European Journal of Clinical Nutrition

https://doi.org/10.1038/s41430-020-00817-x

ARTICLE

Nutrition in acute and chronic diseases

The relationship between body mass index and N-terminal pro-B-

type natriuretic peptide in community-acquired pneumonia
Jong Seok Lee1,2 Seok Hoon Ko3 Jungyoup Lee4 Ki Young Jeong
● ● ●
1,2

Received: 18 May 2020 / Revised: 2 November 2020 / Accepted: 15 November 2020

© The Author(s), under exclusive licence to Springer Nature Limited 2020

Abstract
Background The relationship between body mass index (BMI) and N-terminal pro-B-type natriuretic peptide (NT-proBNP)
has not been fully investigated in patients with community-acquired pneumonia (CAP).
Methods This prospective observational study examined 510 consecutive patients hospitalized for CAP. NT-proBNP, BMI,
and the pneumonia severity index (PSI) were determined for all participants. The moderating effects of BMI on the
relationship between NT-proBNP and CAP mortality were examined using interaction terms in a multivariable regression
model. The ability of NT-proBNP to predict mortality was evaluated using the area under the curve (AUC).
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Results A significant inverse relationship was observed between BMI and NT-proBNP. After multivariable adjustment
including BMI, NT-proBNP remained a significant predictor of CAP mortality. The AUC of the fully adjusted (including
BMI) NT-proBNP model was significantly higher than that excluding BMI (p = 0.021) and that of PSI (p = 0.038),
respectively. The predictive performance of NT-proBNP for mortality significantly differed by BMI group, with the NT-
proBNP of the overweight and obesity group having a significantly higher AUC than that of the underweight and normal-
weight group. The AUC of NT-proBNP was significantly higher and tended to be higher than that of PSI in the overweight
group (p = 0.013) and the obesity group (p = 0.113), respectively.
Conclusions BMI significantly strengthens the prognostic performance of NT-proBNP in CAP patients. The BMI–NT-
proBNP interaction is significantly associated with CAP mortality, but as a prognostic determinant for CAP, NT-proBNP
seems to be more useful for overweight and obese patients than for underweight and normal-weight patients.

Introduction

The mortality rate from community-acquired pneumonia

(CAP) has decreased during the past decade, but CAP remains
a major infectious cause of death throughout the world [1].
Approximately 20% of CAP patients require hospitalization,
Supplementary information The online version of this article (https:// and the overall mortality rate of those patients is 8–15%, and is
doi.org/10.1038/s41430-020-00817-x) contains supplementary
as high as 30% among patients requiring treatment in an
material, which is available to authorized users.
intensive care unit [2, 3]. Therefore, early identification of
* Ki Young Jeong those at risk of poor outcomes is a major goal of clinicians, but
emergency0599@khu.ac.kr this is complicated because risk is influenced by patient
1 characteristics, treatment protocol, and disease severity [4].
Department of Emergency Medicine, Kyung Hee University
Medical Center, Seoul, Republic of Korea Nutritional status, which is commonly estimated by body
2 mass index (BMI), is a representative host factor affecting
Department of Emergency Medicine, School of Medicine, Kyung
Hee University, Seoul, Republic of Korea CAP mortality. Low BMI, indicating poor nutritional status,
3 is associated with the presence of chronic disease, impair-
Division of Pulmonary and Critical Care Medicine, Critical Care
Center, Kyung Hee University Medical Center, Seoul, Republic of ment of immune function, and respiratory muscle dysfunc-
Korea tion, which ultimately weaken host defense mechanisms
4
Department of Emergency Medicine, Graduate School, Kyung against CAP [5, 6]. Meanwhile, overweight and obesity,
Hee University, Seoul, Republic of Korea expressed as high BMI, are related to an increased risk of

