NT-proBNP and its association with autonomous aldosterone production in primary aldosteronism

Abstract

Introduction:

Autonomous aldosterone production and mineralocorticoid receptor activation are key pathophysiologic mechanisms underlying primary aldosteronism (PA). N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a sensitive biomarker for evaluating cardiac stress and fluid status. This study aimed to investigate the association between NT-proBNP and renin-independent autonomous aldosterone production, as well as potential confounding factors.

Methods:

We conducted a retrospective cohort study of 443 patients with PA who underwent both a captopril challenge test (CCT) and measurement of NT-proBNP. The CCT was used to evaluate the degree of renin-independent aldosterone production, and the association between NT-proBNP and renin-independent aldosterone production was assessed using multivariable regression analysis. Echocardiography was performed to evaluate cardiac structure and function.

Results:

After multivariable regression analysis, post-CCT plasma aldosterone concentration (PAC) and aldosterone-renin ratio (ARR) were identified as independent predictors of NT-proBNP levels. In addition, female sex and lower body mass index (BMI) were significantly associated with higher NT-proBNP levels, compared to men or individuals with higher BMI. NT-proBNP also remained a significant predictor of increased left ventricular mass index and impaired diastolic function after adjustment across multiple models, underscoring its strong association with cardiac remodeling and dysfunction in patients with PA.

Conclusion:

Higher post-CCT PAC and ARR were independently associated with NT-proBNP in patients with PA, indicating a pathophysiological link between renin-independent aldosterone production and cardiac stress. Sex and BMI significantly influenced NT-proBNP concentrations, underscoring the importance of considering these factors when interpreting NT-proBNP levels in clinical practice.

Plain language summary

Association between autonomous aldosterone production and NT-proBNP in primary aldosteronism

Primary aldosteronism is a common cause of high blood pressure. We found that higher aldosterone and aldosterone-to-renin ratio (ARR) levels after the captopril challenge test but not baseline aldosterone or ARR were associated with higher NT-proBNP, a blood marker of cardiac stress. Women and people with lower BMI tended to have higher NT-proBNP, suggesting these factors affect its interpretation. NT-proBNP levels were also associated with cardiac remodeling and impaired diastolic function. Overall, NT-proBNP reflects the degree of autonomous aldosterone production in primary aldosteronism, but results should be interpreted with consideration of sex and body mass index.

Keywords

aldosterone captopril challenge test NT-proBNP primary aldosteronism renin

Introduction

Primary aldosteronism (PA) represents the most common form of secondary hypertension, characterized by autonomous aldosterone production and renin suppression due to dysregulated adrenal function.¹ The pathophysiology of PA includes aldosterone production independent of its physiologic regulation mechanism, the renin–angiotensin–aldosterone system, leading to the suppression of renin secretion.² Prevalence studies have shown that more than 14% of patients with hypertension are affected by PA.^1,3 In the recent Endocrine Society Clinical Practice Guideline,¹ universal screening of PA is recommended in patients with newly diagnosed hypertension, emphasizing the importance of early detection and targeted treatment.

Patients with PA often present with renal sodium retention, volume expansion, elevated blood pressure, hypokalemia, and aldosterone-mediated systemic end-organ damages.^2,4
–9 Increasing evidence indicates that PA represents a continuum of aldosterone excess rather than a discrete clinical entity.^2,3,10
–14 Given the elevated cardiovascular and renal risks observed in multiple studies,^1,4,15,16 effective risk stratification is critical in clinical practice. Recent studies demonstrate that renin-independent and autonomous aldosterone production, evaluated by post-captopril challenge test (CCT) plasma aldosterone concentration (PAC), was positively associated with worse cardiac remodeling and function.^8,17 Accordingly, clinically available biomarkers that reflect the severity of autonomous aldosterone production and its downstream cardiac effects are needed for risk stratification in patients with PA.

