Primary aldosteronism patients with previous cardiovascular and cerebrovascular events have high aldosterone responsiveness to ACTH stimulation

Abstract

Aldosterone secretion in primary aldosteronism (PA) is often regulated by adrenocorticotropic hormone (ACTH) in addition to its autonomous secretion. However, the clinical characteristics and risk of cardiovascular and cerebrovascular (CCV) events in PA patients with aldosterone responsiveness to ACTH stimulation remain unclear. This study aimed to investigate the prevalence of CCV events in PA patients with high aldosterone responsiveness to ACTH stimulation. A retrospective cross-sectional study was conducted as part of the Japan Primary Aldosteronism Study/Japan Rare Intractable Adrenal Disease project. PA patients with adrenal venous sampling (AVS) between January 2006 and March 2019 were enrolled. The ACTH-stimulated plasma aldosterone concentration (PAC) of the inferior vena cava during AVS was used to evaluate aldosterone responsiveness to ACTH. We analyzed the relationship between responsiveness and previous CCV events. Logistic regression analysis demonstrated that the ΔPAC (the difference between the PAC measurements before and after ACTH stimulation) significantly increased the odds of previous CCV events in PA patients after adjusting for classical CCV event risk factors, baseline PAC and duration of hypertension (relative PAC: odds ratio [OR], 2.896; 95% confidence interval [CI], 0.989–8.482; ΔPAC: OR, 2.344; 95% CI, 1.149–4.780; ACTH-stimulated PAC: OR, 2.098; 95% CI, 0.694–6.339). This study clearly demonstrated that aldosterone responsiveness to ACTH is closely related to previous CCV events. The responsiveness of the PAC to ACTH could be useful in predicting CCV event risk.

Registration Number in UMIN-CTR is UMIN000032525.

PRIMARY ALDOSTERONISM (PA) is known to cause secondary hypertension through aldosterone production independent of renin [1]. Compared with essential hypertension, PA is associated with an increased risk of cardiovascular and cerebrovascular (CCV) events [2-4]. In PA patients, high plasma aldosterone concentration (PAC), hypokalemia, and unilateral subtype (aldosterone-producing adenoma [APA]) have been reported as CCV event risk factors [5].

The regulation of aldosterone production in PA is regulated by a variety of genetic and molecular mechanisms. Previous studies revealed somatic and germline mutations of PA that induce excessive aldosterone production, such as KCNJ5 mutations [6]. In addition, aldosterone secretion is regulated by various hormone stimulation [7, 8], although a previous study showed that various hormones contribute to the pathology of primary bilateral macronodular adrenal hyperplasia or cortisol-secreting adrenal adenomas [9]. Aldosterone secretion in PA is also highly regulated by the stimulation of adrenocorticotropic hormone (ACTH) [7, 8, 10], 5-hydroxytryptamine type 4 [7, 8, 10], glucagon-dependent insulinotropic peptide [10], gonadotropin releasing hormone (GnRH) [7, 11], vasopressin [7, 8, 10], glucagon [7], thyrotropin releasing hormone [7, 8] and endothelin-1 A and B [12].

With regard to ACTH stimulation in PA, the ACTH receptor (melanocortin 2 receptor [MC2R]) is overexpressed in 9 of 14 APAs [7]. Additionally, a previous study reported that IHA patients had 20-fold greater expression of MC2R than did healthy adrenal glands. Moreover, PA patients with MC2R expression exhibit an aldosterone response to circadian changes in ACTH [13]. However, the clinical characteristics, including CCV events, of PA patients with high aldosterone responsiveness to ACTH stimulation have not been determined.

The aim of our study was to investigate the prevalence of adverse CCV events in PA patients with high aldosterone responsiveness to ACTH stimulation.

Methods

Study design and patients

This study was conducted as part of the Japan Primary Aldosteronism Study/Japan Rare Intractable Adrenal Disease (JPAS/JRAS) project. The nationwide PA registry in Japan includes 22 universities and 19 city hospitals. In this study, patients who were diagnosed with PA and underwent AVS between January 2006 and March 2019 were enrolled. Patients who qualified for JPAS/JRAS were men and women aged >20 to 90 years. The clinical characteristics, biochemical data, AVS results, and related follow-up data were collected electronically using the web registry system. We outsourced the system construction, data security, and maintenance of the registered data to the EPS Corporation (Tokyo, Japan).