CAP and alterations of inflammatory response in the lungs
[7], and thus high BMI has been widely presumed to
adversely affect the clinical course of CAP. However,
although the exact pathophysiology remains unclear, a
review of recent literature has provided clinical evidence that
obesity can act as a protective factor against CAP mortality
in the so-called obesity survival paradox [8, 9].
In an attempt to achieve rapid prediction of CAP mortality,
several biomarkers have been suggested, and efforts to deter-
mine their prognostic value have been continuous. However,
BMI influences the level of several biomarkers and is thus a
determinant of their predictive performance [10, 11]; therefore,
the consideration of nutritional status is essential when eval-
uating the clinical utility of biomarkers for CAP prognosis.
Currently, N-terminal pro-B-type natriuretic peptide (NT-
proBNP), a cardiac NP, is considered a reliable prognostic
biomarker for CAP [12–14]. It appears to correlate positively
with scores on clinical severity scales and to provide prognostic
information equivalent to those scales in hospitalized CAP
patients [15, 16]. Moreover, recent studies have reported that
biomarkers of cardiac dysfunction have superior predictive
ability for CAP mortality compared with other inflammatory
biomarkers because of CAP’s common cardiac complications
[13, 17, 18]. However, because NT-proBNP levels have an
inverse relationship with BMI [19, 20], cautious interpretation
is emphasized. Although the pathophysiological mechanisms
have not yet fully been elucidated, increasing BMI may lower
NT-proBNP through various mechanisms that include sup-
pression of proBNP processing (which is cleaved into NT-
proBNP) due to glycosylation and enhanced secretion of
androgen in increased adipose tissue, resulting in prevention of
NT-proBNP formation and release [21–24]. Moreover, pre-
vious clinical studies have noted that high BMI is associated
with a 17–37% decrease in NT-proBNP levels and obese
patients had lower levels than non-obese people [25, 26].
Consequentially, nutritional status, as represented by
BMI, causes uncertainty in both NT-proBNP levels and
CAP mortality. However, these relationships have not been
fully characterized, and no studies have directly addressed
the predictive ability of NT-proBNP for CAP mortality
while controlling for BMI. Therefore, in this study, we
investigated whether the inclusion of BMI weakens or
strengthens the prognostic ability of NT-proBNP and
assessed how the clinical utility of NT-proBNP for pre-
dicting CAP mortality differs according to BMI.
Material and methods
Study design
This prospective observational study was conducted from
March 1, 2015 to May 31, 2019 in the emergency
J. S. Lee et al.
department (ED) of an academic, urban, tertiary-care hos-
pital. The study protocol was approved by our institutional
review board.
Definition and study population
Patients with CAP requiring hospitalization in the ED were
included in this study. Pneumonia was defined as the pre-
sence of infiltration on chest radiographs together with
symptoms of respiratory tract infection or auscultation
findings consistent with pneumonia. In the ED of the study
hospital, the management of CAP patients follows the
Infectious Disease Society of America’s guidelines, and
hospitalization is determined by the attending ED physician
based on clinical scales such as the pneumonia severity
index (PSI) and other medical conditions. All included CAP
patients were 18 years or older. Patients with hospital-
acquired pneumonia or aspiration pneumonia, acute symp-
tomatic heart or renal failure, or the coexistence of other
infectious diseases; those receiving (or needing) renal
replacement therapy, chronic diuretics, or corticosteroid
therapy within 6 months; those transferred from other
hospitals; those discharged against medical advice during
ED management; and those whose final diagnosis was not
CAP were excluded. If a patient had more than one hos-
pitalization during a 6-month period, only the first was
included.
Data sources and processing
Data for the enrolled patients were prospectively collected
following the study protocol, by interview, which was
facilitated using a standardized case-report form, and by
retrieving medical chart records. All data obtained were
entered into the ED pneumonia registry electronic database.
That registry includes substantial data on demographics,
medical history, hourly ED vital signs, type of ward
admission, length of hospital stay, information related to
antibiotics use, culture study, laboratory and radiologic
findings, PSI scores (evaluated in the ED), initial and final
diagnoses, and 30-day mortality.
BMI was calculated as weight in kilograms divided by
height in meters squared (kg/m2). For all patients admitted
to the ward, body weight and height were measured in the
ED (before admission) or the ward (during the hospital
admission examination or within 12 hours of admission),
using a combined digital electronic scale (precision of
0.1 kg) and stadiometer (precision of 0.1 cm), respectively.
Patients who were admitted to the intensive care unit were
measured immediately on admission using a metric tape (in
the supine position in bed) and with weight-built beds.
However, in 8.6% of cases, such as those involving patients
unable to move or stand, critically ill patients, or equipment
The relationship between body mass index and N-terminal pro-B-type natriuretic peptide in. . .
breakdown, BMI was inevitably calculated using self-
reported body weight and height. An NT-proBNP sample
was taken in routine blood sample analysis or within 12 h of
the ED visit. It was detected in EDTA plasma, and an
electrochemiluminescence immunoassay was used for ana-
lysis (Roche Diagnostics, Mannheim, Germany); the mea-
suring range provided by the manufacturer (the lower
detection limit to the maximum of the master curve) was
5–35,000 pg/ml.
All data collected prospectively were periodically
reviewed for accuracy, and data ambiguities and dis-
crepancies were settled by consensus among the authors.
Measurements of clinical outcomes
The enrolled patients were divided into four groups based
on their BMI: the underweight group (BMI < 18.5 kg/m2),
the normal-weight group (BMI 18.5–24.9 kg/m2), the
overweight group (BMI 25.0–29.9 kg/m2), and the obesity
group (≥30.0 kg/m2). Individual groups were further cate-
gorized by whether the included patients survived for at
least 30 days (the survival and mortality subgroups). Our
primary focus was evaluating the effect of BMI on the
prognostic value of NT-proBNP for 30-day mortality in
hospitalized CAP patients. The secondary outcome was
comparing the performance of NT-proBNP for predicting
mortality in individual BMI groups.
Statistical analyses
Continuous variables, presented as mean ± standard
deviation or median with interquartile range, were com-
pared with the Student’s t test and Mann–Whitney U test.
The chi-square test or Fisher’s exact test were used for
categorical variables, which are presented as absolute
values and percentages. Differences among all enrolled
patients, with adjustment for BMI, were analyzed using a
general linear model (continuous variables) and the
Cochran–Mantel–Haenszel test (categorical variables).
NT-proBNP and BMI values were log transformed for a
normal distribution.
Univariable logistic regression analyses were used to find
variables that could influence 30-day mortality, and vari-
ables with a p value < 0.2 were defined as covariates; this
cutoff was set to prevent missing potentially important
covariates and to protect against residual confounding [27].
In the following multivariable logistic regression models,
those covariates were entered as moderator variables to
estimate odds ratios (ORs) for the relationship between NT-
proBNP values and the dichotomous outcome of 30-day
mortality. Because the focus of this study was the moder-
ating effect of BMI on NT-proBNP in predicting CAP
morality, we additionally conducted a multivariable analysis
considering the interaction between BMI and NT-proBNP.
The equations for the individual models are as follows:
Model 1 : ln½ðy ¼ 1Þ=1  ðy ¼ 1Þ ¼ a1 þ a2  x þ a3  z þ ε;
Model 2 : ln½ðy ¼ 1Þ=1  ðy ¼ 1Þ ¼ a1 þ a2  x þ a3  z
þa4  BMI þ ε;
Model 3 : ln½ðy ¼ 1Þ=1  ðy ¼ 1Þ ¼ a1 þ a2  x þ a3  z
þa4  BMI þ a5  ðx  BMIÞ þ ε;
y : CAP mortality;
x : NT  proBNP;
z : variables with p < 0:2;
ε: error term:
NT-proBNP levels are susceptible to several influencing
factors [20, 21]; therefore, we used correlation analyses to
evaluate potential confounders. After adjusting for the sig-
nificantly correlated variables, we calculated the area under
the receiver operating characteristic (ROC) curve to identify
the adjusted performance of NT-proBNP for predicting
mortality and compared it with the performance of the PSI
within each group and its performance across groups. Each
comparison of the area under the curve (AUC) was per-
formed using the method proposed by DeLong et al. [28].
Based on the cutoff value for NT-proBNP that was deter-
mined as the greatest sum of the sensitivity and specificity
estimates from the ROC curve, the cumulative survival rates
of the enrolled patients were analyzed using the
Kaplan–Meier method. All statistical analyses were per-
formed using SPSS Statistics 22.0 (IBM Corp., Armonk,
NY, USA) and R version 3.3.3 (R Core Team, 2017). A
p-value < 0.05 was considered statistically significant.
Results
The total number of enrolled participants was 510 (Sup-
plementary Fig. S1); the underweight group (134, 26.3%),
normal-weight group (235, 46.1%), overweight group (102,
20.0%), and obesity group (39, 7.6%) had 30-day mortality
rates of 29.9%, 18.7%, 7.8%, and 7.6%, respectively.
The baseline and clinical characteristics of the partici-
pants are shown in Table 1. When taken as a whole and
controlling for BMI, the two subgroups (survival and
mortality) showed similar demographics and underlying
disease, except for neoplastic disease. NT-proBNP levels
and PSI scores between the subgroups of all participants
and for all four BMI groups were significantly higher in the
Table 1 Baseline characteristics of the study population according to BMI classification.
Total Underweight Normal-weight Overweight Obesity

