Europe PMC

This website requires cookies, and the limited processing of your personal data in order to function. By using the site you are agreeing to this as outlined in our privacy notice and cookie policy.

KCNJ5 Somatic Mutation Is Associated With Higher Aortic Wall Thickness and Less Calcification in Patients With Aldosterone-Producing Adenoma.

Author information

Affiliations

  • 1. Department of Medical Imaging, National Taiwan University Hospital, Taipei, Taiwan.
      Authors
    • Lee BC 1, 4
    • Kang VJ 1
    • Huang JZ 1
    • Chang CC 1
    (4 authors)
  • 2. Departments of Internal Medicine, National Taiwan University Hospital Yun-lin Branch, Douliu, Taiwan.
      Authors
    • Pan CT 2
    • Chen ZW 2, 4
    (2 authors)
  • 3. Department of Business Administration and Graduate School of Service Management, Chihlee University of Technology, New Taipei City, Taiwan.
      Authors
    • Lin YL 3
    • Lin YH 3, 8
    (2 authors)
  • 4. Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
      Authors
    • Lee BC 1, 4
    • Chang YY 4, 7, 8
    • Tsai CH 4, 8
    • Chen ZW 2, 4
    (4 authors)
  • 5. Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan.
      Authors
    • Chou CH 5
    (1 author)
    • Show all (8)

ORCIDs linked to this article

Frontiers in Endocrinology, 02 Mar 2022, 13:830130
https://doi.org/10.3389/fendo.2022.830130 PMID: 35311227 PMCID: PMC8924484

This article is in the Europe PMC Open access subset. Refer to the copyright information in the article for licensing details.
Free full text in Europe PMC

Abstract 

Objective

Primary aldosteronism (PA) is the most common type of secondary hypertension, and it is associated with a higher rate of cardiovascular complications. KCNJ5 somatic mutations have recently been identified in aldosterone-producing adenoma (APA), however their influence on vascular remodeling and injury is still unclear. The aim of this study was to investigate the association between KCNJ5 somatic mutation status and vascular status.

Methods

We enrolled 179 APA patients who had undergone adrenalectomy from a prospectively maintained database, of whom 99 had KCNJ5 somatic mutations. Preoperative clinical, biochemical and imaging data of abdominal CT, including abdominal aortic calcification (AAC) score, aortic diameter and wall thickness at levels of superior (SMA) and inferior (IMA) mesenteric arteries were analyzed.

Results

After propensity score matching for age, sex, body mass index, triglycerides and low-density lipoprotein, there were 48 patients in each KCNJ5 (+) and KCNJ5 (-) group. Mutation carriers had a lower AAC score (217.3 ± 562.2 vs. 605.6 ± 1359.1, P=0.018), higher aortic wall thickness (SMA level: 2.2 ± 0.6 mm vs. 1.8 ± 0.6 mm, P=0.006; IMA level: 2.4 ± 0.6 mm vs. 1.8 ± 0.7 mm, P<0.001) than non-carriers. In multivariate analysis, KCNJ5 mutations were independently associated with AAC score (P=0.014) and aortic wall thickness (SMA level: P<0.001; IMA level: P=0.004). After adrenalectomy, mutation carriers had less aortic wall thickness progression than non-carriers (Δthickness SMA: -0.1 ± 0.8 mm vs. 0.9 ± 0.6 mm, P=0.024; IMA: -0.1 ± 0.6 mm vs. 0.8 ± 0.7 mm, P=0.04).

Conclusion

KCNJ5 mutation carriers had less calcification burden of the aorta, thickened aortic wall, and less wall thickness progression than non-carriers.

Free full text 

Logo of frontendoLink to Publisher's site
Front Endocrinol (Lausanne). 2022; 13: 830130.
Published online 2022 Mar 2. https://doi.org/10.3389/fendo.2022.830130
PMCID: PMC8924484
PMID: 35311227

KCNJ5 Somatic Mutation Is Associated With Higher Aortic Wall Thickness and Less Calcification in Patients With Aldosterone-Producing Adenoma

Bo-Ching Lee, 1 , 2 , 3 Victor Jing-Wei Kang, 1 Chien-Ting Pan, 4 Jia-Zheng Huang, 1 Yu-Li Lin, 5 Yi-Yao Chang, 2 , 6 , 7 Cheng-Hsuan Tsai, 2 , 6 Chia-Hung Chou, 8 Zheng-Wei Chen, 2 , 4 Che-Wei Liao, 9 Yu-Wei Chiu, 7 , 10 Vin-Cent Wu, 6 Chi-Sheng Hung, 6 , 11 Chin-Chen Chang,corresponding author 1 , * and Yen-Hung Lin 5 , 6 , 11 , the TAIPAI Study Group
Author information Article notes Copyright and License information Disclaimer