Our study was conducted using a dataset valid as of March 2019. We selected 2,830 patients with data on clinical course, biochemical test results and ACTH-stimulated AVS results. Of these patients, 89 had a significantly greater basal PAC of the inferior vena cava than the basal PAC at diagnosis. Because AVS stress can increase the PAC, these patients were excluded because of inaccurate assessments of PAC responsiveness to ACTH stimulation.

Patients with PA were evaluated with endocrine tests for subclinical Cushing’s syndrome (SCS). Baseline ACTH and cortisol levels were measured, and 1,771 patients underwent a 1 mg dexamethasone suppression test (DST) to exclude SCS. Autonomous cortisol secretion was defined as a serum cortisol concentration ≥1.8 μg/dL after 1 mg of dexamethasone. Previous studies reported that PA patients with mild autonomous cortisol secretion had a greater incidence of cardiovascular events [14]. Therefore, we excluded 469 patients with autonomous cortisol secretion. Finally, 1,302 patients with PA were included in this study (Fig. 1).

Fig. 1

Classification strategy for primary aldosteronism.

We diagnosed diabetes mellitus (DM) according to the Japanese criteria for DM: fasting PG ≥126 mg/dL and HbA1c ≥6.5% or receiving treatment for DM. We diagnosed dyslipidemia (DL) according to the Japanese criteria for DL: fasting TG ≥150 mg/dL, LDL ≥140 mg/dL, HDL <40 mg/dL or receiving treatment for DL. Hypokalemia was diagnosed when potassium was ≤3.5 mEq/L, and if hypokalemia was present, oral K supplementation was administered. The estimated glomerular filtration rate (eGFR) was calculated as follows: eGFR (mL × min^–1 × 1.73 m^–2) = 0.741 × 175 × Age^–0.203 × Serum creatinine^–1.154 × (0.742 if women). Proteinuria was defined as +, 2+ or 3+ protein according to urinalysis. Previous CCV events were defined by each physician at each hospital. The CCV events included myocardial infarction, heart failure, cerebral infarction, and cerebral hemorrhage before the diagnosis of PA.

The study was approved by the Ethics Committee of the participating centers. This study received permission from the director of Osaka University Hospital (approval number: 19100).

Diagnosis of PA

PA was diagnosed according to the guidelines of the Japan Endocrine Society and Japanese Society of Hypertension [15]. PA was diagnosed on the basis of the ratio of PAC (pg/mL) to plasma renin activity (PRA) (ng/mL/h), an aldosterone-to-renin ratio (ARR) >200 and at least 1 positive result on 4 confirmatory tests, including the captopril challenge test, the saline infusion test, the furosemide-upright test, and the oral salt-loading test. Antihypertensive medications were changed to calcium channel blockers or α-blockers before the examination. The present registry includes data on calcium channel blockers or α-blockers, such as the type and dose, only at the time of PA examination.

The PA subtype was diagnosed on the basis of AVS combined with ACTH stimulation. AVS was performed in the supine position. ACTH (250 μg) was administered by a bolus injection followed by continuous injection or continuous injection. Adrenal vein cannulation was considered successful if the selectivity index was >5. The selectivity index was defined as the ratio of the cortisol concentration between the adrenal vein and the inferior vena cava. The lateralized ratio (LR) was defined as the ratio of aldosterone to cortisol between the dominant and nondominant adrenal glands. The contralateral ratio (CR) was defined as the ratio of aldosterone to cortisol between the nondominant adrenal gland and the inferior vena cava. We used AVS data after ACTH stimulation. A diagnosis of the unilateral PA subtype was defined as LR >4 and CR <1. The aldosterone response to ACTH stimulation was expressed as the relative PAC of the inferior vena cava before and after ACTH stimulation (the ratio of ACTH-stimulated PAC to basal PAC). Based on a previous report [8], a positive response to ACTH (ACTH responders) was defined as a relative PAC greater than 1.5. In addition, we evaluated the difference between the PAC measurements before and after ACTH stimulation (ΔPAC) and the ACTH-stimulated PAC.

