Download persistent elevation of neutrophil/lymphocyte ratio associated with

J Ayub Med Coll Abbottabad 2015;27(2)
ORIGINAL ARTICLE
PERSISTENT ELEVATION OF NEUTROPHIL/LYMPHOCYTE RATIO
ASSOCIATED WITH NEW ONSET ATRIAL FIBRILLATION
FOLLOWING PERCUTANEOUS CORONARY INTERVENTION FOR
ACUTE ST SEGMENT ELEVATION MYOCARDIAL INFARCTION
Nelson Chavarria, Cyrus Wong, Hafiz Hussain, Habib Ullah Joiya, Seth Goldbarg, Andrew Buda
New York Hospital Queens, Flushing, New York-USA
Background: Increasing evidence suggests that inflammation plays an important role in initiation and
maintaining of atrial fibrillation (AF). The Neutrophil to Lymphocyte (N/L) Ratio is an easily derived
and readily available parameter that has emerged as marker of inflammation with predictive and
prognostic value. We investigated the association between N/L ratio and incidence of atrial fibrillation
in patients undergoing cardiac catheterization for acute ST-segment elevation myocardial infarction
(STEMI). Methods: This cross sectional descriptive study was carried out at New York Hospital
Queens. We retrospectively analysed clinical, hematologic and angiographic data of 290 patients who
underwent coronary angiography with stent placement for acute ST-segment elevation myocardial
infarction between 2008–2011. Results: Study cohort of 290 patients had mean age 63.3±13.0 years
consisting of 81.4% male. The N/L ratio was measured at time points: <6 hours pre-catheterization,
<12, 48 and 96 hours post catheterization. Patients who developed AF (n=40, 13.8%), had higher post
catheterization N/L ratios at 48hours (median 5.23 vs 3.00, p=0.05) and 96 hours (median 4.67 vs 3.56,
p=0.03), with no differences in the immediate pre and post procedural measurements, <6 hours pre
catheterization (median 2.49 vs 2.82, p=0.467) and <12 hours post catheterization (median 5.93 vs 5.03,
p=0.741) respectively. Conclusion: In conclusion, these findings support an inflammatory aetiology
contributing to new onset AF following percutaneous coronary intervention for acute STEMI. Further
studies are warranted to elucidate these findings.
Keywords: Neutrophil/Lymphocyte ratio, Atrial Fibrillation Coronary Angiography, Myocardial
Infarction
J Ayub Med Coll Abbottabad 2015;27(2):441–7
INTRODUCTION
Inflammation and its role in initiating atrial fibrillation
(AF) was first observed in inflammatory disease states
such as myocarditis, pericarditis and cardiac surgeries.1–3
Early histological studies of patients with atrial
myocarditis who developed lone AF were found to have
inflammatory infiltrates, myocyte necrosis and fibrosis,
not identified in control subjects with sinus rhythm.2,4
Several large, randomized prospective epidemiological
studies have since supported these initial observations
indirectly through the use of inflammatory markers, and
suggest that inflammation plays a crucial role in initiating
and maintaining AF.5–8 The inflammatory response
associated with new onset AF following acute ST
segment elevation myocardial infarction (STEMI) is not
completely understood. In this setting, a pronounced
increase in post procedural white blood cell count (WCC)
has been previously described,9–11 however total WCC is
a composite variable and remains a relatively crude
marker of inflammation. More recently, the use of a
neutrophil to lymphocyte (N/L) ratio, which can be easily
derived from the differential WCC, has emerged as a
potential marker of inflammation.12 As it integrates
changes in neutrophils and lymphocytes, namely
neutrophilia and lymphopenia, the N/L ratio has been
closely associated with mortality in patients undergoing
coronary angioplasty for stable13,14 and unstable coronary
artery disease15,16. It has also been associated with
increased risk of new onset AF following coronary
artery bypass grafting.17 The relationship between the
N/L ratio and post-catheterization incidence of AF in the
acute STEMI setting has not been described. In this
study, we hypothesized that a persistent elevation in N/L
ratio post catheterization is associated with a higher
incidence of AF.
MATERIAL AND METHODS
This cross sectional descriptive study was carried out with
the study cohort consisting of 290 patients who
underwent coronary angiography with stent placement for
acute ST-segment elevation myocardial infarction at New
York Hospital Queens between 2008–2011. The baseline
clinical data was obtained retrospectively, at the time of
interest when the patients underwent coronary
angiography. Clinical and demographic characteristics
encompassing cardiovascular risk factors were noted.
