 0.05 mV) or T-wave inversion (≥ 0.1 mV) in two or more contiguous leads; and 3) absence of ST elevation and new left bundle branch block on the electrocardiogram. Exclusion criteria were; 1) cardiac catheterization more than 5 days after presentation (n = 143); 2) previous coronary artery bypass grafting (n = 60); 3) severe aortic stenosis, hypertrophic cardiomyopathy, cocaine use within 5 days, cardiac arrest on presentation, ventricular tachycardia, supraventricular tachycardia with heart rate greater than 150 beats per minute, implantable cardioverter defibrillator shock, and blood pressure on presentation > 230/130 mmHg (n = 49); 4) subsequent documented diagnosis of Takotsubo cardiomyopathy, myocarditis, and pulmonary embolism (n = 15); 5) clinically suspected infection, chronic autoimmune disease, steroid use, cancer not in remission, and hematologic proliferative disorder (n = 25); and 6) insufficient data for analysis (n = 40).

The present study complied with the Declaration of Helsinki and was approved by the institutional review board of our institution. Patients’ demographic data and risk factors along with admission characteristics including hemodynamic parameters such as blood pressure, heart rate, and Killip class on admission were obtained.

Peripheral venous blood samples were drawn in the emergency department at the time of presentation. Baseline laboratory data including white blood cell count with differential, hemoglobin, creatinine, and troponin I were recorded. The levels of total and differential blood cell counts were analyzed using an automated blood cell counter, the Beckman Coulter LH 750® (Beckman Coulter Inc., CA, USA). NLR was calculated as the ratio of neutrophil to lymphocyte. Troponin I was measured serially at approximately 6-h intervals before and after catheterization, as clinically indicated. Estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease Study formula . Transthoracic echocardiography was performed during hospitalization, and left ventricular ejection fraction was calculated using either the Teichholz or biplane Simpson’s method.

ECGs obtained on presentation were reviewed by two independent reviewers in a blinded fashion. In the event of an interpretative discrepancy, a consensus between reviewers was reached through discussion. ST-segment depression ≥ 0.05 mV in more than two contiguous leads was recorded. The cutoff of ≥ 0.05 mV for ST-segment depression was chosen in line with the current universal definition of myocardial infarction . In addition, ST-segment elevation in lead aVR ≥ 0.05 mV was recorded. The cutoff of ≥ 0.05 mV for ST-segment elevation in lead aVR was chosen in line with a previous study .

All patients underwent cardiac catheterization within 5 days after presentation. An independent cardiologist blinded to the clinical data visually interpreted all coronary angiograms, and the assessment was compared with the primary assessment by the treating cardiologist. In case of discrepancy, a third investigator made the final interpretation. In line with the standard definition of flow-limiting stenosis , obstructive CAD was defined as stenosis greater than or equal to 70% (50% for the left main coronary artery). Angiographic findings including the number of diseased vessels and revascularization procedures were recorded. Revascularization procedures including percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) were performed at the discretion of the treating physician. Three-vessel disease was present if there were obstructive CAD in all 3 major epicardial coronary arteries, namely left anterior descending, left circumflex and right coronary arteries. The primary outcome was the presence of LM/3VD on angiography. In addition, in-hospital mortality, recurrent MI, heart failure, and cardiogenic shock were recorded. Cardiogenic shock was defined as persistent low systolic pressure (< 90 mm Hg) with clinical signs of hypoperfusion, which was nonresponsive to fluid resuscitation and not attributable to other causes. Cardiac death was defined as death from any cardiac cause (lethal arrhythmia, myocardial infarction, or pump failure) or sudden unexpected death.