Measurement

We collected baseline data, including age, sex, duration of hypertension, body mass index, systolic blood pressure, diastolic blood pressure and blood test results, such as metabolic parameters. Blood sampling was performed in the supine position. PAC and PRA were measured by commercially available kits. PAC concentrations were determined via radioimmunoassay (SPAC-S Aldosterone Kit; Fuji Rebio, Co., Tokyo, Japan) in 38 centers and via chemiluminescent enzyme immunoassay (Accuraseed Aldosterone; FUJIFILM Wako Pure Chemical, Co., Osaka, Japan) in 3 centers. The reference ranges of the PAC measured in the supine position were 3.0 to 15.9 ng/dL and 2.99 to 15.9 ng/dL. Plasma renin activity (PRA) was measured by radioimmunoassay or enzyme immunoassay. The reference range of PRA in the supine position was 0.3 to 2.9 ng/mL/h (PRA radioimmunoassay kits; Fuji Rebio, Co., Tokyo, Japan) in 24 centers; 0.2 to 2.3 ng/mL/h (PRA enzyme immunoassay kits; Yamasa, Co., Choshi, Japan) in 13 centers; and 0.2 to 2.7 ng/mL/h (PRA radioimmunoassay kits; Yamasa, Co., Choshi, Japan) in 3 centers. The plasma active renin concentration (ARC) was measured using an immunoradiometric assay (Renin IRMA-FR; Fuji Rebio Co. Ltd.) or chemiluminescent enzyme immunoassay (Accuraseed renin kits; FUJIFILM Wako Pure Chemical, Co., Osaka, Japan) at 1 center, and the ARC was calculated by conversion to PRA. The reference ranges of the ARC in the supine position were 2.5 to 21.4 pg/mL and 2.5 to 21.0 pg/mL.

Statistical analysis

The data are presented as medians (first and third quartiles). The characteristics of the patients were compared using the Wilcoxon test for nonparametric continuous variables. Categorical variables were compared using Pearson’s chi-square test. A p value <0.05 indicated statistical significance. We performed logistic regression analysis to determine the independent risk factors associated with previous CCV events. The logistic regression analysis adjusted for the influence of baseline PAC in addition to the classical CCV event risk factors because high PAC has been reported as a CCV event risk factor [5]. The classical risk factors are sex, age, history of diabetes mellitus, history of dyslipidemia, smoking habits, and the eGFR [16-20]. The analysis did not adjust for PA subtypes because they were associated with the baseline PAC. All the statistical analyses were performed with JMP Pro software (ver. 14, SAS Institute, Cary, NC).

Results

Clinical characteristics of PA patients with and without previous CCV events

The clinical characteristics of the PA patients with and without previous CCV events are shown in Table 1. Patients with previous CCV events had greater relative PAC and ΔPAC counts than did those without previous CCV events (relative PAC: 2.16 [1.61–3.14] vs. 1.90 [1.49–2.61], p < 0.05; ΔPAC: 167 [102–272] vs. 135 [76–219] ng/dL, p < 0.05). However, the ACTH-stimulated PAC was not different between the two groups. In addition, there were no significant differences in the PAC, PRA, ARR, or percentage of patients with APA. Moreover, neither the serum potassium concentration nor the percentage of potassium supplementation was different between the two groups.