Associated Data

Data Availability Statement

Abstract

Objective

Primary aldosteronism (PA) is the most common type of secondary hypertension, and it is associated with a higher rate of cardiovascular complications. KCNJ5 somatic mutations have recently been identified in aldosterone-producing adenoma (APA), however their influence on vascular remodeling and injury is still unclear. The aim of this study was to investigate the association between KCNJ5 somatic mutation status and vascular status.

Methods

We enrolled 179 APA patients who had undergone adrenalectomy from a prospectively maintained database, of whom 99 had KCNJ5 somatic mutations. Preoperative clinical, biochemical and imaging data of abdominal CT, including abdominal aortic calcification (AAC) score, aortic diameter and wall thickness at levels of superior (SMA) and inferior (IMA) mesenteric arteries were analyzed.

Results

After propensity score matching for age, sex, body mass index, triglycerides and low-density lipoprotein, there were 48 patients in each KCNJ5 (+) and KCNJ5 (-) group. Mutation carriers had a lower AAC score (217.3 ± 562.2 vs. 605.6 ± 1359.1, P=0.018), higher aortic wall thickness (SMA level: 2.2 ± 0.6 mm vs. 1.8 ± 0.6 mm, P=0.006; IMA level: 2.4 ± 0.6 mm vs. 1.8 ± 0.7 mm, P<0.001) than non-carriers. In multivariate analysis, KCNJ5 mutations were independently associated with AAC score (P=0.014) and aortic wall thickness (SMA level: P<0.001; IMA level: P=0.004). After adrenalectomy, mutation carriers had less aortic wall thickness progression than non-carriers (Δthickness SMA: -0.1 ± 0.8 mm vs. 0.9 ± 0.6 mm, P=0.024; IMA: -0.1 ± 0.6 mm vs. 0.8 ± 0.7 mm, P=0.04).

Conclusion

KCNJ5 mutation carriers had less calcification burden of the aorta, thickened aortic wall, and less wall thickness progression than non-carriers.

Keywords: hypertension, humans, KCNJ5 somatic mutation, primary aldosteronism, aortic calcification

Introduction

Primary aldosteronism (PA) is characterized by abnormal aldosterone hypersecretion, and it is the most common cause of secondary hypertension. Approximately 5-10% of general hypertensive patients may have PA (1), and this rate can be as high as 20% in patients with resistant hypertension (2). Clinically, PA patients are associated with higher cardiovascular events than those with essential hypertension (3, 4).

Excessive aldosterone is related to various cardiovascular injuries. Animal studies have shown that the infusion of aldosterone can cause increased arterial stiffness and vascular fibronectin accumulation, and that the damage can be reversed by an aldosterone antagonist (5). In human studies, higher pulse wave velocity has been reported in PA patients compared to those with essential hypertension, indicating increased arterial stiffness in PA patients (6, 7). These aldosterone-induced cardiovascular injuries may be reversible, as studies have shown that adrenalectomy can ameliorate increased carotid intima-media thickness and arterial stiffness in patients with aldosterone-producing adenoma (APA) (7, 8).

APA is one of the most common subtypes of PA and is surgically correctable (9). KCNJ5 (coding for potassium channel GIRK4) mutations are the most frequently identified somatic mutations in both Western and Asian countries, with a prevalence rate of 34-45% (10–12) and 55-75%, respectively (13–16). APA patients with KCNJ5 mutations tend to be younger, have a higher aldosterone level, lower potassium level, and higher cure rate after adrenalectomy (17). Regarding the effect of KCNJ5 mutations on the cardiovascular system, mutation carriers have been shown to exhibit greater post-operative regression of observed left ventricular remodeling and improvement in arterial stiffness compared to non-carriers (18–20).

Aortic calcification is considered to be an irreversible endpoint of vascular atherosclerosis and an ideal indicator of vascular injury (21), and it can be quantitatively evaluated on CT. Aortic wall thickness of the common carotid artery, thoracic aorta and abdominal aorta is also regarded to be an important marker of vascular atherosclerosis with the ability to predict cardiovascular events (22, 23), and it has been associated with cardiovascular risk factors such as old age, male sex, smoking, elevated systolic blood pressure and low-density lipoprotein.