N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a well-established biomarker for evaluating cardiac stress and volume status. Under physiological conditions, proBNP is secreted by ventricular myocytes in response to myocardial wall stretch and is subsequently cleaved into biologically active BNP and inactive NT-proBNP fragment.¹⁸ BNP triggers natriuresis, diuresis, vasodilation, and the inhibition of renin–angiotensin–aldosterone system, thereby counteracting volume expansion and elevated cardiac filling pressures.¹⁸ However, in the setting of cardiac injury, increased ventricular wall tension leads to excessive production of both BNP and NT-proBNP.^19,20 Studies showed that elevated serum NT-proBNP levels are independently associated with increased mortality and worse cardiovascular outcomes, highlighting its potential as a useful and non-invasive biomarker.^21,22 However, prior studies into the relationship between NT-proBNP and autonomous aldosterone production yielded inconsistent and inconclusive findings among patients with PA.^23,24

This study aims to establish the relationship between NT-proBNP levels and autonomous aldosterone production. In addition, we examined clinical confounding factors that may influence NT-proBNP levels to improve consistency in clinical interpretation.^22,25,26 Finally, we examined the associations between NT-proBNP levels and echocardiographic measures of cardiac structure and diastolic function to clarify the clinical relevance of NT-proBNP in patients with PA.

Methods

Patients and study design

The study was based on the data from an ongoing longitudinal cohort of hypertensive individuals referred for PA evaluation and management at National Taiwan University Hospital between October 1993 and September 2023. Patients included in the registry were referred to PA testing and clinical management. Detailed clinical histories, biochemical, imaging, and outcome data were prospectively collected for each patient.

Patients with PA were retrospectively identified based on the according to the 2025 Endocrine Society Clinical Practice Guideline, criteria of PA¹: (1) Plasma renin activity (PRA) ⩽1 ng/mL/h and PAC ⩾10 ng/dL, (2) aldosterone–renin ratio (ARR) >20. The CCT was used to measure the renin-independent autonomous aldosterone production.^8,27 Among the 2482 patients screened from the registry, 14 patients did not fulfill the 2025 Endocrine Society criteria. Subsequently, patients who did not undergo serum NT-proBNP measurement (n = 1906) or CCT (n = 119) were also excluded. Finally, a total of 443 patients were enrolled in the current study. Among the patients enrolled in this study, 258 patients with completed echocardiographic measurements were used to further evaluate the association between NT-proBNP and cardiac structure and function as a subgroup analysis. A flowchart of the patient selection process is summarized in Figure 1.

Figure 1.

Study flowchart.

The study had three major aims. First, we investigated the determinants of NT-proBNP levels in patients with PA, focusing on the degree of renin-independent autonomous aldosterone secretion, assessed by post-CCT PAC and other parameters. Second, we identified potential confounding factors while interpreting NT-proBNP levels. Third, we assessed the relationship between NT-proBNP levels and cardiac structure and function, as determined by echocardiographic parameters, to highlight the clinical significance of NT-proBNP in patients with PA. The study complied with the Declaration of Helsinki. Informed consent was obtained from all patients prior to inclusion in the study, which was approved by the Ethics Committee of National Taiwan University Hospital.

Captopril challenge test

According to the clinical guideline, all antihypertensive medications were either discontinued or properly adjusted for a minimum of 2 weeks before conducting CCT.²⁸ On the day of measurement, each patient received 50 mg of captopril orally in the morning and was maintained in an upright position. Phlebotomy was performed, and PRA and PAC were measured before and at 90 min after the administration.²⁸ ARR was calculated by PAC divided by PRA.