All laboratory data including complete white
blood cell count and differentials were obtained from
peripheral venous blood sampling, measured at <6 hours
prior coronary catheterization and <12, 48 and 96 hours
following the procedure. Total WBC, neutrophil,
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441
J Ayub Med Coll Abbottabad 2015;27(2)
lymphocyte and monocyte counts were calculated using
an automated blood cell counter. Coronary interventions
were performed according to current practice guidelines
and recorded in digital storage for quantitative
analysis. Continuous data was presented as median
and interquartile range or mean±SD. Categorical
variables were summarized as percentages and
compared with chi-square test. Comparisons for
continuous variables between patients and controls were
analysed using one-way ANOVA. p<0.05 was
considered significant. Statistical analysis was
performed using SPSS–18.
RESULTS
The study cohort was predominantly male (n=236,
81.4%), with a median age of 63.3±13.0 years. In total
290 patients were enrolled in the study, of which 40
patients (13.8%) developed AF with median onset of
3±2 days (Table 1). The patients who developed AF
were older, had higher rates of dyslipidaemia, peripheral
vascular disease, and lower estimated glomerular
filtration rates on admission. In addition, fewer achieved
TIMI III flow post procedure, had higher levels of total
peak creatine phosphokinase, and had lower left
ventricular ejection fractions prior to discharge as
determined by transthoracic echocardiogram.
The median total WCC was not significantly
different between the two groups at all the measured
time points (Table-2). However, following an initial rise
in the median N/L ratio post catheterization in both
groups, the AF group demonstrated a sustained
elevation at 48 hours (median 5.23 vs 3.00, p=0.05) and
96 hours (median 4.67 vs 3.56, p=0.03) respectively
(Figure-1,2). The N/L ratio remained significantly
higher in the atrial fibrillation group when accounting
for elevated creatine phosphokinase and low post
intervention TIMI III flow. However, glomerular
filtration rate <70 at time of admission and left
ventricular ejection fraction <50% prior to discharge,
remained confounding factors at 48 and 96 hours (Table
3). The patients in both groups were prescribed similar
medical therapy and none received antiarrhythmic
therapy pre or post procedure.
Table-1: Comparison of Basic and demographic profile of both the groups
Age (years)
Male
Body mass index (kg/m2)
Asian
African American
Caucasian
Hispanic
Hypertension
Dyslipidemia
Diabetes Mellitus
Active smoker
Peripheral Vascular Disease
family history of coronary artery disease
known history of coronary artery disease
previous myocardial infarction
previous coronary artery bypass grafting
Catheterization Details
admission serum Creatinine
Admitting Glomerular Filtration Rate (ml/min/1.73 cm2)
Number of coronary arteries with >50% luminal narrowing
1
>1
Target coronary artery
Left Anterior Descending
Right
Left circumflex
Venous Graft
Thrombectomy
Type of stent implanted
drug eluting stent
bare metal stent
Post-intervention TIMI III flow
Admitting Left Ventriculogram Ejection Fraction (%)
Post Catheterization Details
Peak Total Creatine Phospokinase
High-density Lipoprotein Cholesterol (mg/dl)
Low-density Lipoprotein Cholesterol (mg/dl)
Triglyceride (mg/dl)
Discharge serum Creatinine
Discharge Glomerular Filtration Rate (ml/min/1.73 cm2)
Discharge Transthoracic Echocardiogram Ejection Fraction (%)
Time of new onset Atrial Fibrillation (days)
442
New Onset Atrial
Fibrillation (n=40)
70.6±12.4
26 (65%)
26.8±4.7
7 (17.5%)
3 (7.5%)
25 (62.5%)
5 (12.5%)
29 (72.5%)
28 (70%)