The aim of this study was to assess the influence of KCNJ5 mutations on atherosclerotic parameters on CT and use propensity score matching (PSM) analysis to balance possible confounding factors.

Materials and Methods

Patient Enrollment

In this study, we retrospectively analyzed 179 APA patients who underwent adrenalectomy between September 2006 and March 2019 at National Taiwan University Hospital (NTUH) from a prospectively maintained database. This study was approved by the Institutional Review Board of NTUH, and the need for written informed consent was waived. The clinical information of the patients, including demographic data, atherosclerotic parameters of abdominal CT, and histopathological results of APAs were recorded.

Laboratory Measurements

Plasma aldosterone concentration (PAC) and plasma renin activity (PRA) were measured using specific radioimmunoassay kits (Aldosterone Maia Kit; Adaltis Italia, Bologna, Italy and DiaSorin, Stillwater, Minnesota, USA, respectively). The aldosterone-to-renin ratio (ARR) was calculated as PAC/PRA.

Diagnostic Criteria for APA

The diagnosis of APA was established based on the modified four corner criteria as reported previously (19, 24, 25), including: (1) excess aldosterone production confirmed according to an ARR > 35, TAIPAI score > 60%; and seated post-saline loading PAC > 16 ng/dl or urine aldosterone > 12 μg/24 h; (2) identification of adrenal nodules on CT; (3) lateralization of aldosterone hypersecretion by adrenal venous sampling (AVS) or dexamethasone suppression NP-59 single-photon emission CT; (4) pathological evidence of adenoma after adrenalectomy, and subsequent clinical improvement defined by either complete resolution of hypertension or partial resolution of hypertension, potassium, PAC, and PRA.

In this study, successful AVS was defined as a sampled adrenal plasma cortisol concentration (PCC) similar to or two-fold greater than sampled peripheral PCC. The lateralization of PA was determined on the basis of a lateralization index of ≥2.0, which was estimated as the ratio of the sampled adrenal PAC/PCC on the dominant side to the PAC/PCC on the contralateral side.

Imaging Analysis

Abdominal CT data were available for all APA patients and were obtained using routine techniques (helical CT, 5-mm slices). One radiologist (V.J.K) with 3 years of experience independently evaluated the images on a standard imaging workstation and was unaware of the KCNJ5 mutation status. Aortic wall thickness and diameter were measured at superior mesenteric artery (SMA) and inferior mesenteric artery (IMA) levels, respectively. The thickest portion of the aortic wall and maximum aortic transverse diameter were estimated using reconstructed contrast-enhanced CT images perpendicular to the vascular centerline, to avoid overestimation due to tortuous segments of the aorta. Abdominal aortic calcification (AAC) score was calculated using the CT-based Agatston method from unenhanced abdominal CT axial view images using commercial software (Philips IntelliSpace Portal, Best, Netherlands). Vascular calcifications with attenuation greater than the predefined 130-HU threshold were estimated. A region of interest was manually selected so that only calcifications in the abdominal aorta were included. In this study, we used the Agatston score as described by Agatston for abdominal aorta (26).

Histopathologic Study and Sequencing of the KCNJ5 Gene

Laparoscopic adrenalectomy was used for all APA patients in this study. The resected adrenal specimens were blindly inspected by a pathologist. Nodules consisting of adrenal cells and a clearly demarcated pseudo-capsule were defined as adenomas. Before DNA extraction, fresh APA specimens were frozen at −80°C until use. Genomic DNA was prepared using a QIAamp DNA mini kit (Qiagen, Hilden, Germany) for each tissue sample. Exome sequencing was used to assess the coding region of the genomic DNA. Four sets of gene-specific primers were used to amplify and sequence the whole coding sequence (exons 2–3) and the flanking regions of KCNJ5 (27). The PCR reactions was set at 58°C for primer annealing using GoTaq® Master Mix (Promega Corporation, Madison, USA), and DNA fragments were extracted using a GenepHlow™ Gel/PCR Kit (Geneaid, Taipei, ROC). The PCR products were sent for Sanger sequencing using a 3730 DNA Analyzer (Applied Biosystems, Foster City, USA).

