THEMED ARTICLE y Cardiac Imaging & Diagnostic Techniques Review

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Neutrophil to lymphocyte ratio

and cardiovascular diseases:
a review
Expert Rev. Cardiovasc. Ther. 11(1), 55–59 (2013)

Tariq Bhat*1, Sumaya The role of inflammatory markers in cardiovascular diseases has been studied extensively and a
Teli2, Jharendra consistent relationship between various inflammatory markers and cardiovascular diseases has
Rijal3, Hilal Bhat4, been established in the past. Neutrophil to lymphocyte ratio (NLR) is a new addition to the long
list of these inflammatory markers. NLR, which is calculated from complete blood count with
Muhammad Raza3,
differential, is an inexpensive, easy to obtain, widely available marker of inflammation, which
Georges Khoueiry1, can aid in the risk stratification of patients with various cardiovascular diseases in addition to
Mustafain Meghani3, the traditionally used markers. It has been associated with arterial stiffness and high coronary
Muhammad Akhtar1 calcium score, which are themselves significant markers of cardiovascular disease. NLR is reported
and Thomas as an independent predictor of outcome in stable coronary artery disease, as well as a predictor
Costantino1 of short- and long-term mortality in patients with acute coronary syndromes. It is linked with
1
Division of Cardiology, Staten Island
increased risk of ventricular arrhythmias during percutaneous coronary intervention (PCI) and
University Hospital New York, 475 higher long-term mortality in patients undergoing PCI irrespective of indications of PCI. In
Seaview Ave, Staten Island, New York, patients admitted with advanced heart failure, high NLR was reported with higher inpatient
NY 10305, USA mortality. Recently, NLR has been reported as a prognostic marker for outcome from coronary
2
University of Sheffield, School of
Medicine, Sheffield, UK artery bypass grafting and postcoronary artery bypass grafting atrial fibrillation.
3
Department of Medicine, Staten Island
University Hospital New York, 475 Keywords: cardiovascular disease • neutrophil to lymphocyte ratio
Seaview Ave, Staten Island, New York,
NY 10305, USA
4
Department of Medicine, SK Institute Multiple studies have shown a strong and con- Significant evidence has suggested a possible role
of Medical Sciences, Soura, Kashmir,
sistent relationship between inflammation mark- of N count as an independent prognostic factor
India
*Author for correspondence: ers and cardiovascular diseases [1–6] . C-reactive in both acute as well as chronic cardiovascular
Tel.: +1 718 226 9000 protein (CRP) has been studied extensively diseases, which is also supported by some labora-
mohiuddin_bhat@yahoo.com
among all the inflammatory markers and has tory studies explaining different mechanism of
still been in focus in recent studies [3,7] . Being this association [8] . Elevated M count was also
a simple, readily available and inexpensive test, found to carry increased risk in cardiovascular
total white blood cell (WBC) count, has been diseases [10] . The recent remarkable observation
in focus for the last two decades and it has been has been that a ratio of N to L count (NLR) has
suggested in multiple studies that a high level a greater predictability than total WBC count
of total WBC count is not only an independent or N count as a marker in cardiovascular dis-
risk factor for major cardiovascular diseases but eases and is slowly emerging as an independent
can prognosticate outcome of many cardiovas- useful prognostic parameter in cardiovascular
cular diseases [1,4,6,8] . Despite all these studies, diseases [11,12] .
total WBC count has not been explored and The predictive superiority of NLR may be due
exploited for its utility in predicting cardiovas- to many reasons including the fact that it is less
cular risk. It has recently been proposed as one likely to be influenced by various physiological
of the potential biomarkers for risk assessment conditions such as dehydration and exercise,
in ­cardiovascular disease [9] . even though these conditions may affect abso-
There has been a recent focus on differential lute number of individual cell types. Second
white cell count, and identification of a particu- and most importantly, NLR is a ratio of two
lar cell type (neutrophil [N], lymphocyte [L] different yet complementary immune pathways,
and monocyte [M]) as a stronger predictor of thus integrating the deleterious effects of Ns,
cardiovascular risk than the total WBC count. which are responsible for active nonspecific

www.expert-reviews.com 10.1586/ERC.12.159 © 2013 Expert Reviews Ltd ISSN 1477-9072 55