13 (32.5%)
25 (62.5%)
4 (10%)
3 (7.5%)
17 (34%)
2 (5%)
0 (0%)
No Atrial Fibrillation
(n= 250)
60.7±12.8
210 (84%)
27.2±5.8
50 (20%)
8 (3.2%)
135 (54%)
57 (22.8%)
147 (58.8%)
132 (52.8%)
64 (25.6%)
119 (47.6%)
6 (2.4%)
30 (12%)
130 (52%)
10 (4%)
8 (3.2%)
1.05 ± 0.33
73.8 ± 33.9
1.06 ± 0.37
88.2 ± 37.1
0.878
0.022
19 (47.5%)
21 (52.5%)
97 (38.8%)
153 (61.2%)
0.297
0.297
19 (47.5%)
15 (37.5%)
6 (15%)
0 (0%)
26 (65%)
139 (55.6%)
80 (32%)
27 (10.8%)
3 (1.2%)
175 (70%)
0.34
0.491
0.437
0.486
0.524
28 (70%)
9 (22.5%)
32 (80%)
41.9±12.0
184 (73.6%)
63 (25.2%)
234 (93.6%)
44.9±11.0
0.634
0.714
0.004
0.111
3889±4045
39.9±13.2
98.5±29.8
123.3±97.1
1.06±0.54
77.8±38.9
44.7±13.7
3±2
2502±2014
38.1±11.3
119.4±39.1
145.9±107.6
0.99±0.40
94.8±39.5
50.4±11.1
N/A
<0.001
0.368
0.002
0.228
0.346
0.011
0.004
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p value
<0.001
0.004
0.633
0.712
0.186
0.316
0.14
0.099
0.042
0.359
0.08
0.014
0.405
0.02
0.768
0.251
J Ayub Med Coll Abbottabad 2015;27(2)
Table-2: Comparison of Blood profile of both groups
New Onset Atrial Fibrillation
Pre-procedure
Total White Blood Cell Count (x109/L)
Hemoglobin (g/L)
Hematocrit (%)
Platelet (x109/L)
Neutrophil Count (x109/L)
Lymphocytes Count (x109/L)
Monocyte Count (x109/L)
Eosinophil Count (x109/L)
Basophil Count (x109/L)
Neutrophil/lymphocyte ratio
Immediate post-procedure
Total White Blood Cell Count (x109/L)
Hemoglobin (g/L)
Hematocrit (%)
Platelet (x109/L)
Neutrophil Count (x109/L)
Lymphocytes Count (x109/L)
Monocyte Count (x109/L)
Eosinophil Count (x109/L)
Basophil Count (x109/L)
Neutrophil/lymphocyte ratio
48 hours post-procedure
Total White Blood Cell Count (x109/L)
Hemoglobin (g/L)
Hematocrit (%)
Platelet (x109/L)
Neutrophil Count (x109/L)
Lymphocytes Count (x109/L)
Monocyte Count (x109/L)
Eosinophil Count (x109/L)
Basophil Count (x109/L)
Neutrophil/lymphocyte ratio
96 hours post-procedure
Total White Blood Cell Count (x109/L)
Hemoglobin (g/L)
Hematocrit (%)
Platelet (x109/L)
Neutrophil Count (x109/L)
Lymphocytes Count (x109/L)
Monocyte Count (x109/L)
Eosinophil Count (x109/L)
Basophil Count (x109/L)
Neutrophil/lymphocyte ratio
No Atrial Fibrillation
p-value
12.4±3.9
14.0±1.7
41.5±4.60
242.2±54.1
63.1±17.4
28.2±14.9
6.8±2.1
1.6±1.25
0.35±0.23
3.55±3.15
11.00±3.59
14.3±1.7
42.6±4.58
243.2±66.2
65.9±14.4
24.5±12.5
7.2±3.2
2.7±1.65
0.34±0.25
4.19±3.55
0.131
0.546
0.297
0.938
0.555
0.388
0.542
0.753
0.893
0.482
12.0±3.6
12.9±1.9
38.9±5.2
231.5±50.4
79.3±6.8
14.1 ± 6.7
5.9±1.8
0.43±0.78
0.18±0.13
7.14±4.4
11.7±3.7
13.8±1.8
41.2±5.2
221.8±67.8
75.8±9.9
15.9±7.7
7.5±2.6
0.83±1.15
0.24±0.24
6.75±5.2
0.708
0.093
0.108
0.471
0.071
0.256
0.006
0.075
0.086
0.741
11.6±3.2
12.4±1.9
37.5±5.37
194.3±53.1
71.9±10.5
18.2 ± 9.6
8.78±2.39
0.88±0.82
0.2±0.12
5.68±4.1
10.3±3.2
13.1±1.8
39.5±5.04
195.8±61.4
66.5±8.9
21.3±7.8
9.85±2.57
1.75±2.1
0.29±0.20
3.94±2.5
0.126
0.169
0.139
0.915
0.051
0.21
0.089
0.0006
0.01
0.052
10.3±3.3
11.7±2.2
35.6±6.3
220.5±49.3
69.2±10.0
18.1±8.8
10.1±1.7
2.3±1.7
0.25±.12
5.23±.4
9.5±2.9
12.6±1.8
37.9±.6
202.6±7.6
65.7±9.0
20.5±7.5
10.1±2.4
3.0±2.0
0.31±0.21
3.83±1.9
0.391
0.181
0.194
0.232
0.221
0.334
0.972
0.165
0.098
0.028
Table-3: Heart functions of both the groups
Post-intervention < TIMI III flow
Peak Total Creatine Phosphokinase >3000
Admitting Glomerular Filtration Rate <70 (ml/min/1.73 cm2)
Discharge Transthoracic Echocardiogram Ejection Fraction <50(%)
Post-intervention < TIMI III flow
Peak Total Creatine Phosphokinase >3000
Admitting Glomerular Filtration Rate <70 (ml/min/1.73 cm2)
Discharge Transthoracic Echocardiogram Ejection Fraction <50(%)
New Onset Atrial
No Atrial Fibrillation
Fibrillation
N/L Ratio at 48 hours
7.92±2.71 (n=4)
5.19±3.25 (n= 6)
