Circulation: Heart Failure

ORIGINAL ARTICLE

Reference Ranges for NT-proBNP (N-Terminal

Pro-B-Type Natriuretic Peptide) and Risk Factors
for Higher NT-proBNP Concentrations in a Large
General Population Cohort
Paul Welsh , PhD; Ross T. Campbell, PhD; Leanne Mooney, MBChB; Dorien M. Kimenai , MSc; Caroline Hayward , PhD;
Archie Campbell , MA; David Porteous , PhD; Nicholas L. Mills , PhD; Ninian N. Lang , PhD;
Mark C. Petrie , MBChB; James L. Januzzi , MD; John J.V. McMurray MD; Naveed Sattar , PhD

BACKGROUND: Demographic differences in expected NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentration
are not well established. We aimed to establish reference ranges for NT-proBNP and explore the determinants of moderately
elevated NT-proBNP under the universal definition of heart failure criteria.

METHODS: This is a cross-sectional study. NT-proBNP was measured in serum from 18 356 individuals without previous
cardiovascular disease in the Generation Scotland Scottish Family Health Study. Age- and sex-stratified medians and 97.5th
centiles were generated. Sex stratified risk factors for moderately elevated NT-proBNP (≥125 pg/mL) were investigated.

RESULTS: In males, median (97.5th centile) NT-proBNP concentration at age <30 years was 21 (104) pg/mL, rising to 38
(195) pg/ml at 50 to 59 years, and 281 (6792) pg/mL at ≥80 years. In females, median NT-proBNP at age <30 years
was 51 (196) pg/mL, 66 (299) pg/mL at 50 to 59 years, and 240 (2704) pg/mL at ≥80 years. At age <30 years, 9.8%
of females and 1.4% of males had elevated NT-proBNP, rising to 76.5% and 81.0%, respectively, at age ≥80 years. After
adjusting for risk factors, an NT-proBNP ≥125 pg/mL was more common in females than males (OR, 9.48 [95% CI,
5.60–16.1]). Older age and smoking were more strongly associated with elevated NT-proBNP in males than in females
(Psex interaction <0.001, 0.07, respectively). Diabetes was inversely associated with odds of elevated NT-proBNP in females only
(Psex interaction=0.007).
CONCLUSIONS: An NT-proBNP ≥125 pg/mL is common in females without classical cardiovascular risk factors as well as older
people. If NT-proBNP becomes widely used for screening in the general population, interpretation of NT-proBNP levels will
require that age and sex-specific thresholds are used to identify patients with potential pathophysiology.

Key Words: age distribution ◼ demography ◼ heart failure ◼ risk factors ◼ sex

M
easurement of BNP (B-type natriuretic peptide) ambulatory NT-proBNP at 125 pg/mL as a corroborating
or NT-proBNP (N-terminal pro-B-type natriuretic definition of heart failure when accompanied by symptoms
peptide) is now a cornerstone of many clinical or signs of the disease.1 Recently updated guidelines from
guidelines in the diagnosis of heart failure. The recent uni- the European Society of Cardiology also specify the rule
versal definition of heart failure position paper specifies an out heart failure thresholds of NT-proBNP at 125 pg/

Correspondence to: Paul Welsh, PhD, School of Cardiovascular and Metabolic Health, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126
University Pl, Glasgow G12 8TA, United Kingdom. Email paul.welsh@glasgow.ac.uk
This manuscript was sent to John C. Burnett Jr, MD, Guest Editor, for review by expert referees, editorial decision, and final disposition.
Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCHEARTFAILURE.121.009427.
For Sources of Funding and Disclosures, see page 966.
© 2022 The Authors. Circulation: Heart Failure is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access
article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is
properly cited.
Circulation: Heart Failure is available at www.ahajournals.org/journal/circheartfailure

Circ Heart Fail. 2022;15:e009427. DOI: 10.1161/CIRCHEARTFAILURE.121.009427 October 2022 957