Variables Survival group Mortality group pa Survival group Mortality group pb Survival group Mortality group pb Survival group Mortality group pb Survival group Mortality group pb
(N = 415) (N = 95) (N = 94) (N = 40) (N = 191) (N = 44) (N = 94) (N = 8) (N = 36) (N = 3)

Age, yrs 72.3 ± 13.3 75.5 ± 12.5 0.219 75.3 ± 12.2 76.8 ± 12.4 0.483 72.4 ± 14.0 74.9 ± 13.7 0.280 70.4 ± 12.4 74.4 ± 7.7 0.379 68.9 ± 14.1 70.0 ± 5.6 0.797
Sex 0.112 0.212 0.111 0.988 0.540
Male 284 (68.4) 58 (61.1) 70 (74.5) 25 (62.5) 133 (69.6) 25 (56.8) 59 (63.8) 5 (62.5) 22 (61.1) 3 (100.0)
Female 131 (31.6) 37 (38.9) 24 (25.5) 15 (37.5) 58 (30.4) 19 (43.2) 35 (37.2) 3 (37.5) 14 (38.9) 0 (0.0)
b
BMI, kg/m2 22.3 ± 4.7 19.7 ± 4.4 <0.001 16.3 ± 1.5 15.8 ± 1.6 0.111 21.4 ± 1.7 21.1 ± 2.1 0.367 26.6 ± 1.2 26.8 ± 0.9 0.531 31.5 ± 1.3 30.9 ± 1.1 0.442
Underlying disease
Diabetes 121 (29.2) 33 (34.7) 0.128 22 (23.4) 12 (30.0) 0.516 52 (27.2) 13 (29.5) 0.852 37 (39.4) 7 (87.5) 0.020 10 (27.8) 1 (33.3) >0.999
Hypertension 226 (54.5) 47 (49.5) 0.964 43 (45.7) 16 (40.0) 0.573 97 (50.8) 22 (50.0) 0.925 64 (68.1) 7 (87.5) 0.429 22 (61.1) 2 (66.7) >0.999
Neoplastic 88 (21.2) 33 (34.7) 0.011 21 (22.3) 14 (35.0) 0.138 41 (21.5) 14 (31.8) 0.167 18 (19.1) 2 (25.0) 0.653 8 (22.2) 3 (100.0) 0.018
Cardiacc 103 (24.8) 26 (27.4) 0.352 14 (14.9) 7 (17.5) 0.796 56 (29.3) 12 (27.3) 0.855 23 (24.5) 5 (62.5) 0.034 10 (27.8) 2 (66.7) 0.219
Cerebrovascular 127 (30.6) 29 (30.5) 0.760 35 (37.2) 11 (27.5) 0.324 63 (33.0) 14 (31.8) 0.962 22 (23.4) 3 (37.5) 0.401 7 (19.4) 1 (33.3) 0.508
Renal 42 (10.1) 11 (11.6) 0.607 8 (8.5) 5 (12.5) 0.528 16 (8.4) 4 (9.1) 0.773 13 (13.8) 2 (25.0) 0.334 5 (13.9) 0 (0.0) >0.999
Hepatic 24 (5.8) 6 (6.3) 0.831 5 (5.3) 1 (2.5) 0.669 10 (5.2) 3 (6.8) 0.714 7 (7.4) 1 (12.5) 0.492 2 (5.6) 1 (33.3) 0.219
CHF 17 (4.1) 5 (5.3) 0.531 1 (1.1) 1 (2.5) 0.509 10 (5.2) 2 (4.5) 0.852 5 (5.3) 1 (12.5) 0.395 1 (2.8) 1 (33.3) 0.150
COPD 87 (21.0) 13 (13.7) 0.140 19 (20.2) 3 (7.5) 0.079 47 (24.6) 7 (15.9) 0.240 15 (16.0) 2 (25.0) 0.617 6 (16.7) 1 (33.3) 0.457
Signs
SBP, mmHg 130.6 ± 26.9 117.7 ± 26.7 <0.001 124.6 ± 27.8 119.5 ± 32.1 0.355 131.7 ± 27.2 115.5 ± 22.7 <0.001 133.0 ± 26.7 122.0 ± 14.8 0.255 134.9 ± 21.6 114.0 ± 34.8 0.131
DBP, mmHg 71.3 ± 16.0 64.3 ± 18.6 <0.001 68.8 ± 15.3 67.1 ± 24.3 0.694 73.4 ± 17.4 61.4 ± 13.2 <0.001 69.2 ± 14.5 65.9 ± 12.6 0.528 72.4 ± 13.2 65.3 ± 5.5 0.369
PR, beats/min 101.3 ± 22.8 107.4 ± 24.5 0.086 106.1 ± 22.8 111.9 ± 21.6 0.171 101.2 ± 23.0 102.2 ± 23.7 0.790 97.7 ± 21.9 111.2 ± 41.7 0.393 99.1 ± 22.6 112.3 ± 2.3 0.322
RR, breaths/min 23.5 ± 6.1 26.7 ± 6.7 <0.001 24.4 ± 6.6 27.8 ± 7.6 0.016 23.5 ± 6.6 25.7 ± 6.2 0.038 23.3 ± 5.0 26.4 ± 5.1 0.097 23.3 ± 4.8 27.3 ± 2.9 0.088