 Review Bhat, Teli, Rijal et al.
inflammation and lymphopenia, which is a marker of poor gen-
eral heath and physiological stress [13] . Thus, NLR, being an
integrated reflection of two important and opposite immune
pathways, is more predictive than either parameter alone.
In this brief review, the authors will provide a useful summary
of the evidence available in literature about the association of
NLR with various cardiovascular diseases and its possibility of
emerging as a cheap, reliable and independent prognostic marker
of cardiovascular disease.
NLR & stable coronary artery disease
Elevated NLR, independently and in interaction with other
disease markers and risk factors, is a significant predictor of
mortality in stable coronary artery disease (CAD), as well as its
development and progression [11,12,14–16] . Horne et al. were among
the first to observe the significance of NLR in stable CAD. In
their prospective observational study, more than 3000 patients
without acute myocardial infarction (MI) and with angiographi-
cally assessed CAD were followed for more than 6 years [11] . The
predictive ability for death/MI of quartile (Q) 4 versus Q1 total
WBC, N, L and M counts, and NLR were assessed using Cox
regressions. Total WBC count was confirmed to be an inde-
pendent predictor of death/MI in patients with or at high risk
for CAD, but greater predictive ability is provided by high N
(Q4 > 6.6 × 103/μl) or low L counts. The greatest risk prediction
is given by the N/L ratio, with Q4 versus Q1 (>4.71 vs >1.96)
increasing the hazard by 2.2-fold. They reported that incremental
improvement in risk prediction achieved with WBC differential
was similar to or greater than that reported for high-sensitive
CRP [11] . Another prospective study analyzed the predictive abil-
ity for cardiac events of differential WBC against established risk
factors in angiographically proven CAD patients. They evaluated
complete blood count, and other biomarkers of inflammation:
(CRP and serum iron), fasting glucose, total, HDL and LDL
cholesterol) and established risk factors in 422 patients. High
NLR (5.19 ± 3.81), together with CRP, left ventricular ejection
fraction, fasting glucose, HDL and serum iron, was associated
with significantly (p = 0.02) increased cardiac death and nonfatal
MI in patients with stable CAD on a 3-year follow-up. Event-free
survival according to NLR tertiles was 99% for the first tertile
(1.23 ± 0.26), 96.5% for the second (2.05 ± 0.29) and 88.8% for
the third (5.19 ± 3.81) [12] .
In a large Asian cohort of high-risk patients, (patients with
diabetes mellitus and metabolic syndrome) NLR was associated
with both metabolic syndrome and risk of ischemic cardiovascu-
lar diseases [16] . Association between NLR and other established
indirect markers of cardiovascular disease like coronary calcium
score (CCS) was studied in more than 800 Korean adult patients.
The degree of atherosclerosis or arterial stiffness, measured by
brachial–ankle pulse-wave velocity and CCS, was associated to
NLR as higher scores among the patients with high NLR ≥2.5
(p < 0.001 for brachial–ankle pulse-wave velocity and p = 0.032
for CCS) [15] . A recent interesting observation about angiographic
progression of coronary atherosclerosis by Kalay et al. reported
that among the patients with CAD requiring repeat coronary
56
angiography, NLR was higher in the progressive group (5.0 ± 5.1
vs 3.2 ± 3.0; p = 0.001) compared with the nonprogressive group
and progression rate of atherosclerosis was significantly higher
(56 vs 39%; p = 0.03) in patients with high NLR [14] .
NLR & acute coronary syndrome
Acute coronary syndrome (ACS) is one of the commonest admit-
ting diagnoses in the emergency department all over the USA.
Approximately 6 million emergency room visits per year are for
chest pain in USA [17] . Owing to the high mortality of ACS,
different modalities have been utilized to increase the efficacy of
identifying them earlier, which include use of high-sensitive tro-
ponin; emergency-room-based computed tomography coronary
angiographic evaluation of chest pain and creation of separate
fast-track chest pain unit [18–20] . The question of whether NLR
on admission has any diagnostic utility in patients admitted
with chest pain was studied by Zazula et al. Patients diagnosed
with noncardiac chest pain reported lowest admission NLR
(3 ± 1.6), followed by unstable angina (3.6 ± 2.9), non-ST-ele-
vation MI (4.8 ± 3.7) and ST-elevation MI (STEMI) (6.9 ± 5.7)
(p < 0.0001) [21] . NLR above 5.7 reported 91% specificity and
4.51 odds ratio for the final diagnosis of ACS when compared
with the groups with NLR <3.0 (p < 0.001) [21] . Being an inex-
pensive and reproducible predictive marker, NLR can be of rel-
evance while evaluating chest pain. Elevated CRP and NLR,
markers of underlying acute-phase inflammation, serve as indica-
tor for thrombus formation in patients with acute MI. Compared
with the patients with acute MI and no thrombus formation,
the levels of high-sensitivity CRP, total N count and NLR were
substantially higher (p < 0.05) in the patients with acute MI and
thrombus ­formation [22] .
Risk stratification and prediction of outcome is of enormous
importance in management of CAD. There are multiple scor-
ing systems in clinical practice utilized for risk stratification of
patients diagnosed with ACS. NLR itself is not part of any risk
stratification scoring system even though multiple studies have
elucidated this association. High NLR has been associated with
poor outcomes in patients with ACS [23] . In-hospital mortality
(8.5 vs 1.8%; p = 0.013) and 6-month mortality (11.5 vs 2.5%;
p < 0.001) were found to be significantly higher in patients with
ACS with high NLR compared with those with low NLR [24] .
Over a mean follow-up of 32 months in patients with CAD
who had undergone percutaneous coronary angioplasty, the
best survival was seen in patients with low NLR (1.7 ± 0.5) and
an increased mortality seen in patients with NLR ≥3.2 ± 0.6
(p < 0.0001) [25] . After adjusting for age, chronic obstructive pul-
monary disease, left ventricular ejection fraction, serum hemo-
globin, serum creatinine and lesion severity, the log NLR was an
independent significant predictor of long-term mortality (­hazard
ratio; 1.85, p = 0.01) in CAD after percutaneous coronary inter-
vention (PCI) [25] . During median follow-up to 3.6 years in
African–American patients undergoing PCI, mortality rate was
high with 31.1% in the group with preprocedural NLR ≥3.5
whereas it was only 10.4% in the group with preprocedural
NLR <3.5 (p < 0.001) [26] .
Expert Rev. Cardiovasc. Ther. 11(1), (2013)