Table 1

Clinical characteristics of PA patients with and without CCV events

	With CCV events (n = 75)		Without CCV events (n = 1219)		p
	n		n
Sex (%,male)	75	62.6	1,219	48.4	0.0171
Age (years)	75	62 (51–68)	1,218	51 (44–61)	<0.0001
BMI (kg/m2)	75	25.1 (21.8–27.9)	1,210	24.6 (22.2–27.6)	0.7239
Diabetes mellitus (%)	75	34.6	1,219	12.1	<0.0001
Dyslipidemia (%)	75	46.6	1,219	23.9	<0.0001
Ever Smoker (%)	68	50.0	1,106	37.1	0.0342
Drinker (%)	68	42.6	1,093	55.6	0.0369
Duration of hypertension (years)	68	12 (3–20)	1,126	5 (1–10)	<0.0001
No. of antihypertensive drugs	75	2 (1–2)	1,219	1 (1–1)	<0.0001
Systolic blood pressure (mmHg)	75	138 (130–151)	1,204	139 (128–151)	0.5859
Diastolic blood pressure (mmHg)	75	84 (74–90)	1,204	86 (78–95)	0.0262
Serum potassium (mEq/L)	47	3.8 (3.4–4.2)	872	3.9 (3.6–4.1)	0.4418
Potassium supplement (%)	69	30.4	1,143	23.6	0.1982
Creatinine (mg/dL)	75	0.86 (0.67–1.05)	1,212	0.70 (0.60–0.84)	<0.0001
eGFR (mL/min/1.73 m2)	75	66.8 (52.8–79.6)	1,211	79.1 (68.1–91.5)	<0.0001
Proteinuria (%)	70	21.4	1,098	10.6	0.0058
PAC (ng/dL)	75	197 (136–326)	1,219	185 (130–282)	0.3284
PRA (ng/mL/hr)	75	0.4 (0.2–0.6)	1,177	0.3 (0.2–0.5)	0.3412
ARR	75	553 (283–970)	1,177	523 (315–1,050)	0.8573
Relative PAC (fold)	75	2.16 (1.61–3.14)	1,219	1.90 (1.49–2.61)	0.0343
ΔPAC (ng/dL)	75	167 (102–272)	1,219	135 (76–219)	0.0214
ACTH-stimulated PAC (ng/dL)	75	331 (203–454)	1,219	287 (203–440)	0.2660
Subtype (%, APA)	68	35.2	1,066	25.7	0.0815

Compared with the patients without previous CCV events, those with previous CCV events were significantly older (62 [51–68] vs. 51 [44–61] years, p < 0.01) and had a greater proportion of males, smokers, and DM and DL patients (males: 62.6 vs. 48.4%, p < 0.05; smokers: 50.0 vs. 37.1%, p < 0.05; DM: 34.6 vs. 12.1%, p < 0.01; DL: 46.6 vs. 23.9%, p < 0.01); and a lower proportion of drinkers (42.6 vs. 55.6%, p < 0.05). However, there was no significant difference in body mass index (BMI) between the two groups. With regard to hypertension, the patients with previous CCV events had a longer duration of hypertension (12 [3–20] vs. 5 [1–10] years, p < 0.01), a greater number of antihypertensive drugs (2 [1–2] vs. 1 [1–1], p < 0.01), and lower diastolic blood pressure (DBP) (84 [74–90] vs. 86 [78–95] mmHg, p < 0.05) than did those without previous CCV events. Moreover, there was no significant difference in systolic blood pressure (SBP) between the two groups. In addition, the patients with a previous CCV event had higher creatinine levels (0.86 [0.67–1.05] vs. 0.70 [0.60–0.84] mg/dL, p < 0.01), lower eGFRs (66.8 [52.8–79.6] vs. 79.1 [68.1–91.5] mL/min/1.73 m², p < 0.01), and a greater proportion of proteinuria (21.4% vs. 10.6%, p < 0.01) than did those without a previous CCV event.

Clinical characteristics of patients with and without a PAC response to ACTH

The clinical characteristics of the ACTH responders and nonresponders are shown in Table 2. Compared with ACTH nonresponders, ACTH responders had a significantly lower proportion of males, smokers, and drinkers (males: 43.3 vs. 66.6%, p < 0.01; smokers: 36.1 vs. 42.9%, p < 0.05; drinkers: 52.6 vs. 61.6%, p < 0.01). On the other hand, there was no significant difference in age, BMI, or the proportion of patients with DM or DL. With regard to hypertension, there was no significant difference in the duration of hypertension, number of antihypertensive drugs, SBP, or DBP. In addition, ACTH responders had a lower creatinine level and a greater eGFR than did ACTH nonresponders (creatinine: 0.69 [0.58–0.82] vs. 0.76 [0.63–0.90] mg/dL, p < 0.01; eGFR: 78.9 [68.1–91.6] vs. 75.3 [64.9–89.3] mL/min/1.73 m², p < 0.05), although the percentage of proteinuria was not different between the two groups. The PAC, ARR, and percentage of patients with APA were lower in ACTH responders than in ACTH nonresponders (PAC: 178 [128–267] vs. 211 [137–322] ng/dL, p < 0.01; ARR: 503 [310–955] vs. 601 [318–1,441], p < 0.01; APA: 23.2 vs. 35.3%, p < 0.01). Moreover, there was no significant difference in the PRA. Although the serum potassium concentration was not different between ACTH responders and nonresponders, the ratio of patients who received potassium supplementation was lower in ACTH responders than in ACTH nonresponders (20.8 vs. 33.4%, p < 0.01). With regard to the PAC response to ACTH, the relative PAC, ΔPAC, and ACTH-stimulated PAC were greater in ACTH responders than in ACTH nonresponders (relative PAC: 2.24 [1.80–2.98] vs. 1.29 [1.17–1.40], p < 0.01; ΔPAC: 164 [110–254] vs. 57 [33–94] ng/dL, p < 0.01; ACTH-stimulated PAC: 293 [213–428] vs. 277 [168–499] ng/dL, p < 0.05).

