Aldosterone and Impaired Nocturnal Blood Pressure Decline in Primary Aldosteronism

Abstract

Background

The loss of physiological nocturnal blood pressure (BP) decline is a major contributor to cardiovascular risk, yet its endocrine underpinnings in primary aldosteronism (PA) remain underexplored. This study aimed to elucidate the dose‐dependent relationship between aldosterone excess and circadian BP rhythm disruption and assess whether targeted aldosterone suppression could ameliorate nocturnal dipping.

Methods

We prospectively analyzed 24‐hour ambulatory BP data from 681 patients with confirmed PA, stratified by plasma aldosterone concentration. A subset of 99 patients with adrenal vein sampling–confirmed unilateral PA received targeted, minimally invasive vascular intervention for aldosterone suppression and were evaluated for changes in BP rhythm on the basis of treatment response.

Results

In multivariable‐adjusted models, both log‐transformed plasma aldosterone concentration and aldosterone‐to‐renin ratio were inversely associated with the proportion of nocturnal systolic BP decline (log plasma aldosterone concentration: β=−0.054 [95% CI, −0.087 to −0.020]; P=0.002; log aldosterone‐to‐renin ratio: β=−0.016 [95% CI, −0.025 to −0.006]; P=0.001). In patients achieving biochemical remission after selective suppression, nighttime systolic BP decreased significantly (mean reduction=−33 mm Hg; Cohen’s d_z=2.113). The prevalence of the dipper pattern increased from 14.5% to 39.1% (P<0.001), while no rhythm improvement was observed in nonresponders. Multivariable regression confirmed biochemical success as an independent predictor of nocturnal dip amelioration (P=0.045), irrespective of adrenal imaging phenotype.

Conclusions

Aldosterone excess contributes directly to circadian BP rhythm disruption in PA. Selective hormonal suppression can ameliorate physiological BP dipping in responsive patients. These findings highlight the value of rhythm‐based end points and support aldosterone‐targeted modulation as a strategic goal in PA management.

Registration: URL: https://www.chictr.org.cn/; Unique Identifier: ChiCTR2200057297.

Clinical Perspective.

What Is New?

• We demonstrated a dose‐dependent relationship between aldosterone excess and impaired nocturnal blood pressure decline in patients with primary aldosteronism and showed that only those achieving biochemical success after selective aldosterone suppression experienced significant rhythm improvement.

What Are the Clinical Implications?

• Biochemical remission is the key determinant of circadian blood pressure recovery, highlighting circadian rhythm restoration as a clinically relevant end point in the management of primary aldosteronism.

Nonstandard Abbreviations and Acronyms

ARR

aldosterone‐to‐renin ratio

AVS

adrenal vein sampling

CCT

captopril challenge test

PA

primary aldosteronism

PAC

plasma aldosterone concentration

PRA

plasma renin activity

SAAE

selective adrenal arterial embolization

Circadian blood pressure (BP) rhythm, characterized by a physiological decline in nocturnal BP compared with daytime values is a critical component of cardiovascular homeostasis. ¹ A diminished or absent nocturnal BP decline has been independently associated with increased risks of target‐organ damage, cardiovascular morbidity, and all‐cause death, irrespective of absolute BP levels. ² , ³ , ⁴ Consequently, recent hypertension guidelines and expert consensus increasingly emphasize the clinical relevance of evaluating and managing circadian BP abnormalities. ¹ , ⁵

In patients with primary aldosteronism (PA), a common and potentially curable form of secondary hypertension, circadian BP regulation appears to be particularly disrupted. ⁶ , ⁷ , ⁸ Previous studies have reported that patients with PA exhibit higher nighttime BP levels, a lower prevalence of the dipper pattern, and a blunted nocturnal BP decline compared with those with essential hypertension. ⁶ , ⁸ These abnormalities are thought to result not only from sustained volume expansion but also from direct endocrine effects of aldosterone on vascular tone and possibly on circadian clock gene expression. ⁹ While many existing studies compare PA with non‐PA populations, such comparisons are often influenced by differences in comorbidities and medication use, which may obscure the specific role of aldosterone. Stratifying patients with PA by biochemical activity within a homogeneous PA cohort allows a more precise evaluation of this relationship.

While mineralocorticoid receptor antagonists may help ameliorate BP rhythm, ⁶ their effectiveness is often limited by side effects, incomplete biochemical control, or poor long‐term adherence. ¹⁰ , ¹¹ Surgical adrenalectomy is considered the standard treatment for unilateral PA, particularly in cases with a dominant‐side aldosterone‐producing adenoma, typically referring to a unilateral adrenal mass ≥1 cm that corresponds to the dominant side identified by AVS. However, it is increasingly recognized that patients without a distinct adenoma often exhibit heterogeneous pathologies such as micronodular or diffuse hyperplasia, which are associated with a broader range of biochemical and clinical outcomes following intervention, and further high‐quality research is needed to optimize management strategies in these subgroups. ¹² , ¹³

To specifically evaluate the physiological role of aldosterone in circadian BP regulation, this study focused on patients with AVS‐confirmed unilateral PA, a well‐characterized population in whom the source of aldosterone excess is anatomically localized. Within this group, selective adrenal arterial embolization (SAAE) was adopted as a targeted, minimally invasive approach to reduce aldosterone production, particularly in patients who were not candidates for or declined adrenalectomy. ¹⁴ , ¹⁵ , ¹⁶ This approach enabled us to assess the effects of aldosterone reduction across the full spectrum of patients with unilateral PA, encompassing both those with and without radiologically visible adenomas. ¹⁷ , ¹⁸ Moreover, by providing a pathophysiological precise means of suppressing aldosterone independent of systemic pharmacologic therapy, this strategy offers valuable insights into the broader potential of targeted aldosterone reduction as an intervention to modify BP rhythmicity.