BT, °C 37.4 ± 1.1 37.1 ± 0.9 0.002 37.3 ± 1.1 37.4 ± 1.1 0.890 37.5 ± 1.0 36.9 ± 0.7 <0.001 37.3 ± 1.1 37.0 ± 1.0 0.391 37.1 ± 1.0 36.6 ± 0.5 0.401
Laboratory parameters
pH 7.43 ± 0.07 7.39 ± 0.12 <0.001 7.43 ± 0.06 7.40 ± 0.12 0.155 7.43 ± 0.62 7.39 ± 1.00 0.020 7.41 ± 0.08 7.42 ± 0.09 0.856 7.42 ± 0.07 7.21 ± 0.26 0.301
pCO2, mmHg 36.4 ± 11.1 36.5 ± 13.3 0.987 37.8 ± 10.9 38.9 ± 15.8 0.693 35.2 ± 9.7 35.0 ± 11.3 0.939 36.0 ± 10.9 35.9 ± 11.7 0.980 39.6 ± 17.0 28.6 ± 4.2 0.279
pO2, mmHg 70.0 ± 34.1 65.3 ± 29.5 0.381 68.8 ± 37.3 64.2 ± 31.4 0.530 67.4 ± 26.9 62.2 ± 27.0 0.279 76.3 ± 45.4 78.9 ± 34.1 0.883 70.5 ± 22.8 86.4 ± 22.1 0.259
HCO3, mmol/L 23.2 ± 4.9 21.6 ± 6.7 0.003 24.4 ± 5.4 23.5 ± 6.5 0.443 22.7 ± 4.2 20.4 ± 6.0 0.025 22.5 ± 3.8 22.8 ± 7.2 0.833 24.2 ± 6.4 12.3 ± 6.1 0.003
WBC, 103/mm3 12.3 ± 6.1 12.0 ± 7.3 0.795 12.4 ± 4.9 11.2 ± 6.2 0.245 11.9 ± 6.4 13.3 ± 8.6 0.326 12.9 ± 6.7 10.1 ± 2.8 0.032 12.8 ± 5.4 9.3 ± 7.2 0.292
Hematocrit, % 36.4 ± 6.4 34.0 ± 7.4 0.003 36.2 ± 6.1 35.2 ± 6.4 0.374 36.3 ± 6.7 32.8 ± 7.9 0.009 36.6 ± 6.5 35.5 ± 7.1 0.640 37.2 ± 5.5 32.7 ± 13.5 0.624
Sodium, mmol/L 134.9 ± 6.3 134.3 ± 8.9 0.219 136.0 ± 8.1 136.0 ± 9.4 0.996 135.0 ± 5.7 132.6 ± 8.9 0.095 134.4 ± 5.1 133.6 ± 3.7 0.696 133.1 ± 6.4 140.3 ± 7.5 0.068
Potassium, mmol/L 4.2 ± 0.7 4.4 ± 0.8 0.023 4.3 ± 0.7 4.4 ± 0.7 0.274 4.2 ± 0.7 4.4 ± 0.9 0.152 4.3 ± 0.6 4.3 ± 0.9 0.988 4.2 ± 0.6 4.7 ± 1.1 0.203
BUN, mg/dL 24.0 ± 15.8 34.4 ± 21.2 <0.001 26.3 ± 19.8 32.4 ± 17.3 0.094 23.5 ± 14.1 34.2 ± 21.3 0.003 24.1 ± 15.0 32.4 ± 22.7 0.151 20.9 ± 15.1 70.7 ± 40.1 0.163
Creatinine, mg/dL 1.3 ± 1.0 1.8 ± 1.6 <0.001 1.1 ± 0.7 1.5 ± 0.9 0.013 1.3 ± 0.7 1.7 ± 1.4 0.071 1.5 ± 1.5 2.7 ± 2.6 0.220 1.2 ± 1.0 6.1 ± 3.3 0.124
Cholesterol, mg/dL 141.0 ± 39.1 133.2 ± 48.5 0.304 134.5 ± 40.8 132.7 ± 40.2 0.825 138.9 ± 39.7 131.1 ± 55.9 0.279 146.9 ± 34.1 140.6 ± 39.5 0.625 153.2 ± 39.9 151.3 ± 30.3 0.939
Lactate, mmol/L 2.4 ± 1.7 3.6 ± 3.2 <0.001 2.2 ± 1.5 4.2 ± 3.6 0.003 2.4 ± 1.6 2.9 ± 2.5 0.168 2.4 ± 2.0 4.0 ± 3.9 0.295 2.6 ± 1.4 5.6 ± 3.3 0.252
CRP, mg/L 12.7 ± 9.4 15.7 ± 9.3 0.004 12.1 ± 8.9 14.7 ± 10.4 0.145 12.8 ± 9.5 16.8 ± 8.6 0.010 13.2 ± 9.6 16.6 ± 8.8 0.331 12.0 ± 10.1 10.0 ± 3.3 0.729
832.3 2816.5 <0.001 1813.6 2130.2 0.039 803.1 2706.8 0.002 688.6 7865.2 <0.001 614.4 8108.4 0.005
NT-proBNP, pg/ml (339.0–2444.1) (1367.0–8105.5) (580.2–3040.6) (986.4–5167.5) (313.4–2980.5) (1565.2–8002.1) (390.9–2059.1) (2669.4–8180.5) (197.3–1093.6) (5260.1–8349.2)
PSI, score 106.5 ± 32.9 139.7 ± 36.6 <0.001 112.3 ± 31.7 141.9 ± 37.6 <0.001 108.1 ± 33.0 136.0 ± 37.5 <0.001 102.8 ± 32.7 141.0 ± 31.4 0.002 98.1 ± 36.8 162.3 ± 11.7 0.005