Laboratory measurements

PAC was determined via radioimmunoassay (RIA) using the ACTIVE^® Aldosterone RIA kit (DSL8600; Beckman Coulter, Prague, Czech Republic). This assay demonstrated a minimum detection limit of 0.764 ng/dL, with intra-assay and inter-assay coefficients of variation (CVs) of 4.5% or less and 9.8% or less, respectively. PRA was measured by quantifying in vitro angiotensin I generation with an RIA kit (IM3518; Beckman Coulter), which has a minimum detection limit of 0.07 ng/dL. The intra-assay and inter-assay CVs for the PRA assay were 11.3% and 20.9%, respectively.

Echocardiography

Echocardiography was performed using a Philips IE33 system (Royal Dutch Philips Electronics, Bothell, WA, USA), based on the standardized protocols recommended by the American Society of Echocardiography.²⁹ M-mode imaging from the parasternal long-axis view was used to measure left ventricular (LV) end-diastolic and end-systolic diameters, interventricular septal diameter (IVSD), and LV posterior wall diameter (PWD). LV mass (LVM) was calculated by the Devereux and Reichek formula³⁰: {LVM = 1.04 ± [(IVSD + LV end diastolic diameter + PWD) 3 – (LV end diastolic diameter)3]– 13.6}. LV mass index (LVMI) was determined by dividing LVM by body surface area.

Doppler echocardiography was also done to determine the kinetic parameters of blood flow. From an apical four-chamber view, transmitral flow velocity was measured during the early diastole (E) phase by positioning a 3-mm sample volume at the tip of the mitral valve. In addition, tissue Doppler imaging was used to measure early diastolic (e′) mitral annular velocities by placing a 3-mm sample volume at the mitral valve annulus in the same view. The E/e′ ratio was then calculated as an estimate of LV filling pressure in the assessment of diastolic function.^31,32

Statistical analysis

All continuous variables are presented as mean ± standard deviation if normally distributed, and as median with interquartile range (IQR; 25th–75th percentiles) if non-normally distributed. Normality was determined by the Kolmogorov–Smirnov test. Non-normally distributed variables were log-transformed for subsequent regression analyses. Categorical variables were presented as counts (percentages). Group comparisons were performed using Student’s t-test or the Wilcoxon rank-sum test, as appropriate based on data distribution. For comparisons among multiple groups, the Kruskal–Wallis test with Bonferroni adjustment was applied. Comparisons between two category variables were performed by Pearson’s Chi-squared test or Fisher’s exact test, as appropriate. Univariable and multivariable linear regression analyses were conducted to examine the relationships between log-transformed NT-proBNP and post-CCT laboratory values, as well as other clinical and laboratory parameters. Variables with p < 0.1 in univariable linear regression were included in multivariable linear regression to identify significant independent indicators for NT-proBNP levels. Median split analysis based on baseline and post-CCT PAC and post-CCT ARR was performed to further investigate their correlations with NT pro-BNP across sex and body mass index (BMI) subgroups. Box plots were used to illustrate these associations. Additional multivariable regression analyses were conducted to explore the association between NT-proBNP and echocardiographic parameters with subsequent adjustments across four models. A two-sided p-value < 0.05 was considered statistically significant. All statistical analyses were performed through SPSS software for Windows, version 25.0 (IBM Inc., Armonk, NY, USA).

Results

Baseline characteristics of study participants

The baseline characteristics of our patient population are summarized in Table 1. In total, 443 patients were included, and the mean age was 54.8 ± 12.7 years, with 47.2% of them were men. The mean BMI was 25.6 ± 4.2 kg/m², and the median of NT-proBNP level was 47.8 (IQR, 24.8–98.1) pg/mL. The median baseline PAC, PRA, and ARR were 26.0 (IQR, 19.3–34.7) ng/dL, 0.3 (IQR, 0.1–0.6) ng/mL/h, and 82.7 (IQR, 37.3–220.0) ng/dL per ng/mL/h. The median post-CCT PAC, PRA, and ARR were 19.7 (IQR, 13.8–26.0) ng/dL, 0.5 (IQR, 0.2–0.9) ng/mL/h, and 35.3 (IQR, 24.3–82.4) ng/dL per ng/mL/h, respectively.