Patients with non-STEMI and NLR >4.7 had significantly
higher in-patient and 4-year mortality rate (29.8 vs 8.4%) com-
pared with those with NLR <3 (p < 0.0001) [13] . Among the
patients with STEMI, long-term mortality was significantly
higher (47.9 vs 6.4%, p < 0.001) in the group with maximum
NLR compared with those with lowest NLR [27] . Compared with
patient groups with STEMI undergoing PCI who had low NLR
and no anemia, and those with low NLR and anemia on admis-
sion, 6-month mortality was higher (p = 0.036) in those patients
with high NLR and anemia [28] . It clearly suggests that combined
use of hemoglobin level and NLR provides timely information for
early risk stratification in patients with STEMI undergoing PCI.
In summary, NLR has been consistently shown to be an inde-
pendent risk marker for ACS both in the short term as well as
long term but similar association was not found by Kruk et al.
in their more than 1000 with unselected patients STEMI, only
high-­sensitivity CRP and WBC count independent of each
other predicted early outcome in STEMI patients treated with
primary PCI [29] .
NLR & cardiac arrythmias
The association between inflammation and atrial fibrillation (AF)
is well known [2] , and has been studied extensively. Even though
various inflammatory markers have been associated with inci-
dence, recurrence and outcome in AF, association of NLR has
not been much looked into in this group of patients.
Association of inflammation and inflammatory markers in
other arrythmias, especially ventricular arrythmia, is not well
elucidated or understood, and the minimal available evidence is
conflicting [30–33] .
Chatterjee et al. in a retrospective study in patients undergoing
PCI, reported that preprocedural elevated WBC count, neutro-
philia and elevated NLR were significant predictors of ventricular
arrythmias [34] . For all the patients developing ventricular arryth-
mia during PCI compared with a random group, significantly
higher preprocedural total WBC count (means: 14,344 vs 6852;
p = 0.0004), N count (mean: 75.79 vs 58.06%, p < 0.0001) and
NLR (mean: 3.79 vs 1.56, p < 0.0001) were found in this study.
Thus, it is evident that the evidence is not enough to make any
conclusion on association of NLR and various cardic arrythmias.
NLR & heart failure
Previous studies have shown that inflammatory markers such as
increased WBC counts can be associated with increased incidence
of heart failure hospitalization and mortality [35,36] . Relative, neu-
trophilia has been associated with increased incidence of acute
decompensated heart failure (ADHF) in patients admitted with
acute MIs [37] . In a retrospective study of patients who developed
congestive heart failure (CHF) within the first 4 days after acute
MI, 92.5% had relative neutrophilia on admission (N percent-
age >65%) compared with 45% of those in whom CHF did not
develop [38] . In addition, relative lymphocytopenia has shown
to be an independent predictor of mortality in heart failure [39] .
The role of elevated NLR in heart failure incidence and its out-
come has not been dwelled on much. In a recent large prospective
www.expert-reviews.com
NLR & cardiovascular diseases Review
cohort study, NLR was found to be a significant marker of fre-
quent decompensation and long-term mortality in patients with
CHF. During 26-month median follow-up of more than 1000
patients with ADHF, a positive trend between death and NLR
was observed, 32.8, 23.2 and 14.2% of deaths occurred in patients
with admission NLR of 9.6 (7.6–13.1), 5.1(4.5–5.8) and 2.8
(2.2–3.8) (p < 0.001), respectively [40] . Similarly, ADHF patients
with high NLR (≥7.6) had significantly higher 30-day ­readmission
rate (p < 0.001) compared with those with lower NLR [40] .
NLR & coronary artery bypass surgery
NLR, by integrating information on inflammatory milieu and
physiologic stress, can serve as a prognostic marker for post­
operative AF and outcome from coronary artery bypass grafting
(CABG) surgery. Elevated preoperative NLR has been associ-
ated with worse outcome after CABG. During 3.6-year follow-
up in patients undergoing CABG, mortality (hazard ratio: 1.13,
p < 0.001) was significantly high in the group who had preopera-
tive NLR >3.36 (p < 0.001) [41] . In a prospective cohort study in
the patients undergoing nonemergency CABG who developed
AF lasting >30 s, preoperative NLR was greater (median: 3.0 vs
2.4, p < 0.001) and postoperative NLR was also significantly high
(day 2, median: 9.2 vs 7.2; p < 0.001) [42] .
Expert commentary
Despite multiple loopholes and weaknesses in the evidence
described in this review, the relationship between NLR and the
various cardiovascular diseases and their outcomes is strengthened
by the fact that most of the results are uniform and consistent. This
consistent correlation between various cardiovascular disease and
NLR is of more significance because of the potential application of
this inexpensive and easily available marker for risk stratification of
these patients. The predictive superiority of NLR over WBC and
other individual cell types due to being less likely influenced by
various physiological conditions and its integrated reflection of two
important and opposite immune pathways; may elevate its role as a
risk stratification marker. More robust prospective and randomized
studies may help in finding a clear position for NLR among various
markers of risk stratification in cardiovascular diseases.
Five-year view
The science of biomarkers is a highly promising aspect of medi-
cine that is, and will, redefine the whole process of disease man-
agement in the near future. Biomarkers are being utilized in
diagnosing various diseases and they can also prognosticate both
long- and short-term outcomes. They will soon help us in identi-
fying at-risk populations early, leading to primary prevention of
many of these disorders. The role of the available new biomark-
ers in our clinical practice is expected to grow tremendously in
coming years. The exponentially growing burden of health cost
will have a greater influence in the coming years on develop-
ment and application of these markers in daily clinical practice.
The inexpensive and readily available markers like NLR have a
greater potential in the coming years given the circumstance to
surface as useful maker of cardiovascular disease.
57
 Review Bhat, Teli, Rijal et al.