The values (except NT-proBNP) presented are mean ± SD or number (%).

a
P values (except BMI) were calculated using the Cochran–Mantel–Haenszel test for categorical variables and the general linear model for continuous variables (adjusted by BMI).
b
P values were calculated using the Mann–Whitney U test or Fisher’s exact test.
c
Cardiac disease, with the exception of congestive heart failure.
BMI body mass index, BT body temperature, BUN blood urea nitrogen, CHF congestive heart failure, COPD chronic obstructive pulmonary disease, CRP C-reactive protein, CURB65 confusion,
urea, respiratory rate, blood pressure, and aged 65 or more, DBP diastolic blood pressure, NT-proBNP N-terminal pro-B-type natriuretic peptide, PR pulse rate, PSI pneumonia severity index, RR
respiratory rate, SBP systolic blood pressure, WBC white blood cell
J. S. Lee et al.
The relationship between body mass index and N-terminal pro-B-type natriuretic peptide in. . .
mortality subgroup. On the other hand, BMI was sig-
nificantly lower in the mortality subgroup of all participants,
but the subgroups did not differ significantly within BMI
groups.
Effect of BMI on predictive value of NT-proBNP for
mortality among all participants
The multivariable regression model showed a statistically
significant and independent positive association between
NT-proBNP and CAP mortality, both when adjusting for
covariates excluding BMI (OR, 1.747; 95% CI,
1.413–2.161, p < 0.001) and when including BMI (Table 2).
The graph representing the ORs for mortality relative to
NT-proBNP adjusted for covariates including BMI revealed
a linear increasing trend for each incremental NT-proBNP
increase (Fig. 1A).
The potential confounders of NT-proBNP were as follows;
age, diabetes, congestive heart failure, cerebrovascular dis-
ease, hematocrit, creatinine, C-reactive protein, cholesterol,
lactate (data not shown), and BMI (r = –0.344, p < 0.001) had
significant correlations with NT-proBNP. After adjusting for
those confounders (excluding BMI), the AUC of NT-proBNP
for 30-day mortality was comparable to that of PSI
(p = 0.218). Adding BMI to the adjusted NT-proBNP sig-
nificantly increased the AUC (p = 0.021), which was superior
to PSI (p = 0.038) (Fig. 1B).
Value of NT-proBNP for predicting mortality among
BMI groups
The model 3 results showed a significant BMI-by-NT-
proBNP interaction; the OR of NT-proBNP for mortality
increased with increasing BMI, reaching 3.039 (p = 0.045)
(Table 2). Figure 2 shows the ORs of CAP mortality relative
to each interaction term with each incremental NT-proBNP
increase; there was a positive linear association (mortality
increased along with the interaction effect) with increasing
incremental NT-proBNP levels.
This significant interaction allowed us to compare the
predictive ability of NT-proBNP among individual BMI
groups. After applying the same methods explained above,
we performed separate multivariable logistic regression
analyses for each classified group, controlling for individual
covariates (Table 2). Only in the normal-weight and over-
weight groups did NT-proBNP significantly predict CAP
mortality, whereas there was a trend toward significance in
the underweight and obesity group. The AUCs for (adjus-
ted) NT-proBNP in the underweight, normal-weight, over-
weight, and obesity groups were 0.698, 0.798, 0.939, and
0.981, respectively. Within these groups, the AUC of
(adjusted) NT-proBNP was significantly higher than that of
PSI in the overweight group (p = 0.013; Fig. 3C), but it also
tended to be higher than that of PSI in the normal-weight
and obesity group (p = 0.093 and 0.113, respectively; Fig.
3B and D). We compared the AUCs of NT-proBNP across
the groups under the assumption that the individuals were
independent of one another. In the overweight and obesity
group, NT-proBNP had significantly higher AUC values
than it did in both the underweight and normal-weight
groups (Fig. 3).
Mortality rates according to the cutoff value of NT-
proBNP
The cut-off value for NT-proBNP that provided the best
compromise between sensitivity and specificity was
1319.8 pg/ml (78.9% sensitivity and 61.9% specificity).
Among all participants, the 30-day mortality rate was sig-
nificantly higher in the NT-proBNP group above the cutoff
value than in the group below that value (Fig. 4A), with
patients in the high group 3.1 times more likely to die
within 30 days (OR, 3.106; 95% CI, 1.760–5.482; p <
0.001) than patients in the low group. The differences in 30-
day mortality rates between CAP patients above and below
the cut-off value in each BMI group are shown in Fig.
4B–E.
Discussion
NT-proBNP has been widely used for prediction of CAP
mortality, but analysis assessing the impact of nutrition on
the clinical utility of this biomarker is highly relevant due to
the role of nutritional status as a confounder. In this study,
we found that BMI influenced the predictive value of NT-
proBNP for CAP mortality. Adding BMI to the multi-
variable model somewhat attenuated the relationship
between NT-proBNP and CAP mortality, but the correlation
remained significant. This relationship is well supported by
figures showing increasing mortality risk with increases in
NT-proBNP. Moreover, BMI also significantly strength-
ened the predictive performance of this biomarker. The fully
adjusted model (NT-proBNP + BMI) showed a sig-
nificantly stronger performance than NT-proBNP (adjusted
without BMI) and PSI. Consequently, these findings pro-
vide evidence that BMI is a crucial determinant of NT-
proBNP that should be considered in clinical interpretation,
but also suggest that the previously established prognostic
relevance of NT-proBNP (i.e., without accounting for BMI)
could be limited in CAP patients.
However, in stratified analyses, varied prognostic utility
of NT-proBNP was observed between BMI groups. In this
study, median values of NT-proBNP level differed by BMI
group (lower NT-proBNP levels in higher BMI groups),
and although NT-proBNP levels were significantly higher
Table 2 Identification of NT-proBNP as a predictor of 30-day mortality using multivariable logistic regression analyses.
Total (Model 1) Total (Model 2) Total (Model 3)
Variables OR 95% CI P Variables OR 95% CI P Variables OR 95% CI P