Table 1.

Baseline characteristics.

Variables	All PA patients (N = 443)
Age, year	54.8 ± 12.7
Sex, male	209 (47.2)
BMI, kg/m²	25.6 ± 4.2
Diabetes mellitus, %	69 (15.6)
Atrial fibrillation, %	17 (3.8)
Coronary artery disease, %	7 (1.6)
Heart failure, %	6 (1.4)
Hyperlipidemia, %	167 (37.7)
Number of HTN medications, pills	1.7 ± 1.4
Systolic blood pressure, mmHg	147.2 ± 23.6
Diastolic blood pressure, mmHg	87.6 ± 14.8
eGFR, mL/min/1.73 m²	93.1 ± 24.9
Potassium, mmol/L	3.8 ± 0.5
Glucose, mg/dL	99.1 ± 23.3
NT-proBNP, pg/mL	47.8 (24.8, 98.1)
PAC, ng/dL	26.0 (19.3, 34.7)
PRA, ng/mL/h	0.3 (0.1, 0.6)
ARR, ng/dL per ng/mL/h	82.7 (37.3, 220.0)
Post-CCT PAC, ng/dL	19.7 (13.8, 26.0)
Post-CCT PRA, ng/mL/h	0.5 (0.2, 0.9)
Post-CCT ARR, ng/dL per ng/mL/h	35.3 (24.3, 82.4)

ARR, aldosterone to renin ratio; BMI, body mass index; CCT, captopril challenge test; eGFR, estimated glomerular filtration rate; NT-proBNP, N-terminal pro-B-type natriuretic peptide; PA, primary aldosteronism; PAC, plasma aldosterone concentration; PRA, plasma renin activity.

Factors associated with NT-proBNP levels

In univariable linear regression analysis, NT-proBNP levels were significantly associated with age, sex, BMI, systolic blood pressure, estimated glomerular filtration rate (eGFR), post-CCT PAC, and post-CCT ARR, but not baseline with PAC or baseline ARR (Figure 2). All of these covariates were included in the multivariable regression analysis, where all associations remained significant. Notably, post-CCT PAC (β = 0.345, 95% confidence interval (CI): 0.145–0.544, p <0.001) and post-CCT ARR (β = 0.072, 95% CI: 0.002–0.143, p = 0.044) maintained significant associations with NT-proBNP levels after multivariable adjustment. The results of regression analyses are summarized in Table 2.

Figure 2.

The association between baseline PAC, post-CCT PAC, baseline ARR, post-CCT ARR, and the NT-proBNP level. Linear regression models showing the association of (a) log-transformed baseline PAC, (b) post-CCT PAC, (c) baseline ARR, and (d) post-CCT ARR with log-transformed NT-proBNP.

Table 2.

The predictors of NT-proBNP level.

Variables	Univariable linear regression		Multivariable linear regression
Variables	Beta (95% CI)	p Value	Beta (95% CI)	p Value
Age, year	0.013 (0.009, 0.016)	<0.001	0.008 (0.005, 0.012)	<0.001
Male, %	−0.226 (−0.319, −0.132)	<0.001	−0.212 (−0.299, −0.124)	<0.001
BMI, kg/m²	−0.018 (−0.029, −0.007)	0.001	−0.018 (−0.028, −0.007)	0.001
Diabetes mellitus, %	0.061 (−0.071, 0.193)	0.367
Dyslipidemia, %	0.037 (−0.062, 0.136)	0.464
Smoking, %	0.029 (−0.130, 0.188)	0.720
SBP, mmHg	0.003 (0.001, 0.005)	0.003	0.004 (0.002, 0.006)	<0.001
DBP, mmHg	0.002 (−0.002, 0.005)	0.305
eGFR, mL/min/1.73 m²	−0.006 (−0.008, −0.004)	<0.001	−0.005 (−0.007, −0.003)	<0.001
Potassium, mmol/L	−0.095 (−0.195, 0.006)	0.065
Log baseline PAC	−0.023 (−0.241, 0.195)	0.836
Log baseline PRA	−0.047 (−0.151, 0.057)	0.372
Log baseline ARR	0.032 (−0.059, 0.123)	0.488
Log post-CCT PAC	0.371 (0.149, 0.593)	0.001	0.345 (0.145, 0.544)	<0.001
Log post-CCT PRA	−0.062 (−0.144, 0.019)	0.133
Log post-CCT ARR	0.105 (0.026, 0.184)	0.009	0.072 (0.002, 0.143)	0.044