Methods

Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Patient Enrollment and Follow‐Up

The patient enrollment process is detailed in Figure 1. A total of 681 patients with confirmed PA were prospectively enrolled from the Department of Cardiovascular Medicine at the Second Affiliated Hospital of Nanchang University between January 2020 and June 2023. The diagnosis of PA was established according to the 2024 Chinese expert consensus, including an elevated aldosterone‐to‐renin ratio (ARR >30 ng/dL per ng/mL per h) followed by confirmatory testing using either the captopril challenge test (CCT) or saline infusion test. ¹⁹ Before confirmatory testing, interfering antihypertensive medications, including mineralocorticoid receptor antagonists, other diuretics, angiotensin‐converting enzyme inhibitors, angiotensin II receptor blockers, β blockers, and central α₂ agonists, which were withdrawn or replaced with nondihydropyridine calcium channel blockers (eg, verapamil, diltiazem) or α blockers (eg, doxazosin, terazosin) for 2 to 4 weeks. Adrenal computed tomography (CT) was performed in all patients to assess adrenal morphology. Bilateral AVS without adrenocorticotropic hormone stimulation was used to determine lateralization, and a lateralization index ≥2.0 was defined as unilateral aldosterone excess. ¹⁹ All patients underwent 24‐hour ambulatory BP monitoring at baseline using a validated oscillometric device (TeleABP, BI5000; Biomedical Instruments, Shenzhen, China), with measurements every 20 minutes during the daytime (07:00 am to 9:59 pm) and every 30 minutes at night (10:00 pm to 6:59 am). Nocturnal systolic blood pressure (SBP) dip proportion was calculated as (daytime SBP − nighttime SBP)/daytime SBP, and patients were classified as “dippers” if the decline was ≥10%, or “nondippers” otherwise. Obstructive sleep apnea status was collected on the basis of patient self‐report during telephone follow‐up, as routine polysomnography screening was not performed in all patients.

Figure 1. Patient enrollment and follow‐up flowchart.

ABPM indicates ambulatory blood pressure monitoring; AVS, adrenal vein sampling; MRA, mineralocorticoid receptor antagonist; PA, primary aldosteronism; PRA, plasma renin activity; and SAAE, selective adrenal arterial embolization.

For the analysis of circadian BP rhythm after targeted aldosterone suppression, we focused on patients with unilateral PA confirmed by AVS (lateralization index ≥2.0) who underwent SAAE, ²⁰ a targeted intervention aimed at reducing aldosterone production, and had complete follow‐up data. Patients with bilateral PA were excluded to ensure consistency of disease subtypes and to address heterogeneity in aldosterone sources. Only cases with complete follow‐up ambulatory BP monitoring and biochemical reassessment were eligible for inclusion. From the full cohort of 681 patients with confirmed PA, 363 underwent SAAE. Among these, 99 patients met the inclusion criteria and were included in the final analysis. Patients with unilateral PA were eligible for SAAE only if they refused adrenalectomy. The detailed procedure of SAAE has been described previously. ¹⁵ , ²¹ Among these patients, 22 had unilateral adrenal adenoma ≥1 cm on CT located on the dominant side (ie, dominant‐side adenoma), while the remaining 77 had no dominant‐side adenoma. Dominant‐side adenoma was defined as the presence of a unilateral adrenal mass ≥1 cm on CT imaging that corresponded to the dominant side identified by AVS. The median duration of follow‐up was 6 months. Biochemical outcomes were categorized as complete, partial, or absent biochemical success on the basis of PA surgical outcome criteria, ²² and patients were further stratified into responders (complete or partial biochemical success) and nonresponders.

The study protocol was approved by the Ethics Committee of the Second Affiliated Hospital of Nanchang University and all participants provided written informed consent. This study was registered in the Chinese Clinical Trial Registry (ChiCTR2200057297).

Clinical Indexes

Plasma aldosterone concentration (PAC) and plasma renin activity (PRA) were measured using a fully automated chemiluminescence immunoassay system (MAGLUMI 4000 Plus; New Industries Biomedical Engineering Co., Ltd., Shenzhen, China). The PAC was measured using the MAGLUMI Aldosterone Chemiluminescence Kit (New Industries Biomedical Engineering Co., Ltd.). PRA was measured by dividing plasma samples into 2 parts: One part was used to determine plasma angiotensin I concentration at 4 °C, while the other part was incubated at 37 °C for 1 hour to determine plasma angiotensin II concentration. PRA was calculated using the formula (angiotensin II − angiotensin I)/h. Angiotensin I levels were measured using the MAGLUMI Angiotensin I Chemiluminescence Kit (New Industries Biomedical Engineering Co., Ltd.). Serum potassium, creatinine, and other biochemical data were measured by the hospital’s central laboratory.

Clinical and Biochemical Outcomes

Clinical and biochemical outcomes were assessed based on the PA surgical outcome criteria. ²² Ambulatory BP monitoring was used to evaluate clinical success in this study. Complete clinical success was defined as normalized BP without the use of antihypertensive medication. Partial clinical success was defined as a reduction in BP after using fewer or the same number of antihypertensive medications compared with baseline. Lack of clinical success was defined as unchanged or elevated BP despite the same or an increased dosage of antihypertensive medications. Complete biochemical success was defined as the correction of hypokalemia and normalization of the ARR. Partial biochemical success was defined as a reduction in baseline plasma aldosterone concentration by ≥50%, along with the correction of hypokalemia, despite an increase in the ARR. Lack of biochemical success was defined as persistent hypokalemia or an elevated ARR, with <50% reduction in baseline plasma aldosterone concentration.