6.36±3.09 (n=18)
4.59±3.04 (n=50)
7.15±4.20 (n=12)
4.75±2.99 (n= 42)
6.79±4.13 (n=12)
4.39±2.84 (n=87)
New Onset Atrial
No Atrial Fibrillation
Fibrillation
N/L Ratio at 96 hours
5.95±3.87 (n=3)
6.71±0.420 (n=2)
5.01±3.18 (n=7)
3.99±2.13 (n=33)
5.72±3.57 (n=12)
3.97±2.15 (n=27)
5.91± .81 (n=10)
4.06±2.03 (n=36)
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p value
0.252
0.24
0.029
0.011
p value
0.807
0.303
0.064
0.044
443
J Ayub Med Coll Abbottabad 2015;27(2)
Figure-1: Sustained elevation of neutrophil to
lymphocyte ratio at 48 and 96 hours following
percutaneous coronary intervention for acute
STEMI was associated with greater incidence of
atrial fibrillation.
Figure-2: Sustained elevation of neutrophil to
lymphocyte ratio at 48 and 96 hours following
percutaneous coronary intervention for acute
STEMI was associated with greater incidence of
atrial fibrillation.
DISCUSSION
In the present study, we focused on assessing the
relationship between N/L ratio and the incidence of
AF in patients undergoing coronary catheterization
for acute STEMI. We demonstrated that failure to
normalize the N/L ratio at 48 and 92 hours post
catheterization conferred a higher incidence of AF.
Although the underlying causative mechanisms
involved remain to be completely understood and
likely related to underlying renal dysfunction and
depressed left ventricular systolic function,
inflammation appears to be an important component.
In general, mechanisms contributing to inflammation
may stem from multiple parameters including
ischemic reperfusion injury (in the setting of
percutaneous
coronary
intervention),
fluid
hemodynamic
(resulting
from
ventricular
dysfunction)
and
a
pre-existing
systemic
inflammatory state prior to the procedure.
Insight into the mechanistic relationship of
myocardial infarction and arrhythmias stem from
experimental animal studies. Models of atrial
444
ischemia induced by occlusion of the atrial artery
initially demonstrated local slowing of conduction
and subsequent development of re-entry circuits
contributing to a higher incidence of AF.18
Subsequent studies demonstrated that these effects
could be suppressed with β-adrenoceptor blockade,
Ca2+ current inhibition, heat shock protein induction,
and gap junction conduction enhancement.19–21
Similarly, animal models of ventricular infarction
have highlighted the importance of atrial stretch and
neurohormonal activation in AF development.22–24
Stretch and strain patterns of myocytes causing
alterations in cytoskeletal linkages that activate
stretch-sensitive ion channels were shown to regulate
G protein coupled, β-adrenergic and muscarinic
pathways.25–27 Not only do the acute mechanical
changes produce electrophysiologic alterations that
promote arrhythmia, but once AF is induced, rapid
contraction of dispersed atrial segments (contractile
dispersion) is thought to perpetuate the
electrophysiologic derrangements observed.28,29
Recent evidence now suggests that infarct
related fibrosis, apoptosis and structural atrial
remodelling also play key roles in local leuckocyte
recruitment and activation.30,31 Proinflammatory
cytokines and hormones released by injured tissue
such as Angiotensin II, TNF-α, Interleukin 6 and 8
have been implicated in promoting local activation of
polymorphonuclear neutrophils (PMNs).32–37 Once
activated, PMNs are thought to stimulate cardiac
fibroblast differentiation to myofibroblasts.38
Myofibroblasts activation has been implicated in
promoting structural atrial remodelling in acute
injury and AF.39,40 The collective inflammatory
response of myocyte apoptosis, matrix turnover,
structural remodelling and contractile dysfunction
may provide the link between inflammation and AF.