Financial & competing interests disclosure This includes employment, consultancies, honoraria, stock ownership
The authors have no relevant affiliations or financial involvement with or options, expert testimony, grants or patents received or pending, or
any organization or entity with a financial interest in or financial con- royalties.
flict with the subject matter or materials discussed in the manuscript. No writing assistance was utilized in the production of this manuscript.

Key issues
• The relationship between inflammatory markers and cardiovascular diseases is well established.
• Among these inflammatory markers, neutrophil to lymphocyte ratio (NLR) has been a new addition to a long list of these markers.
• NLR is a cheap, easy to calculate and readily available marker that can aid in the risk stratification of patients with various cardiovascular
diseases.
• Elevated NLR is associated with arterial stiffness, high coronary calcium scores and progression of atherosclerosis.
• High NLR is an independent predictor of mortality in stable coronary artery disease, and various acute coronary syndromes including
non-ST-elevation myocardial infarction and ST-elevation myocardial infarction.
• Elevated NLR is associated with increased risk of ventricular arrhythmias during percutaneous coronary intervention (PCI) and increased
long-term mortality in patients undergoing PCI irrespective of indications for PCI.
• Elevated NLR has been associated with higher inpatient mortality in patients admitted with advanced heart failure and an increased
incidence of new-onset atrial fibrillation in patients after coronary artery bypass grafting.

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