Statistical Analysis

All statistical analyses were performed using MedCalc statistical software (MedCalc version 15.4.0.0, Frank Schoonjans, Mariakerke, Belgium). Differences between categorical variables were compared using Fisher’s exact test. For independent continuous variables, the differences were compared using an independent two-sample t-test. Continuous variables with skewed distribution such as PAC, ARR, and calcium score were compared using the Mann-Whitney U test. We used propensity score analysis to eliminate possible confounders between the KCNJ5 mutation carrier and non-carrier groups. Clinical variables including age, sex, body mass index (BMI) and low-density lipoprotein (LDL) were included to generate propensity scores. The maximum allowable difference was 8 for age, 6 for BMI, 14 for LDL, and an exact match for sex, with 1:1 matching to select patients from both groups for subsequent analysis. Independent associations between KCNJ5 mutation status and AAC score, aortic wall thickness, aortic diameter progression, aortic wall thickness progression and AAC score progression were investigated using multivariable regression analyses. For all statistical analyses, the significance was 2-tailed with a threshold for significance of P<0.05.

Results

Clinical Data in All APA Patients Before and After Matching

Of the 179 APA patients, 99 had KCNJ5 mutations and the other 80 did not. A comparison of the pre-operative clinical variables of the two groups are summarized in Table 1. The mutation carriers were younger (P<0.001) and had lower serum levels of potassium (P<0.001) and triglycerides (P<0.001) than the non-carriers. The other clinical variables including sex, BMI, blood pressure, duration of hypertension, and number of hypertensive medications were similar between both groups. After 1:1 PSM for age, sex, BMI and serum triglycerides, each group had 48 patients remained in each group. The matched mutation carriers had a lower serum potassium level (P<0.001) than the non-carriers, while other clinical variables were balanced without significant difference (Table 1).

Table 1

Demographic characteristics in patient with APA before and after propensity score matching.

Before propensity score matchingAfter propensity score matching
KCNJ5(-) (n=80)KCNJ5(+) (n=99)P valueKCNJ5(-) (n=48)KCNJ5(+) (n=48)P value
Age, year 54.4 ± 11.448.6 ± 9.7<0.001***53.6 ± 8.851.8 ± 8.30.306
Sex, male 40 (50.0%)45 (45.4%)0.54823 (47.9%)22 (45.8%)0.838
Height, cm 164.0 ± 9.3163.4 ± 8.70.671164.6 ± 8.8163.3 ± 8.40.475
Weight, kg 67.8 ± 16.266.1 ± 14.80.47468.2 ± 15.265.9 ± 13.50.436
BMI, kg/m2 25.0 ± 4.324.6 ± 4.00.51725.0 ± 4.124.5 ± 3.30.515
SBP, mmHg 152.9 ± 19.3154.0 ± 20.90.720150.7 ± 18.3154.8 ± 20.50.311
DBP, mmHg 91.0 ± 13.294.5 ± 14.80.09691.5 ± 13.195.4 ± 13.20.149
HTN years, n 7.3 ± 6.75.8 ± 5.70.1246.8 ± 5.56.4 ± 5.40.690
HTN drugs, n 2.2 ± 1.42.2 ± 1.10.9301.9 ± 1.31.8 ± 1.10.604
PAC, ng/dL 53.2 ± 35.762.0 ± 41.20.13354.7 ± 36.861.7 ± 38.40.363
PRA, ng/mL/h 0.9 ± 3.20.4 ± 0.60.0931.0 ± 3.60.5 ± 0.80.325
ARR 1295 ± 25981170 ± 25450.7461283 ± 2705974 ± 22550.544
Log PAC 1.63 ± 0.301.69 ± 0.290.1581.65 ± 0.291.72 ± 0.260.240
Log PRA -0.72 ± 0.79-0.77 ± 0.620.631-0.70 ± 0.79-0.70 ± 0.630.974
Log ARR 2.36 ± 0.862.47 ± 0.690.3222.35 ± 0.862.42 ± 0.660.646
K, mmol/L 3.8 ± 0.53.2 ± 0.6<0.001***3.8 ± 0.53.2 ± 0.6<0.001***
Cr, mg/dL 1.0 ± 0.40.9 ± 0.40.2580.9 ± 0.31.0 ± 0.50.326
LDL, mg/dL 109.8 ± 33.1101.6 ± 25.70.090105.7 ± 27.5105.2 ± 24.80.926
TG, mg/dL 144.4 ± 88.6104.0 ± 51.5<0.001***139.2 ± 77.5114.8 ± 54.10.076
TC, mg/dL 189.3 ± 42.9174.9 ± 31.70.018*184.2 ± 39.0177.5 ± 23.80.319

ARR, aldosterone-to-renin ratio; BMI, body mass index; Cr, creatinine; DBP, diastolic blood pressure; EH, essential hypertension; HTN, hypertension; LDL, low-density lipoprotein cholesterol; PAC, plasma aldosterone concentration; PRA, plasma renin activity; SBP, systolic blood pressure; TG, triglyceride; TC, total cholesterol.

