The N-terminal fragment of the prohormone of brain natriuretic peptide (NT-proBNP) plays a central role as a biomarker in the diagnosis of heart failure (HF), a syndrome resulting in reduced cardiac output and/or elevated intracardiac pressure at rest or during stress [
1]. Elevated levels of NT-proBNP are correlated with increased ventricular mass, another hallmark of chronic HF, and identify pulmonary hypertension [
2]. NT-proBNP is the biologically inactive product resulting from the cleavage process which deliberates and activates BNP from proBNP [
3,
4]. BNP is produced and released in response to distension or wall stress of the heart and is known to have essential functions in water balance and blood pressure by inducing vasodilation and thereby acting antagonistically to angiotensin II. Further, BNP increases endothelial permeability, directly inhibits aldosterone synthesis and the release of renin, and induces diuresis and natriuresis in the kidney [
3,
5]. Recent evidence indicates that natriuretic peptides possess functions beyond cardiovascular homeostasis and relates them to the function and development of adipose tissue [
6,
7]. In line with the assumption of an interrelation between body fat and the natriuretic hormone system, higher BNP levels within the reference range were associated with a favorable distribution of adipose tissue meaning lower visceral and liver fat and increased lower-body fat in participants of the DALLAS Heart Study [
8]. NT-proBNP and BNP levels are inversely correlated with BMI in the general population and obese individuals have typically lower BNP concentrations independent of cardiovascular disease (CVD) [
9,
10]. A recent study further revealed that BNP within the reference range (< 100 ng/L) was inversely correlated with total cholesterol, non-HDL cholesterol, and non-fasting triglycerides representing a favorable lipoprotein profile confirming an observation from a number of previous studies [
11‐
13]. In contrast, in CVD—for which dyslipidemia is a well-known risk factor [
14]—NT-proBNP or BNP levels are typically elevated. Importantly, the relation between NT-proBNP and the lipoprotein profile was also observable for concentrations above the reference limit and in the very elderly [
15,
16].
In the disease setting, increased NT-proBNP or BNP levels reflect the attempt of the body to restore homeostasis in response to increased intracardiac pressure and/or reduced cardiac output. Thus, BNP is elevated secondary to cardiac dysfunction and independent of adipose tissue function. Overall, NT-proBNP is involved in very different and independent physiologic processes including cardiovascular homeostasis and adipose tissue function.
In order to improve the understanding of NT-proBNP beyond cardiac dysfunction and to explore the relation to lipoprotein metabolism, the present study aimed to examine the associations of NT-proBNP plasma concentrations with the metabolic profile of a large population. As previous studies on NT-proBNP found adiponectin to be associated in a similar manner with a favorable lipoprotein profile [
17,
18], a mediation analysis was performed. For this purpose, in-depth analyses of the blood lipid profile associated with NT-proBNP were done using highly resolved lipoprotein particle measures obtained by proton nuclear magnetic resonance (
1H-NMR) spectroscopy. In order to further broaden the view on possible metabolic implications of NT-proBNP concentrations we complemented these analyses with an untargeted metabolomics approach based on mass spectrometry (MS) and
1H-NMR spectroscopy using plasma and urine samples from the same individuals.