Statistical Analysis

Continuous variables were assessed for distribution using visual inspection (histograms, quantile–quantile plots) and statistical tests. Homogeneity of variance was evaluated with Levene’s test. Between‐group comparisons were performed as follows: for ≥3 groups, 1‐way ANOVA (equal variance) or Welch’s ANOVA (unequal variance) was used for approximately normal data, and the Kruskal–Wallis test for severely skewed distributions; for comparisons between 2 independent groups, independent samples t tests (with Welch’s correction for unequal variances) or the Mann–Whitney U test was used on the basis of distributional properties. For within‐subject paired comparisons, normality of change scores was assessed. Paired t tests or Wilcoxon signed‐rank tests were used accordingly. Between‐group differences in change scores were compared using independent‐samples t tests or the Mann–Whitney U test. ANCOVA was additionally performed for key outcomes to adjust for potential baseline differences. Categorical variables were summarized as frequencies and percentages and compared using the χ² or Fisher’s exact test, as appropriate. The McNemar test was used for paired dichotomous outcomes. Differences in the change in proportion of these outcomes between 2 groups were compared using the χ² test. Multivariable linear regression with robust standard errors was used to examine associations between log‐transformed aldosterone measures (PAC, ARR, post‐CCT PAC, post‐CCT ARR) and the nocturnal SBP decline proportion. Three models with sequential adjustments were fitted: model 1: unadjusted; model 2: adjusted for sex, age, and body mass index (BMI); model 3: fully adjusted for all covariates in model 2 plus chronic kidney disease, coronary heart disease, diabetes, stroke, obstructive sleep apnea, duration of hypertension, antihypertensive drug use, serum potassium, serum sodium, 24‐hour SBP, and 24‐hour diastolic blood pressure (DBP). Covariates were selected on the basis of their clinical importance, statistical significance in the univariable analysis, and the potential confounders effect estimates individually changed by at least 10%. Variance inflation factors were all <10, indicating no substantial multicollinearity. To identify factors associated with changes in nocturnal SBP decline after SAAE, univariable and multivariable linear regression were performed. The selection of covariates for the multivariable model followed the same procedure as described above, ultimately including age, sex, BMI, baseline PAC, baseline nocturnal SBP decline proportion, and biochemical and clinical success. A tiered approach guided multiple comparisons. The change in nocturnal SBP decline proportion was the sole primary outcome and was not corrected for multiple testing. The dipper pattern prevalence was exploratory and also exempt from correction. The 6 ambulatory BP parameters (24‐hour, daytime, and nighttime SBP and DBP) and the 4 biochemical parameters (serum potassium, PAC, PRA, ARR) were prespecified as separate families of secondary outcomes. A Bonferroni correction was applied within each family, yielding significance thresholds of P<0.0083 for BP outcomes and P<0.0125 for biochemical outcomes. Analyses were conducted using SPSS 26.0 (IBM Corporation, Armonk, NY) and R 4.3.3 (R Foundation for Statistical Computing, Vienna, Austria). Figures were created with Prism 9.0 (GraphPad Software, La Jolla, CA).

Results

Baseline Characteristics of Patients With PA Stratified by Log‐Transformed PAC Levels

A total of 681 patients with confirmed PA were stratified into tertiles on the basis of log‐transformed PAC (log PAC): tertile 1 (<1.30), tertile 2 (1.30–1.47), and tertile 3 (>1.47). As shown in Table 1, there were no significant differences in age, sex, or BMI among the 3 groups.

Table 1.

Baseline Characteristics of the Patients With PA

Variables	Log PAC			P value
	Tertile 1 (<1.30)	Tertile 2 (1.30–1.47)	Tertile 3 (>1.47)
Case number, n	225	231	225
Sex, male, n (%)	126 (56.00)	130 (56.28)	123 (54.67)	0.934
Age, y, mean±SD	50.38±9.73	50.31±10.02	49.46±11.36	0.606
BMI, kg/m2, median (IQR)	26.04 (23.88 to 28.23)	25.71 (23.77 to 27.64)	25.19 (23.07 to 27.55)	0.082
Duration of hypertension, mo, median (IQR)	24 (3 to 84)	48 (8 to 120)	60 (9 to 120)	<0.001
Using antihypertensive drugs, n (%)	51 (22.67)	67 (29.00)	87 (38.67)	<0.001
Diabetes, n (%)	29 (12.89)	28 (12.12)	23 (10.22)	0.664
Chronic kidney disease, n (%)	17 (7.56)	14 (6.06)	24 (10.67)	0.185
Stroke, n (%)	9 (4.00)	10 (4.33)	22 (9.78)	0.015
Coronary heart disease, n (%)	10 (4.44)	7 (3.03)	7 (3.11)	0.657
Obstructive sleep apnea, n (%)	29 (12.89)	26 (11.26)	30 (13.33)	0.778
Serum potassium, mmol/L, mean±SD	3.78±0.40	3.77±0.40	3.46±0.50	<0.001
Serum sodium, mmol/L, median (IQR)	141.30 (139.90 to 142.50)	140.90 (139.59 to 142.60)	141.68 (140.04 to 143.20)	0.017
PAC, ng/dL, median (IQR)	15.85 (13.55 to 18.24)	24.10 (21.85 to 26.50)	39.52 (33.86 to 53.45)	<0.001
PRA, ng/mL per h, median (IQR)	0.14 (0.02 to 0.33)	0.28 (0.04 to 0.59)	0.16 (0.02 to 0.65)	<0.001
ARR, (ng/dL)/(ng/mL per h), median (IQR)	106.00 (44.59 to 521.00)	92.67 (40.16 to 668.00)	255.58 (60.80 to 1830.00)	<0.001
Serum creatinine, μmol/L, median (IQR)	73.89 (60.55 to 87.80)	73.90 (60.98 to 88.16)	78.34 (61.70 to 95.41)	0.075
24‐h SBP, mm Hg, mean±SD	142±15	143±16	147±17	<0.001
24h DBP, mm Hg, mean±SD	86±11	88±12	89±12	0.101
Daytime SBP, mm Hg, mean±SD	143±16	144±17	148±17	0.006
Daytime DBP, mm Hg, mean±SD	88±11	89±12	90±12	0.254
Nighttime SBP, mm Hg, mean±SD	137±18	139±18	145±20	<0.001
Nighttime DBP, mm Hg, mean±SD	81±12	84±12	85±12	0.006
Proportion of nocturnal SBP decline, median (IQR)	0.05 (0.01 to 0.10)	0.04 (−0.02 to 0.08)	0.02 (−0.03 to 0.08)	0.001
Dipper proportion of blood pressure rhythm, n (%)	54 (24.00)	41 (17.75)	37 (16.44)	0.095