ARR, aldosterone to renin ratio; BMI, body mass index; CCT, captopril challenge test; CI, confidence interval; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; NT-proBNP, N-terminal pro-B-type natriuretic peptide; PAC, plasma aldosterone concentration; PRA, plasma renin activity; SBP, systolic blood pressure.

Associations of sex and BMI with NT-proBNP levels

In the multivariable linear regression model, sex and BMI were significantly associated with NT-proBNP levels in patients with PA. Given that these associations might influence the interpretation and normal thresholds of NT-proBNP in this population, we performed subgroup analyses to further explore the relationships between sex, BMI, and NT-proBNP levels in patients with PA.

Baseline characteristics comparing men and women are summarized in Table S1, while those comparing patients with BMI lower or higher than 25 kg/m² are presented in Table S2. A BMI ⩾25 kg/m² was defined as obesity according to the criteria for Asian populations. Compared with women, men had a higher BMI, higher systolic and diastolic blood pressure, lower eGFR, and lower NT-proBNP levels (38.2 pg/mL (IQR: 15.4–75.0) vs 64.9 pg/mL (IQR: 37.0–112.5), p < 0.001). Patients with a BMI ⩾25 kg/m² were predominantly male and had higher systolic and diastolic blood pressure, greater use of antihypertensive medications, and lower NT-proBNP levels (43.5 pg/mL (IQR: 17.8–78.0) vs 60.0 pg/mL (IQR: 32.5–115.9), p < 0.001). Notably, post-CCT PAC and ARR levels were comparable between sexes and between patients with BMI below or above 25 kg/m².

We further explored the associations between sex, BMI, and post-CCT PAC. Patients were divided into two groups based on post-CCT PAC levels in the overall cohort, and subgroup analyses were performed according to sex and BMI categories (⩾25 and <25 kg/m²). In the overall patient cohort, the NT-proBNP level was significantly higher in patients with higher post-CCT PAC (58.1 pg/mL (IQR: 31.7–113.3) vs 44.8 pg/mL (IQR: 16.9–87.8), p = 0.005; Figure 3(a)). This association between NT-proBNP and post-CCT PAC remained significant in all the subgroup of including women (68.0 pg/mL (IQR: 43.2–131.3) vs 52.1 pg/mL (IQR: 30.7–108.8), p = 0.031; Figure 3(b)), men (41.4 pg/mL (IQR: 22.5–89.0) vs 33.1 pg/mL (IQR: 12.7–63.7), p = 0.017; Figure 3(c)) patients with BMI < 25 (76.2 pg/mL (IQR: 39.3–137.1) vs 49.5 pg/mL (IQR: 28.9–103.3), p = 0.015; Figure 3(d)), and BMI ⩾25 (44.6 pg/mL (IQR: 27.2–86.7) vs 37.5 pg/mL (IQR: 13.8–71.2), p = 0.012; Figure 3(e)). The same analyses were done to investigate the relationships between sex, BMI, and post-CCT ARR. NT-proBNP level was significantly higher in patients with higher post-CCT ARR in the overall cohort (p = 0.017). The significance was maintained in men (p = 0.019) and those with a BMI ≥25 (p = 0.024), but not in women (p = 0.161) and those with a BMI < 25 (p = 0.173). The results of post-CCT ARR median split analyses are summarized in Figure S1.

