The present study showed an inverse association between BMI and NT-proBNP levels in patients with heart failure. The novelty of this study is that it found other factors independent of or in combination with BMI that affect the NT-proBNP values in heart failure patients and estimated the extent to which BMI changes may affect the NT-proBNP values.

The inverse association between BMI and NT-proBNP levels in heart failure patients found in our study has been reported in many previous studies [1, 11,12,13,14, 16,17,18,19, 22,23,24,25,26]. The exact mechanism of the inverse association between obesity and NT-proBNP levels remains unclear [2, 23, 27, 28]. It is hypothesized that obesity increases BNP clearance of adipocytes and reduces BNP release from the ventricles [5, 9, 23, 29]. NT-proBNP is a biologically inactive peptide, so it is not cleared by NPR-C (natriuretic peptide clearance receptor-C) of adipocytes, and the decreased release can play an important role in lowering the NT-proBNP levels in obesity [1, 12, 16, 22]. Some studies have shown that NT-proBNP is inversely related to muscle mass rather than fat composition [22, 30].

However, the inverse association between BMI and NT-proBNP values was weak at correlation coefficient r = − 0.29 in the present study, although the concentration of NT-proBNP in heart failure patients with obesity was significantly lower (38%) than that in heart failure patients with normal BMI. The weak inverse correlation between BMI and NT-proBNP values was also noted in the previous studies [12, 14, 22, 23, 27], such as Kim HL's study on 1877 heart failure patients who reported an inverse association between BMI and NT-proBNP values with r = − 0.232 [17]. Besides, many studies showed that NT-proBNP assay remains valuable in diagnosis and prognosis in both obese and nonobese patients with heart failure, although there is a significant association between NT-proBNP values and BMI [12, 13, 23]. Our study also found that each standard deviation increase in BMI (4 kg/m2) was only associated with a 7% decrease in NT-proBNP values. This indicated that the decrease in NT-proBNP levels did not correspond to the increase in BMI. Thus, there will be other independent or combined factors together with BMI affecting NT-proBNP values ​​in heart failure patients.

In this study, the independent variables having a stronger correlation with NT-proBNP levels than BMI were male gender, EF ≤ 40%, and NYHA class III–IV heart failure. Furthermore, diabetes and hypertension may be combined with obesity in affecting NT-proBNP values in heart failure patients to some extent.

Our study found that male gender was an independent inverse determinant of NT-proBNP levels, and the NT-proBNP concentration was significantly lower in male patients than in female patients in the overweight BMI category. In particular, the present study noted that the decrease in NT-proBNP corresponding to each standard deviation increment in BMI was greater in males than in the total population (21% vs. 7%). This finding demonstrated that male gender has a stronger effect on NT-proBNP levels than BMI alone. The fact that the male gender is one of the independent factors inversely related to NT-proBNP levels in heart failure patients has been described in many previous studies [14, 19, 22, 23]. Conversely, Suthahar N. found that the NT-proBNP levels were higher in females than in males, and the author explained the reverse by increased circulating testosterone levels in females with abdominal obesity [25]. The suppressive effect on NT-proBNP levels may be explained by testosterone (male hormone), which tends to inhibit NT-proBNP release [2, 19, 22]. Thus, gender should be considered as a factor in adjustment to NT-proBNP values in obesity.

Heart failure with EF ≤ 40% and NYHA class III–IV heart failure were variables that were linked with an increase in NT-proBNP levels independently of BMI in this study. The NT-proBNP levels in patients with NYHA class III–IV heart failure and heart failure with an EF ≤ 40% were higher than those in patients with NYHA class II heart failure and heart failure with an EF > 40% in both lean and obese patients. These findings were also noted in previous studies [13, 14, 19, 28]. This is explained by severe heart failure leading to increased release of natriuretic peptides, including NT-proBNP, which offsets the NT-proBNP reduction caused by BMI increment [2, 21]. Previous studies have also shown that NT-proBNP levels are a direct predictor of cardiovascular events in both obese and nonobese individuals [1, 11, 12, 19, 24, 31]. It is assumed that NT-proBNP levels are clinically useful in assessing the severity of heart failure irrespective of BMI status.

In the present study, a significant difference was found in NT-proBNP levels in diabetic patients across three BMI categories, while the difference in NT-proBNP levels among the three BMI strata was not significant in patients without diabetes. This finding suggests that diabetes has a certain effect on NT-proBNP values, although diabetes was not found to have a significant association with NT-proBNP levels in the multivariate regression analysis. However, some previous studies have documented that diabetes results in a significant decrease in NT-proBNP levels [11, 19, 23]. This is explained by the increased proBNP glycosylation promoted by elevated blood glucose and insulin resistance status associated with obesity causing a decreased release of NT-proBNP [11, 24].

Theoretically, hypertension exerts a pressure overload on the ventricular myocardium that contributes to NT-proBNP release [2, 21]. However, many studies have shown that hypertension is not significantly associated with NT-proBNP levels [14, 23]. The finding that hypertension was not an independent determinant of NT-proBNP levels was also noted in this study. The reason may be that hypertension patients often have comorbid obesity and/or diabetes, and these disorders reduce the enhancing effect of hypertension on NT-proBNP levels. Indeed, there is an association between obesity and hypertension, and obese individuals have low natriuretic peptide levels that may cause salt retention and excessive adrenergic tone, leading to persistently elevated blood pressure [23].

Thus, diabetes, hypertension, and obesity, which are disorders commonly encountered in heart failure patients, interact with each other to impact the NT-proBNP levels, in which obesity plays a more significant role. Further research is needed to fully explain how these associations affect the NT-proBNP values to manage patients with heart failure more effectively.

All study participants were discharged from the hospital in stable condition. Since this is a cross-sectional study, the analysis of the association between NT-ProBNP and BMI to the outcome of patients with heart failure falls outside the objectives of our investigation. However, numerous studies have reported that the NT-proBNP value is an independent predictor of outcomes in both obese and nonobese patients with heart failure [8, 12, 13, 19, 23, 31]. Further research is also required to confirm this issue in Vietnam.

Because of the inverse relationship between BMI and NT-proBNP values ​​in heart failure patients, some authors recommended BMI-adjusted NT-proBNP values ​​in the diagnosis and prognosis of heart failure [15, 17, 18]. However, this recommendation has not yet been supported by controlled studies, and further clinical trials are needed to verify it [9]. Therefore, the evidence has not been strong enough to change the guidelines for the diagnosis of heart failure. The 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure continue to include NT-proBNP without adjustment based on BMI [6]. The results of this study are consistent with this point of view. The NT-proBNP values remain useful in the diagnosis of heart failure in all BMI categories.

This study has some limitations. Firstly, it was a cross-sectional study, which made it impossible to evaluate the impact of BMI and NT-proBNP values on the prognosis of patients with heart failure. Secondly, the sample size was small compared to previous studies, which may have affected the significance of the results. However, a sample size of 297 cases is still sufficient to yield meaningful results. Furthermore, the study was conducted using rigorous methods, with accurate data collection and appropriate statistical analysis. It was conducted at a sizable 900-bed university hospital over one year, so the results can be considered valid for the study population. To the best of our knowledge, this is one of the first studies in Vietnam to investigate the effect of BMI and other factors on NT-proBNP values in heart failure patients and can provide useful information in the management of heart failure patients.