Unexpectedly Low Natriuretic Peptide Levels in Patients With Heart Failure

Katherine N. Bachmann, MD, MSCI; Deepak K. Gupta, MD, MSCI; Meng Xu, MS; Evan Brittain, MD, MSCI; Eric Farber-Eger, BS; Pankaj Arora, MD; Sheila Collins, PHD; Quinn S. Wells, MD, PHARMD, MSCI; Thomas J. Wang, MD


JACC Heart Fail. 2021;9(3):192-200. 

In This Article

Abstract and Introduction


Objectives: The purpose of this study was to determine the frequency of unexpectedly low natriuretic peptide (NP) levels in a clinical population.

Background: Higher NP concentrations are typically observed as a compensatory response to elevated cardiac wall stress. Under these conditions, low NP levels may be indicative of a "NP deficiency."

Methods: We identified 3 clinical scenarios in which high B-type natriuretic peptide (BNP) levels would be expected: 1) hospitalization for heart failure (HF); 2) abnormal cardiac structure or function; or 3) abnormal hemodynamics. In Vanderbilt's electronic health record, 47,970 adult patients had BNP measurements. A total of 13,613 patients had at least 1 of the 3 conditions (hospitalized HF, n = 9,153; abnormal cardiac structure/function, n = 7,041; abnormal hemodynamics, n = 363). We quantified the frequency of low BNP levels. We performed whole exome sequencing of the NPPB gene in a subset of 9 patients.

Results: Very low BNP levels (<50 pg/ml) were observed in 4.9%, 14.0%, and 16.3% of patients with hospitalized HF, abnormal cardiac structure/function, or abnormal hemodynamics, respectively. A small proportion (0.1% to 1.1%) in each group had BNP levels below detection limits. Higher body mass index was the strongest predictor of unexpectedly low BNP. Exome sequencing did not reveal coding variation predicted to alter detection of BNP by clinical assays.

Conclusions: A subset of patients with confirmed HF or cardiac dysfunction have unexpectedly low BNP levels. Obesity is the strongest correlate of unexpectedly low BNP levels. Our findings support the possible existence of NP deficiency, which may render some individuals more susceptible to volume or pressure overload.


Natriuretic peptides (NPs) are cardiac hormones with beneficial effects on renal, vascular, and myocardial function.[1–3] NPs serve a key role as counter-regulatory hormones against sodium overload and excessive neurohormonal activation. Animals with NP deficiency have salt-sensitive hypertension, cardiac hypertrophy, and glucose intolerance.[4] It has not been established whether humans can have NP deficiency, analogous to other endocrine deficiencies.

Because of an endocrine feedback loop, deficient NP production cannot be reliably determined by assessing NP levels alone. Circulating NP concentrations are determined not only by the ability to produce, secrete, and clear the peptides, but also by underlying cardiac wall stress, the principal trigger for NP release. One strategy for determining whether NP deficiency exists is to identify individuals with unexpectedly low NP levels in the context of a large, obvious stimulus for NP release. This is analogous to the assessment of other hormonal deficiencies. For instance, adrenal insufficiency can be diagnosed by documenting inappropriately low cortisol levels in the setting of a large stimulus (e.g., critical illness).