Figure 3.

Stratification of NT-proBNP levels by post-CCT PAC, sex, and BMI. Log-transformed NT-proBNP levels in groups stratified by post-CCT PAC. Participants were divided into a lower PAC group (⩽median) and a higher PAC group (>median). Comparisons are shown for (a) the overall cohort, (b) women, (c) men, (d) participants with BMI < 25 kg/m², and (e) participants with BMI ⩾25 kg/m².

To assess the combined effects of sex and BMI, NT-proBNP levels were compared across four sex-BMI subgroups. The Kruskal–Wallis test revealed significant differences among the groups, with female patients with BMI < 25 exhibiting significantly higher NT-proBNP levels (77.3 pg/mL (IQR: 42.7–127.2)) compared to the other three subgroups (Figure 4). This analysis was intended to illustrate known sex- and adiposity-related differences in NT-proBNP levels rather than to imply differential aldosterone-mediated cardiovascular risk.

Figure 4.

Combined effects of sex and BMI on NT-proBNP levels. Log-transformed NT-proBNP levels in groups stratified by sex and BMI.

The relationships between NT-proBNP levels and cardiac structure under echocardiography

Echocardiographic data were available for 258 patients in this study population. Serial regression analyses were performed in this subgroup across four sequential models (Table 3). In the multivariable regression analysis, log-transformed NT-proBNP levels were significantly associated with LVMI (β = 0.002; 95% CI: 0.001–0.003; p = 0.001) and the E/e′ ratio (β = 0.032; 95% CI: 0.014–0.050; p < 0.001) after adjustment for age, sex, BMI, systolic blood pressure, eGFR, and log-transformed post-CCT PAC. This finding established the association between NT-proBNP levels and cardiac remodeling and diastolic dysfunction in patients with PA, and also the potential clinical implications. Clinical characteristics comparing patients with and without available echocardiographic data are summarized in Table S3. Patients with echocardiographic data had significantly higher BMI, blood pressure, antihypertensive medication use, NT-proBNP levels, baseline ARR, and post-CCT PAC, ARR and significantly lower potassium level, baseline PRA and post-CCT PRA.

Table 3.

Associations of NT-proBNP with LVMI and E/e′.

Log NT-proBNP (N = 258)	LVMI		Diastolic function (E/e′)
Log NT-proBNP (N = 258)	Beta (95% CI)	p Value	Beta (95% CI)	p Value
Model 1	0.002 (0.001, 0.003)	<0.001	0.054 (0.036, 0.071)	<0.001
Model 2	0.002 (0.001, 0.003)	<0.001	0.046 (0.028, 0.064)	<0.001
Model 3	0.002 (0.001, 0.003)	<0.001	0.035 (0.018, 0.053)	<0.001
Model 4	0.002 (0.001, 0.003)	0.001	0.032 (0.014, 0.050)	<0.001

Model 1: No adjustment. Model 2: Adjust with age, sex, and BMI. Model 3: Adjust with age, sex, BMI, SBP. eGFR. Model 4: Adjust with age, sex, BMI, SBP. eGFR, log post-CCT PAC.

BMI, body mass index; CCT, captopril challenge test; CI, confidence interval; E/e′, the ratio of early mitral inflow velocity to early diastolic mitral annular velocity; eGFR, estimated glomerular filtration rate; LVMI, left ventricular mass index; NT-proBNP, N-terminal pro-B-type natriuretic peptide; PAC, plasma aldosterone concentration; SBP, systolic blood pressure.