P value <0.05 was considered statistically significant.

ARR indicates aldosterone‐to‐renin ratio; BMI, body mass index; DBP, diastolic blood pressure; IQR, interquartile range; PA, primary aldosteronism; PAC, plasma aldosterone concentration; PRA, plasma renin activity; and SBP, systolic blood pressure.

The proportion of nocturnal SBP decline progressively decreased across PAC tertiles (P=0.001), indicating a negative association between aldosterone level and circadian BP rhythm. Similarly, nighttime SBP increased stepwise with higher PAC levels (P<0.001), with corresponding increases in 24‐hour and daytime SBP as well. Although the prevalence of dipper pattern declined numerically across groups (24.00% in tertile 1 to 16.44% in tertile 3), the difference did not reach statistical significance (P=0.095).

Biochemically, a graded increase in PAC and ARR was observed from tertile 1 to tertile 3 (median PAC, 15.85 to 39.52 ng/dL; ARR, 106.00 to 255.58; P<0.001 for both), accompanied by a significant decrease in serum potassium (from 3.78 to 3.46 mmol/L; P<0.001). These findings are consistent with the known pathophysiological effects of aldosterone excess.

Other clinical characteristics such as duration of hypertension, antihypertensive drug use, and stroke history also showed differences among groups, with patients in tertile 3 having longer disease duration (60 versus 24 months) and higher antihypertensive drug use (38.67% versus 22.67%) compared with tertile 1, as well as a higher prevalence of stroke. No significant differences were noted in the prevalence of diabetes, coronary heart disease, obstructive sleep apnea, or chronic kidney disease.

Association of Log‐Transformed PAC and ARR With Nocturnal BP Decline in Patients With PA

Multivariable linear regression analyses were conducted to evaluate the association between log PAC, log ARR, and the proportion of nocturnal SBP decline in patients with PA (Table 2). In the fully adjusted model (adjustment II), log PAC was negatively associated with nocturnal SBP decline (β=−0.054 [95% CI: −0.087 to −0.020]; P=0.002). When stratified by tertiles, patients in the highest PAC tertile (tertile 3) had significantly lower nocturnal SBP decline compared with those in the lowest tertile (tertile 1) (β=−0.021 [95% CI, −0.038 to −0.005]; P=0.012), with a significant trend observed across tertiles (P for trend=0.010). Similarly, log ARR was also inversely associated with nocturnal SBP decline in the fully adjusted model (β=−0.016 [95% CI, −0.025 to −0.006]; P=0.001). In tertile‐based analysis, patients in the highest ARR tertile (tertile 3) had significantly lower nocturnal SBP decline compared with tertile 1 (β=−0.023 [95% CI, −0.040 to −0.007]; P=0.006), with a statistically significant trend across groups (P for trend=0.007). These associations remained consistent across unadjusted and partially adjusted models.

Table 2.

Multifactor Regression Analysis of Log PAC, Log ARR, and Proportion of Nocturnal SBP Decline in Patients With PA

Variables	PA group β/OR (95% CI) P value
	Not adjusted	Adjustment I	Adjustment II
Log PAC	−0.063 (−0.093 to −0.032) <0.001	−0.064 (−0.095 to −0.034) <0.001	−0.054 (−0.087 to −0.020) 0.002
Tertile 1	Reference	Reference	Reference
Tertile 2	−0.016 (−0.031 to 0.000) 0.051	−0.016 (−0.032 to −0.000) 0.048	−0.014 (−0.030 to 0.001) 0.074
Tertile 3	−0.027 (−0.043 to −0.012) 0.001	−0.029 (−0.044 to −0.013) <0.001	−0.021 (−0.038 to −0.005) 0.012
P for trend	0.001	<0.001	0.010
Log ARR	−0.021 (−0.030 to −0.012) <0.001	−0.019 (−0.028 to −0.010) <0.001	−0.016 (−0.025 to −0.006) 0.001
Tertile 1	Reference	Reference	Reference
Tertile 2	−0.008 (−0.023 to 0.008) 0.337	−0.005 (−0.021 to 0.010) 0.500	−0.002 (−0.019 to 0.014) 0.779
Tertile 3	−0.033 (−0.048 to −0.017) <0.001	−0.029 (−0.045 to −0.013) <0.001	−0.023 (−0.040 to −0.007) 0.006
P for trend	<0.001	<0.001	0.007

All multivariable linear regression models were fitted using robust standard errors. P value <0.05 was considered statistically significant. Adjustment I: adjusted for sex, age, and BMI. Adjustment II: adjusted for sex, age, BMI, chronic kidney disease, coronary heart disease, diabetes, stroke, obstructive sleep apnea, duration of hypertension, using antihypertensive drugs, serum potassium, serum sodium, 24‐h SBP, and 24‐h DBP.