Welsh et al NT-proBNP in the General Population

As well as the heart failure diagnosis pathway, there

WHAT IS NEW? is also increasing interest in using NT-proBNP in a wider
• The Universal definition of heart failure states that range of indications and patient populations, including
NT-proBNP (N-terminal pro-B-type natriuretic pep- to predict cardiovascular disease risk in those without
tide) ≥125 pg/mL is corroborating evidence of heart established heart failure,6–8 to screen for heart failure in
failure in the acute setting, but this single threshold the general population as part of an integrated cardio-
may not be optimal for screening in the general vascular disease risk screening approach,9,10 and to use
population. In this general population study, we
NT-proBNP in emerging conditions such as prognosis of
report that NT-proBNP ≥125 pg/mL is frequently
observed in many demographic groups, including
COVID-19 infection.11 In each of these settings, higher
in around 10% of young females, many of whom NT-proBNP concentrations predict future heart failure
are unlikely to have preclinical heart failure. Indeed, onset or its complications; however, when using lower NT-
NT-proBNP ≥125pg/mL was much more common proBNP cut-points (such as 125 pg/mL), it is reasonable
in females than in males (adjusted odds ratio 9.48). to expect a significant overlap between those with unsus-
pected structural heart disease and those without obvi-
WHAT ARE THE CLINICAL IMPLICATIONS? ous prevalent disease. To incorporate more widespread
• Clinical indications for NT-proBNP measurement NT-proBNP testing into clinical practice, it is important
are likely to expand in the general population in to understand what NT-proBNP levels are typically seen
the future. The reference ranges we present in this in the general population across a wide range of ages.
work will help guide understanding of expected Although consensus has developed around use of an NT-
NT-proBNP concentrations in the general popula- proBNP cut-point of 125 pg/mL as a moderate eleva-
tion, as well as determinants of moderately elevated tion that may be clinically significant, more understanding
NT-proBNP.
is needed regarding factors influencing the biomarker
• Before NT-proBNP can be used as a general popu-
lation screening tool, a better understanding of among individuals without established cardiovascular
the definition, determinants, and consequences of disease. Published data from general populations explor-
moderately elevated NT-proBNP is required. This ing the age- and sex-stratified reference ranges for NT-
includes study of younger people in the general proBNP, and these have generally been from smaller
population, as well as individuals in middle-age and cohorts with restricted age ranges, limiting exploration of
older-age. reference ranges by age and sex stratified groups.12–14
The aims of this study were therefore to use a large
general population with a wide age distribution to (1)
report normative reference ranges for NT-proBNP, (2)
Nonstandard Abbreviations and Acronyms report prevalence of participants in different demo-
graphic groups with elevated NT-proBNP according to
BMI body mass index
the existing clinical thresholds, and (3) report risk fac-
BNP B-type natriuretic peptide tors associated with elevated NT-proBNP, stratified by
cTnI cardiac troponin I sex. We hypothesised that a single threshold to identify
cTnT cardiac troponin T moderately elevated NT-proBNP (≥125 pg/mL) in the
eGFR estimated glomerular filtration rate context of a general population is unlikely to identify
ESC European Society of Cardiology participants in all demographic groups with NT-proBNP
HDL high-density lipoprotein concentrations that may require clinical investigation.
NT-proBNP N-terminal pro-B-type natriuretic
peptide
SBP systolic blood pressure METHODS
SMR Scottish morbidity record The data, analytic methods, and study materials will be made
available to other researchers for purposes of reproducing the
results or replicating the procedure subject to a successful proj-
mL in the nonacute setting,2 a threshold which is also ect application to the Generation Scotland Access Committee.
supported by a position paper on the use of natriuretic
peptides.3 The UK National Institute for Health and Care Generation Scotland Scottish Family Health
Excellence guidelines specify a rule-out threshold for
Study (GS:SFHS)
chronic heart failure at NT-proBNP of 400 pg/mL, with
This is a cross-sectional study within the cohort. The recruit-
guidance to refer for echocardiography above this level.4 ment and design of the GS:SFHS has been reported in detail
The higher threshold in the National Institute for Health previously.15,16 During 2006 to 2010, potential participants
and Care Excellence model was chosen due to an original (aged 35–65 years) were identified at random from collaborat-
cost-effectiveness analysis (based on data from a diag- ing general medical practices in Scotland and invited to partici-
nostic accuracy study5), conducted for the guidelines. pate. Participants were also asked to identify ≥1 first-degree

Circ Heart Fail. 2022;15:e009427. DOI: 10.1161/CIRCHEARTFAILURE.121.009427 October 2022 958