Discussion

This study yields three important findings. First, we established an association between the degree of renin-independent and autonomous aldosterone production, as indicated by post-CCT PAC, post-CCT ARR, and NT-proBNP levels in patients with PA. Second, sex and BMI were found to influence NT-proBNP levels, with higher levels observed in female patients and those with a BMI below 25 kg/m². Third, elevated NT-proBNP levels were associated with more pronounced cardiac hypertrophy and diastolic dysfunction. Together, these findings suggest that NT-proBNP is a biomarker linked not only to autonomous aldosterone production but also to adverse cardiac remodeling and dysfunction in patients with PA. However, interpretation of NT-proBNP levels should account for sex and BMI, as they may confound the results.

NT-proBNP is a well-established biomarker of myocardial wall stress and has been shown to independently predict cardiovascular outcomes.^21,22 In our study, NT-proBNP serum levels were significantly associated with post-CCT PAC and post-CCT ARR, but not with baseline PAC or baseline ARR. This supports the idea that post-CCT indices, markers of renin-independent, autonomous aldosterone secretion, are more relevant to aldosterone-induced cardiac damages.^8,17 Despite baseline PAC and ARR are commonly used as diagnostic criteria of PA,¹ they can be influenced by numerous physiological factors, including posture, fluid status, circadian rhythm, and medication use, leading to substantial variability in both aldosterone and renin measurements.^33
–38 Thus, baseline PAC may not reliably indicate the magnitude of sustained autonomous aldosterone excess that drives chronic cardiovascular injury.

By contrast, post-CCT PAC and post-CCT ARR assess aldosterone secretion under standardized suppression of the renin-angiotensin-aldosterone system; therefore, they more accurately indicate the sustained pathological aldosterone excess associated with long-term cardiovascular damage.^8,39,40 A recent study also revealed the superior predictive value of post-CCT PAC for LV remodeling, diastolic dysfunction, and the therapeutic effects in PA patients, indicating its potential utility as an indicator of cardiovascular involvement and clinical risk stratification.^8,17 Consistent with these observations, our findings show that post-CCT measures, including particularly post-CCT PAC and post-CCT ARR, better predict elevated NT-proBNP levels than baseline measures.

Excessive aldosterone may elevate NT-proBNP levels through several pathways. First, the physiological effect of aldosterone on renal sodium retention increases intravascular volume and cardiac preload, contributing to ventricular wall stress and NT-proBNP release. Second, aldosterone shows direct effects on the myocardium, promoting hypertrophy and fibrosis by increasing extracellular matrix deposition.^4,41
–44 In individuals with PA, concurrent autonomous cortisol secretion is also common and may further contribute to cardiovascular remodeling.^1,23,45,46 These pathological remodeling contributes to diastolic dysfunction and increased myocardial wall stress, both of which can contribute to the elevation of NT-proBNP levels.⁴⁷ Our finding of a significant association between NT-proBNP levels and both LVMI and the E/e′ ratio reinforces the link between autonomous aldosterone production, NT-proBNP, and cardiac remodeling.

Interestingly, recent studies in normotensive populations suggest that aldosterone may suppress NT-proBNP expression via inhibition of CREB phosphorylation in cardiomyocytes.^24,48 In addition, a recent study demonstrated the maladaptive natriuretic peptide in patients with subclinical PA.²⁴ These findings imply that while elevated NT-proBNP in PA likely reflects aldosterone-driven cardiac remodeling and secondary myocardial stress, the interaction between aldosterone and NT-proBNP production is complex and not yet fully understood. Further mechanistic studies are warranted to elucidate these pathways.

Sex and BMI may act as confounding factors in the interpretation of NT-proBNP levels. Female sex and lower BMI were observed to have higher NT-proBNP serum levels in our cohort, consistent with prior studies.^49
–54 Multiple studies demonstrate that NT-proBNP levels were associated with lower testosterone levels, increased sex hormone binding globulin concentrations, and subsequent alteration in neprilysin activity.^50
–54 Obesity, on the other hand, exhibited lower NT-proBNP levels due to natriuretic peptide deficiency.^49,54,55 The combination of female sex and lower BMI, therefore, likely contributes to higher observed NT-proBNP in this subgroup. However, NT-proBNP distributions differ by sex and adiposity, which can also modify the prognostic interpretation of measured NT-proBNP concentrations.⁵⁶ Recent studies demonstrated that the best cutoffs of NT-proBNP for prognostic prediction were lower as BMI increased, and similar issues were being discussed in sex differences.^56
–58 To account for these potential confounders, we adjusted for sex and BMI in our analyses, and the association between NT-proBNP and post-CCT indices remained robust. These findings highlight the importance of interpreting NT-proBNP levels in the context of sex and body composition, despite its consistently strong prognostic value across populations.^57,58

