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Alexander G. Semenov and Alexey G. Katrukha. Can Dysregulation in pro–B-type Natriuretic Peptide Glycosylation Explain Decreased B-type Natriuretic Peptide Concentrations in Obese Heart Failure Patients?. Clin Chem 2019;65:1070-2.
Dr. Alexander Semenov, Project Manager in the R&D Department of the biotech company HyTest located in Turku, Finland and also from the School of Biology Lomonosov Moscow State University in Moscow, Russia.
This is a podcast from Clinical Chemistry, sponsored by the Department of Laboratory Medicine at Boston Children’s Hospital. I am Bob Barrett.
B-type natriuretic peptide or BNP and N-terminal proBNP or NT-proBNP are peptides produced in the heart in response to increased wall stretch and volume overload. As their production and secretion increases in the heart with regression of heart failure, they have emerged as useful and cost-effective heart failure biomarkers. Since the discovery of BNPs in 1988, much effort has been made to precisely determine the BNP and NT-proBNP levels via immunoassays for reliable heart failure diagnostics. As a result, the measurements of these biomarkers is globally accepted and used as a tool by clinicians to diagnose acute and chronic heart failure, stratify risk, and monitor response to therapy.
Obesity is on the rise worldwide and it’s a risk factor for systemic hypertension, hyperlipidemia, diabetes mellitus, and left ventricular hypertrophy, all of which are conditions associated with an increased prevalence of heart failure. However, the applications of BNP and NT-proBNP as biomarkers in obese patients are limited, as the relationship between their levels and myocardial stiffness is complex. An Editorial appearing in the September 2019 issue of Clinical Chemistry examines the interrelationship between obesity and BNP and NT-proBNP measurements. The authors of that Editorial are Alexander Semenov and Alexey Katrukha, both are from the biotech company HyTest located in Turku, Finland, and the School of Biology Lomonosov Moscow State University in Moscow, Russia. Dr. Semenov is our guest in this podcast. So, doctor, what are the relationships among B-type natriuretic peptide and NT-proBNP levels, body mass index, and heart failure?
Well, obesity is a well-known risk factor for systemic hypertension, hyperlipidemia, diabetes, and left ventricular hypertrophy. These conditions, in turn, are associated with an increased prevalence of chronic heart failure and the proportion of heart failure patients with significant obesity has increased dramatically, owing to the increase in obesity
in the general population.
Notably, obese patients present unique challenges in the
diagnosis of heart failure and particularly in the Emergency
Department. Obesity may mask signs of edema during
physical examination. Thus, the use of biomarkers to aid in
the diagnosis and management of heart failure would be
particularly valuable in obese patients. Natriuretic peptides,
BNP and NT-proBNP are widely used nowadays to establish
or exclude the diagnosis of heart failing patients with acute
dyspnea. However, the use of these biomarkers is
compromised in obese patients as the levels tend to be
lower. Obese individuals have an impaired natriuretic
peptide response, a so called natriuretic handicap.
So, since the relationship between BNP and NT-proBNP
levels and myocardial stiffness is complex, do you agree
that applications of BNP and NT-proBNP as biomarkers in
obese patients are limited?
Well, definitely. Considering that the established clinical
thresholds are not relevant to distinguish heart failure from
non-heart failure conditions among obese patients, the
interpretation of results and clinical decisions are indeed
rather complicated, and consequently, the applications of
both BNP and NT-proBNP as biomarkers in obese patients
are limited. Thus, a more precise understanding of the
interrelationship between the BMI and natriuretic peptide
measurement is of crucial importance, not only to accurately
diagnose heart failure in obese patients, but also to
formulate new therapeutic strategies.
What hypotheses had been proposed to explain the inverse
relationship between obesity and circulating BNP and NTproBNP
Actually, a number of hypotheses have been proposed to
explain the inverse relationship between obesity and
circulating concentrations of natriuretic peptides. The
suggested mechanisms include altered renal clearance,
altered activity or concentration of receptors responsible for
clearance of natriuretic peptide’s reduction, and stimulus
from wall stretch caused by increased epicardial fat and
altered activity of proteolytic enzymes. However, no
conclusive evidence has yet been obtained in favor of any
Dr. Semenov, how do the results of the study by Lewis et al.
recently published in Clinical Chemistry improved our
current understanding of reduced circulating concentrations
of both BNP and NT-proBNP in obese heart failure patients?
The authors of the study explored this phenomenon from
the viewpoint of in fact proBNP process in heart failure, both
generally and particularly with respect to obesity. The
appearance of BNP and the NT-proBNP in the blood is
ultimately caused by proteolytic process which is a precursor
proBNP. Glycosylation of the region close to the proBNP
clearing site 30971, was shown to play a pivotal role in
regulating the intermediate processing of proBNP. That also
associated increased BMI with increased ratio of total
proBNP to proBNP non-glycosylated at 30971 thereby
suggesting a decrease in the production of potential source
of BNP and NT-proBNP. A decreased proBNP process then
could at least partially explain the lower NT-proBNP and BNP
concentrations observed in obese individuals. This is a
novel view on the complex interrelationship between obesity
and natriuretic peptide concentration.
So, what differentiates the method used by the authors to
detect different proBNP forms from previous studies?
Well, glycosylation profile analysis of endogenous proteins is
known to be a laborious process that requires complex
methodological approach. For example, HPLC coupled to
mass spectrometry base methods are known to have quite
limited throughput. The authors used an alternative
approach. They developed three immunoassays to
distinguish between total proBNP, proBNP not glycosylated
at 30971 and proBNP not glycosylated in the central region.
These assays allow both directed and high throughput
determination of the proBNP glycosylation profiles and
facilitated glycosylation profile comparison in different
subgroups of heart failure patients.
Do you think that this method can be used in other studies
on the regulation of proBNP processing?
Yes, definitely. By using antibodies of the highly specific
and high affinity tool is principally possible to develop an
assay for almost any particular form of BNP related peptide.
I hope that these studies would encourage future research
on the regulation of proBNP process in different subgroups
of patients with different etiologies of heart failure. These
studies might help to improve our understanding for heart
failure development and the clinical significance of different
forms of BNP related peptides.
Well, finally, Dr. Semenov, what limitations of the study by
Lewis et al. do you think are to be considered while
interpreting the results?
I would imagine a few limitations of the study. First, total
BNP concentrations were not evaluated in the analyzed samples. Thus, it’s not possible to estimate the ratio of the
different proBNP forms in the total BNP pool and make a
conclusion regarding alterations in BNP production in
different subgroups of heart failure patients. Second, in key
proBNP assay used to determine plasma proBNP
concentrations was sensitive to NT-proBNP glycosylation.
Consequently, the difference in NT-proBNP measurement in
heart failure patients with and without obesity may be
influenced by alterations in the glycosylation state in the
central region of the NT-proBNP. And the validity of the
conclusions that show a difference in NT-proBNP
concentrations, in obese versus non-obese heart failure
patients might be compromised because of the effects of
glycosylation on antibody binding.
That was Dr. Alexander Semenov, Project Manager in the
R&D Department of the biotech company HyTest located in
Turku, Finland and also from the School of Biology
Lomonosov Moscow State University in Moscow, Russia. He
has been our guest in this podcast on the interrelationships
between obesity and BNP and NT-proBNP measurements.
His Editorial on that topic appears in the September 2019
issue of Clinical Chemistry. I’m Bob Barrett. Thanks for