ARR indicates aldosterone‐to‐renin ratio; BMI, body mass index; DBP, diastolic blood pressure; OR, odds ratio; PA, primary aldosteronism; PAC, plasma aldosterone concentration; and SBP, systolic blood pressure.

In supplementary analyses, higher post‐CCT PAC was inversely associated with nocturnal systolic BP decline. Log‐transformed post‐CCT PAC showed a significant negative correlation with nocturnal dipping both in unadjusted and fully adjusted models (β=−0.052, P<0.001; β=−0.039, P=0.009). Across tertiles, patients with higher post‐CCT PAC exhibited a progressively lower proportion of nocturnal BP decline, with the trend approaching significance after full adjustment (P for trend=0.071; Table S2).

Baseline BP Rhythm and Clinical Characteristics of PA Patients Undergoing SAAE, Stratified by Biochemical Outcomes

Among the 99 patients with unilateral PA who underwent SAAE, 69 were classified as biochemical responders and 30 as nonresponders according to the PA surgical outcome criteria (Table 3). There were no statistically significant differences between the 2 groups in sex distribution (P=0.089), age (0.382), BMI (P=0.052), duration of hypertension (P=0.463), or duration of follow‐up (P=0.695). The prevalence of diabetes, chronic kidney disease, stroke, and coronary heart disease was also comparable between groups. Biochemical indices, including baseline PAC (median, 25.99 versus 25.22 ng/dL), PRA (0.23 versus 0.04 ng/mL per h), serum potassium, and sodium levels, did not differ significantly between responders and nonresponders. Serum creatinine levels were slightly higher in responders (80.10 versus 67.30 μmol/L; P=0.103) but not statistically significant.

Table 3.

Baseline Characteristics of Patients With Responders and Nonresponders of Biochemical Success

Variable	Responders (n=69)	Nonresponders (n=30)	P value
Male sex, n (%)	49 (71.01)	16 (53.33)	0.089
Age, y, mean±SD	47.94±9.77	49.90±11.12	0.382
BMI, kg/m2, median (IQR)	27.18 (24.49 to 30.07)	25.31 (23.65 to 28.28)	0.052
Duration of hypertension, mo, median (IQR)	72 (24 to 120)	48 (24 to 120)	0.463
Duration of follow‐up, mo, median (IQR)	6 (1 to 12)	6 (1 to 12)	0.695
Diabetes, n (%)	12 (17.39)	6 (20.00)	0.757
Chronic kidney disease, n (%)	34 (49.28)	10 (33.33)	0.142
Stroke, n (%)	18 (26.09)	9 (30.00)	0.688
Coronary heart disease, n (%)	3 (4.35)	2 (6.67)	1.000
Serum potassium, mmol/L, median (IQR)	3.71 (3.25 to 3.97)	3.49 (3.23 to 3.73)	0.104
Serum sodium, mmol/L, median (IQR)	141.50 (140.34 to 143.20)	141.95 (141.09 to 143.10)	0.491
PAC, ng/dL, median (IQR)	25.99 (20.43 to 37.22)	25.22 (19.83 to 33.02)	0.306
PRA, ng/mL per h, median (IQR)	0.23 (0.02 to 0.54)	0.04 (0.02 to 0.15)	0.063
ARR, (ng/dL)/(ng/mL per h), median (IQR)	101.60 (49.43 to 920.79)	524.00 (159.00 to 1181.83)	0.066
Serum creatinine, μmol/L, median (IQR)	80.10 (66.33 to 95.30)	67.30 (60.20 to 87.80)	0.103
Clinical success, n (%)	40 (57.97)	15 (50.00)	0.463
24‐h SBP, mm Hg, mean±SD	152±14	150±12	0.528
24h DBP, mm Hg, mean±SD	94±11	93±11	0.594
Daytime SBP, mm Hg, mean±SD	153±14	152±13	0.739
Daytime DBP, mm Hg, mean±SD	94±15	95±12	0.845
Nighttime SBP, mm Hg, mean±SD	151±18	147±14	0.264
Nighttime DBP, mm Hg, mean±SD	91±11.07	88±11	0.285
Proportion of nocturnal SBP decline, median (IQR)	0.02 (−0.02 to 0.07)	0.04 (−0.01 to 0.08)	0.363
Dipper proportion of blood pressure rhythm, n (%)	10 (14.49)	5 (16.67)	0.768

P value <0.05 was considered statistically significant.

ARR indicates aldosterone‐to‐renin ratio; BMI, body mass index; DBP, diastolic blood pressure; IQR, interquartile range; PA, primary aldosteronism; PAC, plasma aldosterone concentration; PRA, plasma renin activity; and SBP, systolic blood pressure.

Ambulatory BP monitoring showed no significant differences in 24‐hour, daytime, or nighttime SBP and DBP between the 2 groups. Similarly, the baseline proportion of nocturnal SBP decline was comparable (median, 0.02 [interquartile range (IQR), −0.02 to 0.07] in responders versus 0.04 [IQR, −0.01 to 0.08] in nonresponders; P=0.363). The proportion of patients with a dipper BP pattern was 14.49% in responders and 16.67% in nonresponders (P=0.768).