Table 2

Clinical characteristics of the patients with and without the PAC response to ACTH

	Relative PAC				p
	n	≥1.5 (n = 970) ACTH responder	n	<1.5 (n = 332) ACTH non-responder
Sex (%, male)	970	43.3	332	66.6	<0.0001
Age (years)	969	52 (44–61)	332	52 (44–62)	0.9097
BMI (kg/m2)	962	24.6 (22.1–27.6)	330	24.9 (22.1–27.9)	0.3342
Diabetes mellitus (%)	969	13.7	332	12.7	0.6203
Dyslipidemia (%)	969	25.3	332	25.3	0.9950
Ever Smoker (%)	870	36.1	308	42.9	0.0354
Drinker (%)	860	52.6	305	61.6	0.0060
Duration of hypertension (years)	888	5 (1–10)	313	6 (2–11)	0.1617
No. of antihypertensive drugs	970	1 (1–2)	332	1 (1–2)	0.0812
Systolic blood pressure (mmHg)	959	139 (128–150)	329	140 (128–152)	0.2421
Diastolic blood pressure (mmHg)	959	86 (78–95)	329	86 (77–96)	0.4792
Serum potassium (mEq/L)	717	3.9 (3.6–4.1)	207	3.8 (3.5–4.1)	0.1673
Potassium supplement (%)	908	20.8	311	33.4	<0.0001
Creatinine (mg/dL)	965	0.69 (0.58–0.82)	330	0.76 (0.63–0.90)	<0.0001
eGFR (mL/min/1.73 m2)	963	78.9 (68.1–91.6)	331	75.3 (64.9–89.3)	0.0413
Proteinuria (%)	869	10.5	305	13.4	0.1758
PAC (ng/dL)	970	178 (128–267)	332	211 (137–322)	0.0003
PRA (ng/mL/hr)	925	0.3 (0.2–0.5)	315	0.3 (0.2–0.5)	0.2456
ARR	901	503 (310–955)	300	601 (318–1,441)	0.0012
Relative PAC (fold)	970	2.24 (1.80–2.98)	332	1.29 (1.17–1.40)	<0.0001
ΔPAC (ng/dL)	970	164 (110–254)	332	57 (33–94)	<0.0001
ACTH-stimulated PAC (ng/dL)	970	293 (213–428)	332	277 (168–499)	0.0217
Subtype (%, APA)	878	23.2	300	35.3	<0.0001
CCV events (%)	964	6.2	330	4.6	0.2600
Myocardial infarction (%)	964	1.0	330	0.9	0.8402
Heart failure (%)	964	0.1	330	0.9	0.0229
Cerebral infarction (%)	964	3.8	330	2.4	0.2263
Cerebral hemorrhage (%)	964	1.7	330	0.9	0.3278

Clinical characteristics of ACTH responders and nonresponders with and without CCV events

Among the ACTH responders, the patients with previous CCV events were significantly older and had a greater proportion of males, smokers, and DM and DL patients than did those without previous CCV events. With regard to hypertension, patients with a previous history of CCV events had a longer duration of hypertension and were treated with more antihypertensive drugs than were those without a previous history of CCV events. In addition, patients with a previous CCV event had higher creatinine levels, a lower eGFR, and a greater proportion of proteinuria than did those without a previous CCV event (Supplementary Table 1). Similarly, among the ACTH nonresponders, the patients with previous CCV events were significantly older and had a greater proportion of DM and DL patients than were those without CCV events. With regard to hypertension, patients with a previous history of CCV events had a longer duration of hypertension and were treated with more antihypertensive drugs than were those without a previous history of CCV events. In addition, the patients with a previous CCV event had higher creatinine levels and a lower eGFR than did those without a previous CCV event (Supplementary Table 2).