Finally, although the CCT is no longer emphasized as a confirmatory test for the diagnosis of PA based on recent studies and guideline,^{1,36,59
–61} the present findings highlight that post-CCT indices still carry important physiological and clinical information. Specifically, its strong association with NT-proBNP and cardiac remodeling suggests that the post-CCT response may reflect the degree of sustained renin-independent aldosterone activity and consequent myocardial stress. Therefore, while CCT may no longer be required for case detection, post-CCT PAC and ARR could remain useful for risk stratification or prognostic assessment in clinical practice.

This study has several limitations. First, although the cohort was prospectively maintained, the analysis was retrospective, which may introduce selection bias and unmeasured confounding. Second, a substantial number of PA patients were excluded due to missing NT-proBNP or CCT data, potentially limiting the generalizability of the findings. Third, echocardiographic data were only available in a subset of patients, who exhibited higher aldosterone levels and NT-proBNP concentrations, possibly reflecting a more severe clinical disease. Fourth, our study did not include long-term follow-up or treatment monitoring, limiting the assessment of the prognostic value of NT-proBNP in patients with PA. Fifth, potential confounding factors influencing NT-proBNP levels other than sex and BMI were not fully analyzed in this study. Finally, while our study established a cross-sectional association between autonomous aldosterone production, NT-proBNP levels, and cardiac remodeling, it does not confirm a causal relationship. Further longitudinal and mechanistic studies are warranted to elucidate the underlying pathways.

Conclusion

This study demonstrated that NT-proBNP is associated with autonomous aldosterone production, and it could serve as an indicator of subclinical cardiovascular involvement in patients with PA in clinical practice. In addition, female sex and lower BMI were found to influence NT-proBNP levels, highlighting the importance of considering these factors when interpreting NT-proBNP in this population. From a clinical perspective, NT-proBNP could aid in risk stratification and potentially guide surgical treatment or the use of mineralocorticoid receptor antagonists, which have been shown to be effective in patients with PA. Early identification and treatment of these patients may attenuate or reverse cardiac remodeling, reduce long-term cardiovascular risk, and improve clinical outcomes.

Supplemental Material

sj-docx-1-tae-10.1177_20420188261448647 – Supplemental material for NT-proBNP and its association with autonomous aldosterone production in primary aldosteronism

Supplemental material, sj-docx-1-tae-10.1177_20420188261448647 for NT-proBNP and its association with autonomous aldosterone production in primary aldosteronism by No-Ting Lin, Cheng-Hsuan Tsai, Yu-Ching Chang, Uei-Lin Chen, Yi-Yao Chang, Tsung-Yan Chen, Xue-Ming Wu, Che-Wei Liao, Chin-Chen Chang, Bo-Ching Lee, Ching-Chu Lu, Zheng-Wei Chen, Jeff S. Chueh, Vin-Cent Wu, Yen-Hung Lin and Hung Chi-Sheng in Therapeutic Advances in Endocrinology and Metabolism

Footnotes

Acknowledgements

We thank the staff of the Eighth and Second Core Lab in the Department of Medical Research at National Taiwan University Hospital for technical support. We also thank all members of the TAIPAI Study Group () for help during the study.

Declarations

ORCID iD

Cheng-Hsuan Tsai

Supplemental material

Supplemental material for this article is available online.

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