Changes in Ambulatory BP and Circadian Rhythm Following Targeted Aldosterone‐Lowering Intervention

To evaluate the effect of targeted adrenal aldosterone suppression, we examined ambulatory BP and circadian rhythm changes before and after SAAE, a minimally invasive intervention aiming to reduce unilateral aldosterone overproduction. The results of this analysis, stratified by biochemical response, are summarized in Table 4 and illustrated in Figures 2 and 3.

Table 4.

Pre‐ and Post‐SAAE Ambulatory Blood Pressure Data of Patients With Responders and Nonresponders of Biochemical Success

Variable	Pre‐responders (n=69)	Post‐responders (n=69)	P value	△	Pre‐nonresponders (n=30)	Post‐nonresponders (n=30)	P value	△	P value*	P value†
24‐h SBP, mm Hg, mean±SD	152±14	125±9	<0.001	−27±15	150±12	133±14	<0.001	−17±15	0.004	0.001
24‐h DBP, mm Hg, mean±SD	94±11	79±6	<0.001	−15±10	93±11	84±10	<0.001	−9±11	0.013	0.002
Daytime SBP, mm Hg, mean±SD	153±14	127±10	<0.001	−26±16	152±13	135±14	<0.001	−17±15	0.020	0.003
Daytime DBP, mm Hg, mean±SD	94±15	81±7	<0.001	−13±15	95±12	86±10	<0.001	−9±12	0.233	0.013
Nighttime SBP, mm Hg, mean±SD	151±18	118±11	<0.001	−33±17	147±14	128±13	<0.001	−19±14	<0.001	<0.001
Nighttime DBP, mm Hg, mean±SD	91±11	73±11	<0.001	−18±14	88±11	79±8	<0.001	−9±11	0.004	0.004
Proportion of nocturnal SBP decline, median (IQR)	0.02 (−0.02, 0.07)	0.08 (0.02, 0.12)	<0.001	0.04 (0.01, 0.11)	0.04 (−0.01, 0.08)	0.05 (0.01, 0.08)	0.360	0.01 (−0.04, 0.07)	0.026	0.043
Dipper proportion of blood pressure rhythm, n (%)	10 (14.49)	27 (39.13)	<0.001		5 (12.82)	5 (12.82)	1.000		0.039

P value: within‐group comparison (pre‐ vs posttreatment).

DBP indicates diastolic blood pressure; IQR, interquartile range; and SBP, systolic blood pressure.

^* P value: between‐group comparison of pre–post change differences.

^† P value: adjusted for covariates.

Figure 2. Changes in 24‐hour, daytime, and nighttime SBP before and after SAAE in patients.

A, Twenty‐four‐hour SBP changes before and after SAAE in patients; (B) daytime SBP changes before and after SAAE in patients; (C) nighttime SBP changes before and after SAAE in patients. Data are presented as mean±SD. Statistical significance for within‐group comparisons was determined by paired‐samples t test. SAAE indicates selective adrenal arterial embolization; and SBP, systolic blood pressure.

Figure 3. Changes in nocturnal blood pressure decline proportion before and after SAAE in patients with responders and nonresponders of biochemical success.

A, Changes in nocturnal blood pressure decline proportion before and after SAAE in all patients; (B) changes in nocturnal blood pressure decline proportion before and after SAAE in responders; (C) changes in nocturnal blood pressure decline proportion before and after SAAE in nonresponders. Data are presented as median with interquartile range. P values are derived from Wilcoxon signed‐rank tests for within‐group comparisons. SAAE indicates selective adrenal arterial embolization; and SBP, systolic blood pressure.

In the biochemical responder group (n=69), 24‐hour SBP decreased significantly from 152±14 mm Hg to 125±9 mm Hg (P<0.001, Cohen’s d_z=2.233), and DBP from 94±11 mm Hg to 79±6 mm Hg (P<0.001, Cohen’s d_z=1.443). Daytime and nighttime BP also declined significantly. Nighttime SBP decreased from 151±18 mm Hg to 118±11 mm Hg (P<0.001, Cohen’s d_z=2.113), and nighttime DBP from 91±11 mm Hg to 73±11 mm Hg (P<0.001, Cohen’s d_z=1.243). These reductions are illustrated in Figure 2A through 2C. In the nonresponder group (n=30), significant reductions in ambulatory SBP and DBP were also observed across all time periods (all P<0.001), but the absolute changes were smaller compared with responders.

With respect to circadian rhythm, responders exhibited a significant increase in the proportion of nocturnal SBP decline, from a median of 0.02 (IQR, −0.02 to 0.07) to 0.08 (IQR, 0.02–0.12) after SAAE (P<0.001). The proportion of patients with a dipper BP pattern also increased from 14.49% to 39.13% (P<0.001), as shown in Figure 3B. In contrast, nonresponders showed no significant change in either nocturnal SBP dip proportion (0.04 [IQR, −0.01 to 0.08] to 0.05 [IQR, 0.01–0.08]; P=0.360) or dipper prevalence (12.82% before and after, P=1.000; Figure 3C). In the overall cohort, a significant increase in nocturnal BP dip was also observed after treatment (P<0.001; Figure 3A).

Between‐group comparisons revealed that responders had significantly greater improvements in nighttime BP parameters and circadian rhythm indices. The increase in nocturnal SBP dip proportion was greater in responders than nonresponders (Δ=0.04 [IQR, 0.01–0.11] versus 0.01 [IQR, −0.04 to 0.07]; P=0.026), and this difference remained significant after adjustment for baseline covariates (P=0.043). Similarly, the reduction in nighttime SBP was more pronounced in the responder group (P<0.001; Cohen’s d=0.806), as was the reduction in nighttime DBP (P=0.004; Cohen’s d=0.649).

