Diurnal Variations in Natriuretic Peptide Levels: Clinical Implications for the Diagnosis of Acute Heart Failure

Tobias Breidthardt, William P T M van Doorn, Noreen van der Linden, Matthias Diebold, Desiree Wussler, Isabelle Danier, Tobias Zimmermann, Samyut Shrestha, Nikola Kozhuharov, Maria Belkin, Caroline Porta, Ivo Strebel, Eleni Michou, Danielle M Gualandro, Albina Nowak, S J R Meex, Christian Mueller, Tobias Breidthardt, William P T M van Doorn, Noreen van der Linden, Matthias Diebold, Desiree Wussler, Isabelle Danier, Tobias Zimmermann, Samyut Shrestha, Nikola Kozhuharov, Maria Belkin, Caroline Porta, Ivo Strebel, Eleni Michou, Danielle M Gualandro, Albina Nowak, S J R Meex, Christian Mueller

Abstract

Background: Current guidelines recommend interpreting concentrations of NPs (natriuretic peptides) irrespective of the time of presentation to the emergency department. We hypothesized that diurnal variations in NP concentration may affect their diagnostic accuracy for acute heart failure.

Methods: In a secondary analysis of a multicenter diagnostic study enrolling patients presenting with acute dyspnea to the emergency department and using central adjudication of the final diagnosis by 2 independent cardiologists, the diagnostic accuracy for acute heart failure of BNP (B-type NP), NT-proBNP (N-terminal pro-B-type NP), and MR-proANP (midregional pro-atrial NP) was compared among 1577 daytime presenters versus 908 evening/nighttime presenters. In a validation study, the presence of a diurnal rhythm in BNP and NT-proBNP concentrations was examined by hourly measurements in 44 stable individuals.

Results: Among patients adjudicated to have acute heart failure, BNP, NT-proBNP, and MR-proANP concentrations were comparable among daytime versus evening/nighttime presenters (all P=nonsignificant). Contrastingly, among patients adjudicated to have other causes of dyspnea, evening/nighttime presenters had lower BNP (median, 44 [18-110] versus 74 [27-168] ng/L; P<0.01) and NT-proBNP (median, 212 [72-581] versus 297 [102-902] ng/L; P<0.01) concentrations versus daytime presenters. This resulted in higher diagnostic accuracy as quantified by the area under the curve of BNP and NT-proBNP among evening/nighttime presenters (0.97 [95% CI, 0.95-0.98] and 0.95 [95% CI, 0.93-0.96] versus 0.94 [95% CI, 0.92-0.95] and 0.91 [95% CI, 0.90-0.93]) among daytime presenters (both P<0.01). These differences were not observed for MR-proANP. Diurnal variation of BNP and NT-proBNP with lower evening/nighttime concentration was confirmed in 44 stable individuals (P<0.01).

Conclusions: BNP and NT-proBNP, but not MR-proANP, exhibit a diurnal rhythm that results in even higher diagnostic accuracy among evening/nighttime presenters versus daytime presenters.

Registration: URL: https://www.

Clinicaltrials: gov; Unique identifiers: NCT01831115, NCT02091427, and NCT02210897.

Keywords: circadian rhythm; diagnostic techniques, cardiovascular; dyspnea; heart failure; natriuretic peptides.

Figures

Figure 1.
Figure 1.
Whisker plots displaying spot measurements of natriuretic peptide concentrations with acute heart failure according to quintiles of presentation time. A, BNP (B-type natriuretic peptide), (B) NT-proBNP (N-terminal pro-B-type natriuretic peptide), and (C) MR-proANP (midregional pro-atrial natriuretic peptide). P values are derived from Jonckheere-Terpstra trend test. Results are displayed as median concentrations; whisker bars display interquartile ranges. Dashed line highlights median concentrations according to different presentation times. No serial measurements were performed. ED indicates emergency department.
Figure 2.
Figure 2.
Whisker plots displaying spot measurements of natriuretic peptide concentrations with noncardiac dyspnea according to quintiles of presentation time. A, BNP (B-type natriuretic peptide), (B) NT-proBNP (N-terminal pro-B-type natriuretic peptide), and (C) MR-proANP (midregional pro-atrial natriuretic peptide). P values are derived from the Jonckheere-Terpstra trend test. Results are displayed as median concentrations; whisker bars display interquartile ranges. Dashed line highlights median concentrations according to different presentation times. No serial measurements were performed. ED indicates emergency department.
Figure 3.
Figure 3.
Receiver operating characteristic (ROC) curves displaying the diagnostic accuracy of natriuretic peptides with acute heart failure in daytime and nighttime presenters. A, BNP (B-type natriuretic peptide) and (B) NT-proBNP (N-terminal pro-B-type natriuretic peptide). P values are derived from comparison of areas under independent ROC curves as recommended by Hanley et al. AUC indicates area under the curve; NPV, negative predictive value; Sens, sensitivity; and Spec, specificity.
Figure 4.
Figure 4.
Diurnal variation of natriuretic peptides in nondyspneic participants according to renal function. A, BNP (B-type natriuretic peptide) and (B) NT-proBNP (N-terminal pro-B-type natriuretic peptide). CKD indicates chronic kidney disease.
Figure 5.
Figure 5.
Diurnal variation of natriuretic peptides in nondyspneic participants according to body mass classes. A, BNP (B-type natriuretic peptide) and (B) NT-proBNP (N-terminal pro-B-type natriuretic peptide).

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