Logistic regression analysis for cerebrocardiovascular events

We performed logistic regression analysis to investigate the association between the PAC response to ACTH stimulation and previous CCV events (Table 3). The ΔPAC (OR, 2.344; 95% CI, 1.149–4.780) was found to be independent previous CCV event risk factors but the relative PAC (OR, 2.896; 95% CI, 0.989–8.482) and the ACTH-stimulated PAC were not (OR, 2.098; 95% CI, 0.694–6.339).

Table 3

ORs and 95% CIs after separately adjusting for classical CCV event risk factors, baseline PAC and duration of hypertension

Variable	Unadjusted Analysis			Adjusted Analysis
	OR	95% CI	p	OR	95% CI	p
log10Relative PAC (fold)	2.000	0.817–4.898	0.1289	2.896	0.989–8.482	0.0524
log10ΔPAC	1.842	1.049–3.235	0.0333	2.344	1.149–4.780	0.0191
log10ACTH-stimulated PAC (ng/dL)	1.543	0.709–3.361	0.2740	2.098	0.694–6.339	0.1886

Discussion

The present study showed for the first time that the aldosterone response to ACTH stimulation was related to previous CCV events. First, PA with previous CCV events had a greater response of PAC to ACTH stimulation (the relative PAC and the ΔPAC). Second, logistic regression analysis demonstrated that ΔPAC was previous CCV risk factors. Therefore, aldosterone responsiveness to ACTH stimulation might impact CCV disease. On the other hand, the relative PAC and ACTH-stimulated PAC did not significantly increase the odds of previous CCV events.

In the present study, logistic regression analysis was adjusted for the influence of baseline PAC in addition to classical CCV event risk factors because high PAC has been reported to be a CCV event risk factor [5]. In addition, the analysis was adjusted for hypertension duration because patients with a previous CCV event had a longer duration of hypertension than did those without a previous CCV event. Nevertheless, the ΔPAC was found to be independent previous CCV risk factors. Therefore, the responsiveness of the PAC to ACTH as well as baseline PAC might be important as previous CCV events risk factors. Previous studies reported that aldosterone production follows the ACTH circadian rhythm in PA patients [13]. Because previous studies have revealed rapid effects of aldosterone on vascular tone [21-23], the circadian variation of aldosterone might play a role in short-term blood pressure (BP) regulation. Additionally, blood pressure variability has been reported to be associated with the development of CCV events [24]. Therefore, circadian variation in aldosterone might influence short-term BP regulation and contribute to CCV events in ACTH responders. On the other hand, no significant difference was observed in the incidence of CCV events between ACTH responders and nonresponders. However, ACTH nonresponders had more CCV event risk factors, such as baseline PAC, duration of hypertension, sex, smoking status, and eGFR, than did ACTH responders. In addition, both ACTH responders and nonresponders with CCV events had more CCV event risk factors than did those without CCV events. More CCV event risk factors of ACTH nonresponders may have impact on no difference in the prevalence of previous CCV events between ACTH responders and nonresponders. Therefore, PAC responsiveness to ACTH stimulation might be significant for CCV events because logistic regression analysis was adjusted for baseline PAC, duration of hypertension and these CCV event risk factors.

In this study, the proportion of unilateral PA tended to be greater in the group with CCV events than in the group without CCV events, similar to the findings in the previous JRAS study [5]. However, there was no significant difference in the basal PAC between patients with and without CCV events, unlike in the previous study. The difference in patient selection between the present and the previous study might influence the results of these studies. For example, in this study, patients whose basal PAC in the inferior vena cava was significantly greater than the basal PAC at diagnosis were excluded. Additionally, the cutoff values of the serum cortisol concentration in the 1 mg DST for the exclusion of SCS were different between the present and previous studies (present: 1.8 μg/dL, previous: 3 μg/dL). Finally, there were 1,302 and 2,582 PA patients included in the present and previous studies, respectively. Therefore, the difference in the study subjects between the present and previous studies may have impacted the results of these studies.