Among patients with a lateralization index ≥4, biochemical responders exhibited a significant increased nocturnal SBP dip proportion and dipper prevalence, whereas nonresponders showed no such improvement (Table S4). Similarly, when restricting the analysis to patients with the contralateral suppression index ≥1, only biochemical responders demonstrated consistent improvements in circadian rhythm indices (Table S5).

Predictors of Improvement in Nocturnal SBP Decline After Targeted Aldosterone‐Lowering Intervention

To identify factors associated with changes in nocturnal BP rhythm following SAAE, univariable and multivariable linear regression analyses were conducted (Table 5). In univariable analysis, baseline nocturnal SBP dip proportion was negatively associated with subsequent improvement (β=−0.810 [95% CI, −0.963 to −0.657]; P<0.001), indicating that patients with a lower baseline dip exhibited greater increases after treatment. Biochemical success was positively associated with improvement in nocturnal BP rhythm (β=0.042 [95% CI, 0.003–0.080]; P=0.029). Other baseline variables, including age, sex, BMI, PAC, and clinical success, were not significantly associated with changes in BP rhythm. In the multivariable model adjusted for age, sex, BMI, baseline PAC, and clinical success, both baseline nocturnal SBP decline (β=−0.805 [95% CI, −0.973 to −0.637]; P<0.001) and biochemical success (β=0.030 [95% CI, 0.001 to 0.059]; P=0.045) remained independently associated with change in nocturnal SBP decline. No other variables retained significance in the fully adjusted model.

Table 5.

Univariate and Multivariate Linear Regression of the Proportion of Nocturnal SBP Decline Changes

Variable	Univariate		Multivariate
	β (95% CI)	P value	β (95% CI)	P value
Male, n (%)	0.011 (−0.027 to 0.049)	0.546	−0.010 (−0.037 to 0.018)	0.473
Age, y	0.001 (−0.001 to 0.003)	0.294	0.000 (−0.001 to 0.001)	0.877
BMI, kg/m2	0.002 (−0.003 to 0.006)	0.402	0.001 (−0.003 to 0.004)	0.664
PAC, ng/dL	0.000 (−0.000 to 0.001)	0.491	0.000 (−0.000 to 0.001)	0.607
Baseline proportion of nocturnal SBP decline	−0.810 (−0.963 to 0.657)	<0.001	−0.805 (−0.973 to −0.637)	<0.001
Biochemical success, n (%)	0.042 (0.003 to 0.080)	0.029	0.030 (0.001 to 0.059)	0.045
Clinical success, n (%)	0.015 (−0.021 to 0.052)	0.393	−0.006 (−0.032 to 0.020)	0.686

All multivariable linear regression models were fitted using robust standard errors. P value <0.05 was considered statistically significant.

BMI indicates body mass index; PAC, plasma aldosterone concentration; and SBP, systolic blood pressure.

Changes in Ambulatory Biochemical Indicators Before and After SAAE in Biochemical Responders and Nonresponders

Changes in key biochemical parameters before and after SAAE, stratified by biochemical response, are presented in Table S1. In the biochemical responder group (n=69), serum potassium levels increased significantly from a median of 3.71 mmol/L (IQR, 3.25–3.97) at baseline to 4.08 mmol/L (IQR, 3.84–4.31) following treatment (P<0.001). PAC decreased from 25.99 ng/dL (IQR, 20.43–37.22) to 12.60 ng/dL (IQR, 9.59–16.82; P<0.001), and PRA increased from 0.23 ng/mL per h (IQR, 0.02–0.54) to 1.06 ng/mL per h (IQR, 0.48–4.22; P<0.001). The ARR declined markedly from 101.60 (IQR, 49.43–920.79) to 12.60 (IQR, 3.05–21.88; P<0.001). Among nonresponders (n=30), serum potassium also increased, although to a lesser extent, from 3.49 mmol/L (IQR, 3.23–3.73) to 3.74 mmol/L (IQR, 3.50–4.11; P=0.006). PAC decreased from 25.22 ng/dL (IQR, 19.83–33.02) to 17.60 ng/dL (IQR, 14.14–25.92; P=0.003). However, changes in PRA were not statistically significant (0.04 [IQR, 0.02–0.15] to 0.11 [IQR, 0.01–0.30]; P=0.538), and ARR remained largely unchanged (524.00 to 200.42, P=0.855). Between‐group comparisons of pre–post changes confirmed significantly greater reductions in PAC and ARR, as well as greater increases in PRA, in the responder group (all adjusted P<0.05), while the change in serum potassium did not differ significantly between groups (P=0.143).

BP Rhythm and Ambulatory BP Changes After Aldosterone Suppression Stratified by Dominant‐Side Adenoma

Ambulatory BP and circadian rhythm parameters were compared between patients with and without adrenal adenomas on the dominant side, defined by the presence of a unilateral adrenal mass ≥1 cm on CT imaging that corresponded to the dominant side identified by AVS (Table S3). In both groups, significant reductions in 24‐hour, daytime, and nighttime SBP and DBP were observed following treatment (all within‐group P<0.001). Among patients without dominant‐side adenoma (n=77), nighttime SBP decreased from 147±16 mm Hg to 122±12 mm Hg; in those with dominant‐side adenoma (n=22), the decrease was from 157±19 mm Hg to 119±11 mm Hg. Although the absolute reduction in nighttime SBP was greater in the adenoma group (P=0.006), this difference was not statistically significant after adjustment for covariates (P=0.109). The proportion of nocturnal SBP decline improved significantly in both groups. In the nonadenoma group, it increased from a median of 0.03 (IQR, −0.02 to 0.07) to 0.07 (IQR, 0.01–0.11; P<0.001); in the adenoma group, it increased from 0.03 (IQR, −0.01 to 0.09) to 0.07 (IQR, 0.02–0.12; P=0.007). The magnitude of dip improvement was similar between groups (unadjusted P=0.279; adjusted P=0.340). The dipper pattern prevalence also increased in both groups after SAAE (nonadenoma: 14.29% to 32.47%, P=0.003; adenoma: 18.18% to 31.81%, P=0.125), with no significant between‐group difference (P=0.741).

