The Paradox of low B-Type Natriuretic Peptide Levels in Obesity Revisited: Does Sex Matter?

This article refers to ‘Sex-specific associations of obesity and N-terminal pro-B-type natriuretic peptide levels in the general population’ by N. Suthahar et al., published in this issue on pages 1205–1214. Obesity has reached epidemic proportions worldwide and represents a common co-morbidity in patients with heart failure (HF), especially in those with preserved ejection fraction (HFpEF).1, 2 Obesity has many deleterious effects on the cardiovascular system, mediated by changes in volume status, cardiac load, energy substrate utilization, tissue metabolism, and systemic inflammation, which are believed to promote cardiac disease progression.3-5 Furthermore, obesity is strongly associated with other common non-cardiac clinical conditions, such as systemic arterial hypertension, diabetes mellitus, metabolic syndrome, and obstructive sleep apnoea; these co-morbidities are also common in patients with HFpEF.2, 6 Several studies reported that circulating levels of B-type natriuretic peptide (BNP) and its related peptide N-terminal fragment of proBNP (NT-proBNP) are inversely related to body mass index (BMI) in the general population, as well as in HF patients, as recently reviewed.1, 2 It is also well known that both atrial natriuretic peptide and BNP circulating levels are strongly gender-dependent in healthy subjects. Plasma BNP concentration is minimal during the first years of life with similar values in children and pre-adolescent girls and boys, while the normal cycling women have about two-fold higher BNP levels than men at the same age.1, 2, 7 These data suggest that sex steroid hormones play a relevant role in the regulation of production/secretion of cardiac natriuretic peptides. Clinical studies demonstrate that oestrogens, administered as hormonal contraceptives in pre-menopausal women or as hormone replacement therapy in postmenopausal women, increase the circulating levels of BNP and NT-proBNP.7 Moreover, androgen receptor blockade and, to a lesser extent, androgen suppression cause an increase in NT-proBNP in men with prostate cancer.7 These data suggest antagonist effects of androgens (inhibitory) and oestrogens (excitatory) on cardiac endocrine function. In this issue of the Journal, Suthahar et al.8 evaluated the hypothesis that low NT-proBNP levels in obese individuals could be attributed, at least in part, to differences in sex. To this purpose, the authors analysed a subgroup taken from a general population sample (n = 85 421) of Groningen citizens (The Netherlands), previously enrolled in the PREVEND (Prevention of REnal and Vascular ENd-stage Disease) study.8 Pregnant women and individuals of both sexes with prevalent type 1 diabetes mellitus or HF were excluded from the study. All remaining subjects (n = 8592) with an urinary albumin excretion (UAE) of ≥10 mg/L (n = 6000) and a randomly selected control group with UAE <10 mg/L (n = 2592) constituted the study cohort. The authors evaluated in 8260 individuals from this cohort the relationships between NT-proBNP levels and some obesity-related parameters, including waist circumference (WC), BMI, and body weight,8 and confirmed higher NT-proBNP levels in females than in males. Moreover, in the overall population, NT-proBNP levels were significantly lower in heavier individuals, displaying an ‘U-shaped’ relation with increasing WC, but were not associated with BMI.8 However, considering men and women separately, there was no significant association between NT-proBNP concentration and anthropometric measures in women. On the contrary, increasing WC and BMI were associated with higher NT-proBNP levels in men, while increasing body weight was associated with slightly lower biomarker levels. Furthermore, at multivariable regression analysis, an inverse association between obesity and NT-proBNP levels was significantly affected by sex, with lower level with increasing WC, BMI and body weight among females, as compared to males. After correction for the BMI variable, abdominal obesity, as assessed by WC, was significantly associated with lower NT-proBNP levels only in women, not in men.8 The results of the study by Suthahar et al.8 significantly increase our knowledge on the complex inter-relationships between the cardiac and sex endocrine systems. However, several issues of this study require some pathophysiological and methodological considerations. First, WC is assumed as a reliable estimation of abdominal obesity in this study, as also suggested by the most authoritative guidelines.9, 10 However, other methods, usually based on magnetic resonance imaging or dual X-ray absorptiometry scan, are currently considered more accurate than WC for the estimation of abdominal fat, although cannot be easily used in large population studies.1, 11 Furthermore, it is conceivable that an accurate estimation of localized fat depots around the heart, including pericardial and epicardial fat, could be more accurately associated with cardiovascular events in the general population, as compared to the estimate of abdominal fat.1, 11, 12 Another important issue not considered by Suthahar and colleagues is that individuals (especially women) with hypertension, obesity and diabetes mellitus are at higher risk for HF with mid-range ejection fraction (HFmrEF) and HFpEF.2, 6, 13 Therefore, it is likely that some individuals enrolled in this study (especially women) may have either HFmrEF or HFpEF.2, 6 Unfortunately, an accurate clinical and echocardiographic evaluation was not performed in this study. The complex relationships between obesity, sex and HFpEF have recently been discussed in detail.2 The results of this study confirm previous suggestions2 that using cut-off values adjusted for sex, age, and BMI, should increase the diagnostic and prognostic accuracy of natriuretic peptides in HFpEF patients. From a pathophysiological point of view, it is important to consider that the authors measured circulating levels of NT-proBNP, which is an inactive peptide, instead of the active hormone, BNP. Recent studies demonstrated that circulating BNP derives not only from cardiomyocyte production and release, but also by specific action of some proteolytic enzymes on circulating levels of the precursor proBNP14 (Figure 1). In conclusion, we agree with Suthahar et al.8 that natriuretic peptide deficiency in obesity is much more complex than previously supposed. Therefore, further studies are needed to understand the complex inter-relationship between sex, fat deposition in cardiac and peri-cardiac tissues, and cardiac endocrine system both in the general population and in patients with HF. Conflict of interest: none declared.