The use of inflammatory mediators as
markers of prognosis and AF risk has been the
subject of intense clinical investigation. Various
biomarkers including C-reactive protein, tumour
necrosis factor-α, Interleukins-2, 6, 8 and monocyte
chemoattractant protein-1 have been linked with the
presence and outcomes of AF.41–45 More recently, the
N/L ratio has emerged as a marker of inflammation
with predictive and prognostic value in various
diseases states including coronary artery disease
(CAD) and AF, respectively. Independently, an
elevated leuckocyte count is associated with
increased risk of future cardiovascular events,12,46 and
when in combination with a reduced lymphocyte
count, is known to confer a worsening prognosis.47,48
The N/L ratio has been associated with arterial
stiffness and high coronary calcium scores49, and is a
reported independent predictor of short and long term
mortality in patients with acute coronary
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J Ayub Med Coll Abbottabad 2015;27(2)
syndromes.50,51 It has also been associated with
greater risk of ventricular arrhythmias during
percutaneous coronary intervention52 and higher
mortality rates in patients undergoing primary PCI
irrespective of the indication.53 In AF, an elevated
N/L ratio has been associated with an increased risk
of new onset AF following coronary artery bypass
grafting.17 It has also been used to measure
thromboembolic risk and predict AF recurrence
following electrical cardioversion in patients with
non-valvular atrial fibrillation.54,55
In our present study, we demonstrate a
positive association between post catheterization
incidence of Afib and N/L ratio in patients presenting
with acute STEMI. However, the findings do not
clarify whether the association reflects a local or
systemic inflammation response. There is limited
data available on the systemic or local nature of AF
related inflammation. Prior studies have attempted to
identify the source. In one such study, chronic AF
patients had higher plasma levels of Interleukin-8 in
the femoral vein, right atrium and coronary sinus
compared to the pulmonary veins56, suggesting a
possible systemic source of inflammation. A separate
study however, detected higher levels of C-reactive
protein in the left atrium compared to the coronary
sinus, suggesting a local retention of inflammatory
cytokines in the heart.57 Much work remains to be
done to further elucidate these observations.
The retrospective nature of our single centre
study may limit the ability to generalize our present
findings. The use of continuous hospital telemetry
monitoring during the first 96 hours post procedure
allowed for detection of AF. In addition, review of
electrocardiographic analysis and medical records
provided additional resources for detection. However
it remains possible that some patients may have
developed AF that was not clinically documented.
Furthermore, the analysis of hematologic samples
was restricted to one sample per time point, which
does not lend itself to addressing potential changes in
N/L ratio and the stability of the data point.
CONCLUSION
Our study demonstrates that patients presenting with
acute STEMI, post-catheterization elevations in N/L
ratio on days 2 and 4 are associated with higher
incidence of AF. In contrast, to the immediate pre or
post-procedural levels which do not demonstrate this
association. Although the relationship might be
limited by the previously stated factors, the N/L ratio
can be an easily derived and routinely measured.
Future prospective studies with large sample sizes
may further assess the clinical importance of this
inflammatory parameter.
Disclosure: The authors declare that there is no
conflict of interest regarding publication of this paper
and there is no relevant financial disclosures.
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Address for Correspondence:
Dr. Hafiz Hussain, Division of Cardiology, New York Hospital Queens, 5645 Main Street, flushing, New YorkUSA 11355
Email [email protected]
http://www.jamc.ayubmed.edu.pk
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