NT-proBNP 1.662 1.339–2.063 <0.001 NT-proBNP 0.037 0.011–1.202 0.053 NT-proBNP 0.062 0.004–1.534 0.089
BMI 0.164 0.048–0.560 0.004 BMI 0.001 0.001–0.182 0.020 BMI 0.001 0.001–0.158 0.018
PSI 1.022 1.014–1.031 <0.001 PSI 1.017 0.964–1.072 0.541 PSI 1.021 1.012–1.030 <0.001
NT-proBNP*BMI 3.020 0.998–9.143 0.049 NT-proBNP*BMI 3.039 1.025–9.015 0.045
NT-proBNP*PSI 1.001 0.994–1.007 0.863
Underweighta Normal-weightb Overweightc Obesityd
Variables OR 95% CI P Variables OR 95% CI P Variables OR 95% CI P Variables OR 95% CI P
NT-proBNP 1.286 0.924–1.799 0.132 NT-proBNP 1.687 1.255–2.267 0.001 NT-proBNP 8.520 1.938–37.458 0.005 NT-proBNP 6.466 0.826–50.622 0.078
PSI 1.021 1.007–1.035 0.004 PSI 1.018 1.005–1.030 0.006 PSI 1.017 0.983–1.053 0.331 PSI 1.065 0.945–1.200 0.299
Model 1 (for total populations) was adjusted by variables with a p value < 0.2 (in univariable logistic regression analyses).
Model 2 (for total populations) was adjusted by BMI and variables with a p value < 0.2 (in univariable logistic regression analyses).
Model 3 (for total populations) was assessed by adding the interaction term (between NT-proBNP and BMI) to Model 2.
a
Adjusted by NT-proBNP, PSI, COPD, CRP, and lactate.
b
Adjusted by NT-proBNP, PSI, CRP, potassium, and lactate.
c
Adjusted by NT-proBNP, PSI, cardiac disease, and WBC.
d
Adjusted by NT-proBNP and PSI
BMI body mass index, NT-proBNP N-terminal pro-B-type natriuretic peptide, PSI pneumonia severity index
J. S. Lee et al.
The relationship between body mass index and N-terminal pro-B-type natriuretic peptide in. . .
Fig. 1 The predictive performance of NT-proBNP for the whole
population. A The odds ratio of 30-day mortality according to
incremental changes in NT-proBNP levels (using a fully adjusted
model including BMI). In each section, the odds ratio (95% confidence
interval [CI]) for mortality was as follows: 1.011 (1.006–1.016) for a
100 pg/ml increase in NT-proBNP, 1.058 (1.032–1.085) for a 500
pg/ml increase, 1.120 (1.066–1.177) for a 1000 pg/ml increase, 1.253
(1.134–1.385) for a 2000 pg/ml increase, 1.403 (1.208–1.630) for a
Fig. 2 The interaction effect for mortality according to incremental
changes in NT-proBNP levels. In each section, the odds ratio (95%
confidence interval [CI]) for 30-day mortality was as follows: 1.160
(1.050–1.281) for a 500 pg/ml increase in NT-proBNP, 1.345
(1.102–1.641) for a 1000 pg/ml increase, 1.809 (1.215–2.694) for a
2000 pg/ml increase, 2.434 (1.340–4.421) for a 3,000 pg/ml increase,
3.274 (1.477–7.256) for a 4,000 pg/ml increase, and 4.404
(1.628–11.909) for a 5000 pg/ml increase. Solid and dashed lines
represent odds ratios and 95% CIs, respectively. NT-proBNP N-
terminal pro-B-type natriuretic peptide, BMI body mass index.
in the mortality subgroup of all BMI groups, this difference
was much greater in the overweight and obesity group.
Moreover, through the interaction model, the positive
influence of increasing BMI on the strength of the rela-
tionship between NT-proBNP and CAP mortality proved to
3000 pg/ml increase, 1.571 (1.287–1.919) for a 4000 pg/ml increase,
and 1.759 (1.370–2.258) for a 5000 pg/ml increase. Solid and dashed
lines represent odds ratios and 95% CIs, respectively. B ROC curves
for fully adjusted NT-proBNP (NT-proBNP + BMI), NT-proBNP
(adjusted without BMI), and PSI. AUC area under the ROC curve,
BMI body mass index, NT-proBNP N-terminal pro-B-type natriuretic
peptide, PSI pneumonia severity index.
be significant, and this interaction effect for mortality
increased curve-linearly with incremental increases in NT-
proBNP. Given these findings, the application of NT-
proBNP as a prognostic determinant might be more
appropriate for CAP patients with higher BMI than lower
BMI. This inference turned out to be reasonable based on
the following observations. The ORs and AUCs of NT-
proBNP for CAP mortality proportionally increased with
(incremental) BMI group. NT-proBNP in the overweight
and obesity groups exhibited significantly superior pre-
dictive performance compared with the underweight and
normal-weight groups. In comparison with within-group
PSI, its performance was significantly higher (in the over-
weight group) or trended higher (in the obesity group) than
that of PSI. Moreover, the difference in survival rates
according to the cut-off value was significant except for the
low BMI (underweight) group. Therefore, we considered
the prognostic superiority of NT-proBNP in CAP more
prominent as BMI increased, suggesting that it is more
useful for overweight and obese patients with CAP.
With respect to CAP, the prognostic value of NT-
proBNP based on BMI strata has not previously been
addressed. On the other hand, Horwich et al. reported that
BNP showed high prognostic ability despite its relatively
low levels in overweight and obese patients with HF [29].
Bayes-Genis et al. showed that in patients with and without
acute HF, NT-proBNP levels were strongly prognostic