With regard to the subtype of PA, ACTH responders had both APA and IHA. PAC responsiveness to ACTH stimulation and overexpressed MC2R has been reported in both APA and IHA patients [7, 8]. Therefore, the difference in aldosterone responsiveness to ACTH stimulation might influence CCV events in both subtypes. ACTH responders with APA might have some mutations because a previous study showed that MC2R expression was greater in APAs with CACANA1D or ATP1A1 mutations than in those with KCNJ5 [25].

Our study has several limitations. First, this was a retrospective cross-sectional study. We could evaluate previous CCV events but not prospective CCV development. Therefore, further research is needed to prospectively determine the long-term course of CCV events in PA patients. Second, the PAC may have increased prior to ACTH stimulation because the subjects may have experienced stress during AVS. However, stress might have less influence on the PAC because patients with a higher basal PAC in the inferior vena cava than in the basal PAC at diagnosis were excluded. In addition, because the dose of ACTH used in AVS is significantly high, AVS stress could have less impact on the PAC than pharmacological ACTH.

In conclusion, PAC responsiveness to ACTH stimulation was related to previous CCV events. Responsiveness could be potentially useful for evaluating CCV event risk. Physicians should focus on the aldosterone responsiveness of PA to ACTH stimulation as well as previously reported CCV event risk factors for PAs.

Disclosure

The authors report no conflicts of interest related to this work.

Michio Otsuki, Daisuke Yabe, Masakatsu Sone, and Takuyuki Katabami are members of Endocrine Journal’s Editorial Board.

Acknowledgments

We thank the JPAS/JRAS Study Group for collecting the clinical data.

Funding Statement

This study was conducted as a part of the Japan PA Study (JPAS) and Japan Rare Adrenal Diseases Study (JRAS) by a research grant from the Japan Agency for Medical Research and Development (AMED) under grant numbers JP17ek0109122 (JPAS) and JP20ek0109352 (JRAS) and the National Center for Global Health and Medicine, Japan (27–1402, 30–1008).

Data Availability Statement

The datasets analyzed in this study are not publicly available but may be available from the corresponding author upon reasonable request.