Discussion

This study provides novel evidence linking aldosterone excess to disrupted circadian BP rhythm in PA. Unlike prior studies focusing on binary PA versus non‐PA comparisons, ⁶ , ⁸ we demonstrated a clear dose–response relationship between PAC and the degree of nocturnal BP decline, underscoring aldosterone’s direct role in rhythm disruption. Notably, in patients undergoing targeted aldosterone suppression, only those achieving biochemical success showed significant rhythm improvements, regardless of adrenal morphology. These findings suggest that effective hormonal suppression, rather than anatomic features, is central to restoring physiological BP patterns and raise the possibility that minimally invasive vascular interventions aimed at adrenal‐specific aldosterone reduction may offer rhythm‐modifying benefits in PA.

Circadian BP rhythm, particularly nocturnal decline, is a well‐established predictor of cardiovascular risk in the general population with hypertension. ²³ , ²⁴ However, its clinical significance in PA remains underappreciated. ⁸ Although previous studies have reported a higher prevalence of nondipping patterns in PA compared with essential hypertension, ⁶ , ⁸ most data are derived from cross‐sectional comparisons, often confounded by comorbidities and medication use. Moreover, few studies have explored intragroup variation in BP rhythm among patients with PA with differing aldosterone activity. ²⁵ This gap limits our understanding of whether rhythm abnormalities in PA reflect secondary effects or a direct endocrine mechanism. Our study addresses this limitation by focusing on rhythm characteristics within PA subgroups, providing evidence that nocturnal BP dysregulation is not uniform but may be directly modulated by the severity of aldosterone excess.

The observed association between elevated aldosterone levels and impaired nocturnal BP decline supports a pathophysiological role of aldosterone in rhythm disruption beyond its hemodynamic effects. Both continuous and categorical analyses revealed a consistent inverse relationship between aldosterone burden and nocturnal dipping, reinforcing the notion of a dose‐dependent endocrine impact. Emerging mechanistic studies suggest that aldosterone may interfere with circadian clock gene expression and vascular endothelial function, providing a plausible biological link. ⁹ , ²⁶ Our findings strengthen this hypothesis in a clinical context, highlighting aldosterone excess not only as a driver of hypertension but also as a modifiable factor contributing to circadian dysregulation.

Given the pathogenic role of aldosterone in circadian BP disruption, selective suppression of adrenal aldosterone secretion represents a promising therapeutic strategy. ²⁵ In our study, rhythm improvement was observed only among patients who achieved biochemical remission, regardless of the presence of adrenal adenomas, suggesting that targeted hormonal modulation, rather than anatomic correction, may be sufficient to ameliorate BP rhythmicity. Notably, the recently published FABULAS (Endoscopic, Ultrasound‐Guided, Radiofrequency Ablation of Aldosterone‐Producing Adenomas) trial assessed endoscopic ultrasound‐guided radiofrequency ablation and reported a 57% complete biochemical success rate at 6 months. ²⁷ In our study, the rate of biochemical success was 70% at a median of 6 months after SAAE. By comparison, historical cohorts undergoing adrenalectomy for unilateral PA have reported complete biochemical success rates ranging from 70% to >80%. ¹³ , ²² , ²⁸ While our PA surgical outcome–defined success rate appears modest, several factors may account for this. Our cohort included a high proportion of patients without CT‐detectable adenomas, and recent histopathological studies show that such patients often harbor nonclassical features such as micronodular hyperplasia, which are associated with reduced and less durable biochemical remission, even after surgery. ¹³ , ²⁹ Therefore, the relatively lower success rate observed in our study may reflect the intrinsic heterogeneity of disease severity and morphology in real‐world unilateral PA cases, particularly when intervention targets are less anatomically defined. We also emphasize that adrenalectomy remains the guideline‐recommended standard of care for AVS‐confirmed unilateral PA. In our study, SAAE should not be interpreted as an alternative to surgery but rather as an investigational approach that enabled us to assess the mechanistic relationship between aldosterone suppression and BP rhythmicity.

Several limitations merit consideration. First, although the study included a large overall cohort, the interventional subgroup was relatively small and derived from a single center, limiting generalizability. Additionally, many patients did not complete postintervention ambulatory BP monitoring measurements, which may have introduced potential bias and further limited the external validity of the findings. Second, while antihypertensive drug use and timing were carefully controlled, residual confounding cannot be fully excluded. Third, mechanistic insights, such as molecular markers of circadian regulation, were not directly assessed. Fourth, obstructive sleep apnea was assessed only by patient self‐report without systematic polysomnography, which may underestimate its prevalence and introduce residual confounding. Finally, the median follow‐up duration was 6 months, which limits our ability to assess the long‐term sustainability of BP rhythm improvements and their potential impact on cardiovascular outcomes. Future studies should validate these findings in multicenter cohorts, incorporate longer‐term cardiovascular outcomes, and explore the molecular pathways linking aldosterone to circadian rhythm disruption. Defining rhythm restoration as a therapeutic end point may offer a new dimension in the personalized management of PA.

Supporting information

Tables S1–S5

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