Fig. 3 Comparison of NT-proBNP and PSI for predicting 30-day
mortality. ROC curves for NT-proBNP and PSI in the underweight
group (A), the normal-weight group (B), the overweight group (C),
Fig. 4 The comparison of mortality rates according to the cut-off
value of NT-proBNP. The 30-day Kaplan–Meier survival curve for
the whole population (A), the underweight group (B), the normal-
weight group (C), the overweight group (D) and the obesity group (E)
according to the optimal cut-off value for NT-proBNP (1319.8 pg/ml).
In each BMI group, the odds ratio (95% confidence interval [CI]) for
J. S. Lee et al.
and the obesity group (D). AUC area under the ROC curve, BMI body
mass index, NT-proBNP N-terminal pro-B-typenatriuretic peptide, PSI
pneumonia severity index.
30-day mortality above and below the cut-off value was as follows:
1.309 (0.526–3.258, p = 0.562) for the underweight group, 5.017
(2.139–11.770, p < 0.001) for the normal-weight group, and 4.778
(0.844–27.050, p = 0.066) for the overweight group, respectively. In
the obesity group, all patients who died had NT-proBNP levels above
cutoff value.
The relationship between body mass index and N-terminal pro-B-type natriuretic peptide in. . .
across all BMI groups (<25.0, 25.0–29.9, and ≥30.0), even
though its levels were lower in overweight (25.0–29.9) and
obese (≥30.0) patients with acute dyspnea [30]. Con-
ceptually, however, these findings seem to be consistent
with our results, and to provide additional evidence for the
prognostic utility of NT-proBNP, notwithstanding its
inverse relationship with BMI, supporting our comparative
results between BMI groups.
Traditionally, high BMI is associated with cardiac stress
through volume overload, arterial hypertension, and ven-
tricular dysfunction [31], and it is also a major risk factor
for various diseases including diabetes, hypertension, car-
diovascular disease, renal disease, and HF [32, 33], which
all lead to increased circulating levels of NT-proBNP.
However, as confirmed both here and in other studies, BMI
and NT-proBNP have an inverse relationship. Although this
phenomenon is counterintuitive, it is supported by our
results suggesting the lower NT-proBNP levels observed in
the higher-BMI group despite a relatively high proportion
of disease in the high BMI (overweight and obesity) group,
and by previous studies suggesting that BMI independently
determines NT-proBNP levels irrespective of hemodynamic
stress and causes of respiratory distress [34–36]. Moreover,
a recent study by Kahlon et al. [37] showed that obese
patients with pneumonia had lower PSI scores than non-
obese patients. Given the clinically strong correlation
between NT-proBNP and PSI reported in previous studies
[12–16], these lines of evidence further suggest the presence
of this inverse relationship in CAP.
Two potential mechanisms have been suggested to explain
the inverse relationship between BMI and NPs; one is the
increased clearance of NPs via an adipocyte-related pathway,
such as increased NP clearance receptors or neutral endo-
peptidase degradation [23, 38], and the other is decreased
production of NPs from cardiomyocytes in obesity, which is
mediated by sex steroid hormones including androgen, altered
neurohormonal interactions and differences in glycosylation
[20–24]. However, because NT-proBNP is cleared only by
the kidneys, independent of the clearance pathway, impaired
mechanism of production is a more persuasive explanation for
its low levels in obesity. Although our finding of a relation-
ship between BMI and NT-proBNP is in line with previous
studies, it does not shed new light on the mechanisms of this
relationship. Instead, given that most studies concerning this
relationship have been restricted to cardiovascular diseases
and HF, our results on CAP could contribute to NT-proBNP’s
general application by providing additional data. To establish
acceptable evidence for the utility of NT-proBNP as a prog-
nostic determinant, further studies are required to elucidate the
pathophysiology of its mechanisms.
The reasons for a lack of any relationship between NT-
proBNP and CAP mortality in the underweight group are
unclear, but we presume that the relatively high NT-
proBNP levels with older age observed in the survival
subgroup might be a cause of that statistically weak asso-
ciation. The median value of that group’s NT-proBNP
levels was 1813.6 pg/ml, which was much higher than that
of survivors in other groups and close to that of non-
survivors in the same group. The clinical properties inherent
in low BMI also seem to contribute to this weakness.
Subnormal BMI (underweight) itself commonly indicates
malnutrition and a debilitating condition [9, 39], therefore
the finding of high NT-proBNP levels in underweight
patients with CAP can be simply explained by disease
severity. In addition, the finding that the inverse magnitude
of correlation between BMI and NT-proBNP for survivors
was the highest in this group by a significant margin (data
not shown) might support this finding.
A survival benefit from higher BMI was observed in this
study. Although debate about this phenomenon is ongoing,
our finding reinforces its existence in pneumonia [8]. In
addition, we found an inverse trend between 30-day mor-
tality and the BMI categories (data not shown). However,
the main focus of our work is the association between BMI
and NT-proBNP, not between BMI and CAP mortality;
therefore, we did not conduct specific analyses to confirm
the obesity survival paradox.
To the best of our knowledge, this is the first prospective
observational study to demonstrate the prognostic utility of
NT-proBNP in CAP while incorporating the confounding
effect of BMI and a significant interaction effect of BMI on
the association between NT-proBNP and CAP mortality.
The strengths of our study include the homogeneous CAP
population-based design, the high proportion of BMI mea-
sured objectively, a low number of patients with underlying
congestive HF evenly distributed among the BMI groups,
the well-established parametric profiles of all enrolled
patients, and adjustment for numerous potential covariates,
including PSI, that could affect NT-proBNP levels. How-
ever, several limitations should be considered. First, this is a
single-center study with an observational design and could
be biased by its stringent eligibility criteria. In addition,
only hospitalized CAP patients were enrolled, most of
whom were elderly with diverse comorbidities, which could
limit the external validity or generalizability of our results.
Second, our population included a relatively small number
of obese patients with CAP, and their low mortality rate
made it difficult to draw definitive conclusions. Third, this
is not a mechanistic study, and we did not identify the exact
relationship mechanism between BMI and NT-proBNP.
Proinflammatory cytokines, such as tumor necrosis factor-α
and interleukin-1, are elevated in obese patients with
pneumonia, and some studies have demonstrated a corre-
sponding increase in NP levels [40, 41]. Therefore, further
investigation is needed in this area to establish the findings
of this study. Finally, cardiac function was not evaluated