Receiver operating characteristic curve was constructed to determine an optimal NLR cutoff value in predicting LM/3VD. Patients were divided into two groups based on the cutoff value. Data are expressed as number (percentage) or median (interquartile range). Dichotomous variables were compared using the chi-squared test or Fisher’s exact test. For continuous variables, the Shapiro–Wilk test was used to check the normality of the distribution. Continuous variables were compared using either the Student’s t-test or Wilcoxon rank sum test, as appropriate. Univariate and multivariate analyses were performed to assess predictors of LM/3VD. The following variables were evaluated first in a univariate model: age, sex, hypertension, diabetes, hyperlipidemia, current smoking, previous MI, TIMI risk score 5–7, heart rate on presentation, Killip class > 1 on admission, eGFR < 60 mL/min/1.73 m ² , NLR, positive troponin I on presentation (> 0.034 μg/L), ST-segment depression ≥ 0.05 mV and ST-segment elevation in lead aVR ≥ 0.05 mV. Significant variables with p value < 0.25 in the univariate analysis were then entered into a multivariate logistic regression analysis using backward stepwise selection. A significance level of 0.10 was required to allow a variable to remain in the model. A 2-sided p value < 0.05 was considered statistically significant. All statistical analyses were performed with R software version 3.0.1 (The R Foundation for Statistical Computing, Vienna, Austria).

3

Results

Of the 728 patients who met the inclusion criteria, 332 patients were excluded according to the pre-specified exclusion criteria. In all, 396 patients who underwent coronary angiography within 5 days after presentation with the diagnosis of NSTEMI were included in the final analysis.

Median NLR in the entire study population was 3.43 (interquartile range, 2.12–5.51). By receiver operating characteristics curve analysis ( Figure. 1 ), the optimal cutoff value of NLR in predicting LM/3VD was 2.80 (area under the curve 0.60, sensitivity 73%, specificity 43%). Of the 396 patients, 244 patients (62%) were categorized into the high NLR group. Baseline characteristics are summarized in Table 1 . Patients with high NLR were significantly older. With respect to the laboratory data, patients with high NLR had a significantly higher white blood cell count and peak troponin I values.

Receiver operating characteristic (ROC) curve for neutrophil-to-lymphocyte ratio for prediction of left main and/or three-vessel disease. ROC curve demonstrates area under the curve of 0.60 (95% confidence interval; 0.53–0.66). The optimal cutoff value is 2.80 (sensitivity 73% and specificity 43%).

Table 1

Patients’ baseline characteristics, hemodynamic and laboratory data.

	NLR ≥ 2.8 (n = 244)	NLR < 2.8 (n = 152)	p value
Age (years)	67 [60–79]	65 [56–73]	< 0.001
Men	145 (59)	90 (59)	0.97
Hypertension	179 (73)	109 (72)	0.72
Diabetes	88 (36)	55 (36)	0.98
Hyperlipidemia	129 (53)	94 (62)	0.08
Current smoking	51 (21)	43 (28)	0.09
Family history of coronary artery disease	50 (21)	34 (22)	0.66
Previous myocardial infarction	40 (16)	19 (13)	0.29
Previous PCI	71 (29)	47 (31)	0.7
High TIMI risk score (5–7)	66 (27)	35 (23)	0.37
Hemodynamic and laboratory data
Systolic blood pressure (mm Hg)	141 [125–159]	145 [130–158]	0.56
Heart rate (beats per min)	81 [71–96]	78 [70–90]	0.06
Killip class > 1 on admission	35 (14)	14 (9)	0.13
White blood cell count (10 9 /L)	8 .9 [7.2–10.8]	7.5 [6.1–9.3]	< 0.001
Neutrophil-to-lymphocyte ratio	4.8 [3.6–6.7]	1.9 [1.4–2.3]	< 0.001
Hemoglobin (g/dL)	13.2 [11.8–14.3]	13.3 [12.0–14.4]	0.43
eGFR < 60 (mL/min/1.73 m 2 )	78 (32)	28 (25)	0.14
Troponin I on presentation > 0.034 μg/L	211 (87)	122 (80)	0.1
Peak troponin I (μg/L)	1.28 [0.15–7.11]	0.26 [0.06–1.30]	< 0.001
Left ventricular ejection fraction (%)	60 [35–61]	60 [45–65]	0.22

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