References

• 1   Funder  JW,  Carey  RM,  Fardella  C,  Gomez-Sanchez  CE,  Mantero  F, et al. (2008) Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical guideline. J Clin Endocrinol Metab 93: 3266–3281.
• 2   Mulatero  P,  Monticone  S,  Bertello  C,  Viola  A,  Tizzani  D, et al. (2013) Long-term cardio- and cerebrovascular events in patients with primary aldosteronism. J Clin Endocrinol Metab 98: 4826–4833.
• 3   Milliez  P,  Girerd  X,  Plouin  PF,  Blacher  J,  Safar  ME, et al. (2005) Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol 45: 1243–1248.
• 4   Murata  M,  Kitamura  T,  Tamada  D,  Mukai  K,  Kurebayashi  S, et al. (2017) Plasma aldosterone level within the normal range is less associated with cardiovascular and cerebrovascular risk in primary aldosteronism. J Hypertens 35: 1079–1085.
• 5   Ohno  Y,  Sone  M,  Inagaki  N,  Yamasaki  T,  Ogawa  O, et al. (2018) Prevalence of cardiovascular disease and its risk factors in primary aldosteronism: a multicenter study in Japan. Hypertension 71: 530–537.
• 6   Nanba  K,  Yamazaki  Y,  Bick  N,  Onodera  K,  Tezuka  Y, et al. (2020) Prevalence of somatic mutations in aldosterone-producing adenomas in Japanese patients. J Clin Endocrinol Metab 105: e4066–e4073.
• 7   Zwermann  O,  Suttmann  Y,  Bidlingmaier  M,  Beuschlein  F,  Reincke  M (2009) Screening for membrane hormone receptor expression in primary aldosteronism. Eur J Endocrinol 160: 443–451.
• 8   St-Jean  M,  Bourdeau  I,  Martin  M,  Lacroix  A (2021) Aldosterone is aberrantly regulated by various stimuli in a high proportion of patients with primary aldosteronism. J Clin Endocrinol Metab 106: e45–e60.
• 9   Lacoix  A,  Baldacchino  V,  Bourdeau  I,  Hamet  P,  Tremblay  J (2004) Cushing’s syndrome variants secondary to aberrant hormone receptors. Trends Endocrinol Metab 15: 375–382.
• 10   Lampron  A,  Bourdeau  I,  Oble  S,  Godbout  A,  Schürch  W, et al. (2009) Regulation of aldosterone secretion by several aberrant receptors including for glucose-dependent insulinotropic peptide in a patient with an aldosteronoma. J Clin Endocrinol Metab 94: 750–756.
• 11   Albiger  NM,  Sartorato  P,  Mariniello  B,  Iacobone  M,  Finco  I, et al. (2011) A case of primary aldosteronism in pregnancy: do LH and GNRH receptors have a potential role in regulating aldosterone secretion? Eur J Endcrinol 164: 405–412.
• 12   Rossi  GP,  Ganzaroli  C,  Cesari  M,  Maresca  A,  Plebani  M, et al. (2003) Endothelin receptor blockade lowers plasma aldosterone levels via different mechanisms in primary aldosteronism and high-to-normal renin hypertension. Cardiovasc Res 57: 277–283.
• 13   Sonoyama  T,  Sone  M,  Tamura  N,  Honda  K,  Taura  D, et al. (2014) Role of endogenous ACTH on circadian aldosterone rhythm in patients with primary aldosteronism. Endocr Connect 3: 173–179.
• 14   Nakajima  Y,  Yamada  M,  Taguchi  R,  Satoh  T,  Hashimoto  K, et al. (2011) Cardiovascular complications of patients with aldosteronism associated with autonomous cortisol secretion. J Clin Endocrinol Metab 96: 2512–2518.
• 15   Naruse  M,  Katabami  T,  Shibata  H,  Sone  M,  Takahashi  K, et al. (2022) Japan endocrine society clinical practice guideline for the diagnosis and management of primary aldosteronism 2021. Endocr J 69: 327–359.
• 16   Nakai  M,  Watanabe  M,  Kokubo  Y,  Nishimura  K,  Higashiyama  A, et al. (2020) Development of a cardiovascular disease risk prediction model using the Suita Study, a population-based prospective cohort study in Japan. J Atheroscler Thromb 27: 1160–1175.
• 17   Haffner  SM,  Lehto  S,  Rönnemaa  T,  Pyörälä  K,  Laakso  M (1998) Mortality from coronary heart disease in subjects with type2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 339: 229–234.
• 18   Imamura  T,  Doi  Y,  Arima  H,  Yonemoto  K,  Hata  J, et al. (2009) LDL cholesterol and the development of stroke subtypes and coronary heart disease in a general Japanese population: the Hisayama study. Stroke 40: 382–388.
• 19   Hata  J,  Doi  Y,  Ninomiya  T,  Fukuhara  M,  Ikeda  F, et al. (2011) Combined effects of smoking and hypercholesterolemia on the risk stroke and coronary heart disease in Japanese: the Hisayama study. Cerebrovasc Dis 31: 477–484.
• 20   Kokubo  Y,  Nakamura  S,  Okamura  T,  Yoshimasa  Y,  Makino  H, et al. (2009) Relationship between blood pressure category and incidence of stroke and myocardial infarction in an urban Japanese population with and without chronic kidney disease: the Suita Study. Stroke 40: 2674–2679.
• 21   Wehling  M,  Spes  CH,  Win  N,  Janson  CP,  Schmidt  BM, et al. (1998) Rapid cardiovascular action of aldosterone in man. J Clin Endocrinol Metab 83: 3517–3522.
• 22   Romagni  P,  Rossi  F,  Guerrini  L,  Quirini  C,  Santiemma  V (2003) Aldosterone induces contraction of the resistance arteries in man. Atherosclerosis 166: 345–349.
• 23   Schmidt  BM,  Montealegre  A,  Janson  CP,  Martin  N,  Stein-Kemmesies  C, et al. (1999) Short term cardiovascular effects of aldosterone in healthy male volunteers. J Clin Endocrinol Metab 84: 3528–3533.
• 24   Mancia  G,  Bombelli  M,  Facchetti  R,  Madotto  F,  Corrao  G, et al. (2007) Long-term prognostic value of blood pressure variability in the general population: results of the Pressioni Arteriose Monitorate e Loro Associazioni Study. Hypertension 49: 1265–1270.
• 25   Lim  JS,  Plaska  SW,  Rege  J,  Rainey  WE,  Turcu  AF (2021) Aldosterone-regulating receptors and aldosterone-driver somatic mutations. Front Endocrinol (Lausanne) 12: 644382.