using echocardiography. However, because the prevalence
of enrolled patients with existing congestive HF was very
low and patients with acute cardiac problems mimicking
pneumonia were excluded, we believe that this issue did not
significantly affect the validity of NT-proBNP as a pre-
dictive biomarker in our population.
Conclusion
We found that BMI plays a significant role in determining
the utility of NT-proBNP as a prognostic biomarker in
CAP; it significantly strengthens the predictive performance
of NT-proBNP. Moreover, in a comparative analysis based
on the significant interaction term between them, the pre-
dictive performance of NT-proBNP for mortality was
highest in overweight and obese patients with CAP and
lowest in underweight patients. Our finding furthers
understanding of the relationship between BMI and the
predictive utility of NT-proBNP for CAP mortality, and it
elucidates the potential effects of BMI. However, because
these results do not incontrovertibly imply a causal rela-
tionship due to insufficient mechanistic evidence, larger
multi-center clinical trials with further detailed data,
including proinflammatory cytokines, are needed to validate
our findings.
Acknowledgements The authors are grateful to all (rotating) residents
and fellows of the Department of Emergency Medicine involved in the
ED pneumonia registry, for assistance with collection and organization
of interview and questionnaire data. Our thanks are also due to Su Jin
Jeong (Kyung Hee University Medical Center, Medical Science
Research Institute) for statistical advice and interpretation of analysis
results.
Author contributions JKY: conceptualization, methodology, formal
analysis, original draft, critical revision, and supervision; LJS: con-
ceptualization, methodology, original draft, editing, and data man-
agement; KSH: conceptualization, formal analysis, original draft,
review and editing; LJ: conceptualization, methodology, formal ana-
lysis, review and editing.
Compliance with ethical standards
Conflict of interest The authors have no conflicts of interest to
disclose.
Publisher’s note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
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