Age, sex, BMI and LDL were matched in propensity score analysis.

*P < 0.05, ***P < 0.001.

Atherosclerotic Parameters Before and After Matching

The atherosclerotic parameters on abdominal CT, including aortic diameter, aortic wall thickness and AAC score, were evaluated for both groups in this study. Before PSM, the mutation carriers had an increased aortic wall thickness at the SMA (P=0.001) and IMA levels (P=0.001), but a lower rate of mitral valve calcification (P=0.026) and lower AAC score (P<0.001) compared to the non-carriers (Table 2). After PSM, the mutation carriers still had a higher aortic wall thickness at the SMA (P=0.006) and IMA levels (P<0.001), but a lower AAC score (P=0.018) than the non-carriers (Table 2).

Table 2

Abdominal aortic calcification, diameter and thickness in patient with APA before and after propensity score matching.

Before propensity score matchingAfter propensity score matching
KCNJ5(-) (n=80)KCNJ5(+) (n=99)P valueKCNJ5(-)(n=48)KCNJ5(+)(n=48)P value
SMA level
Diameter, mm 20.8 ± 2.620.4 ± 2.30.24521.1 ± 2.420.6 ± 2.30.318
Thickness, mm 1.8 ± 0.62.1 ± 0.60.001**1.8 ± 0.62.2 ± 0.60.006**
IMA level
Diameter, mm 16.7 ± 2.216.6 ± 2.10.76816.8 ± 2.016.8 ± 1.91.000
Thickness, mm 2.0 ± 0.82.3 ± 0.60.001**1.8 ± 0.72.4 ± 0.6<0.001***
MV calcification, n 9/802/980.026*3/481/480.307
AAC 796.7 ± 1607.3160.4 ± 432.5<0.001***605.6 ± 1359.1217.3 ± 562.20.018*

AAC, abdominal aortic calcification; IMA, inferior mesenteric artery; MV, mitral valve; SMA, superior mesenteric artery.

*P < 0.05, **P < 0.01, ***P < 0.001.

Factors Associated With Baseline Aortic Wall Thickness

In univariate analysis (Table 3), aortic wall thickness at the SMA level was associated with KCNJ5 mutations (P=0.001) and the duration of hypertension (P=0.044), and aortic wall thickness at the IMA level was associated with KCNJ5 mutations (P=0.001), potassium (P=0.034) and creatinine (P=0.002) levels. In multivariable analysis, KCNJ5 mutations were independently associated with aortic wall thickness at the SMA (β=0.279, P<0.001) and IMA (β=0.251, P=0.004) levels.

Table 3

Multivariable regression analyses for factors associated with the aortic wall thickness.

Thickness (SMA level)Thickness (IMA level)
UnivariateMultivariateUnivariateMultivariate
β coefficientP valueβ coefficientP valueβ coefficientP valueβ coefficientP value
KCNJ5 mutations 0.2540.001**0.279<0.001***0.2480.001**0.2510.004**
Age, year 0.1080.1700.0420.590
Sex, male 0.0840.289-0.0880.263
Height, cm -0.0750.3400.1050.181
Weight, kg -0.0380.6280.0950.228
BMI, kg/m2 -0.0020.9770.0610.442
SBP, mmHg 0.0130.8710.0750.338
DBP, mmHg -0.0670.3980.0150.849
HTN years, n 0.1580.044*0.1930.012*0.0290.717
HTN drugs, n 0.0830.2960.1250.113
Log PAC 0.0490.5370.1380.080
Log PRA -0.0220.778-0.0210.793
Log ARR 0.0390.6210.0710.366
K, mmol/L -0.1480.060-0.1670.034*-0.0430.620
Cr, mg/dL 0.0110.8910.2440.002**0.268<0.001***
LDL, mg/dL -0.0710.413-0.1290.136
TG, mg/dL 0.0070.934-0.0030.967
TC, mg/dL -0.0760.364-0.0890.284

Factors with P value less than 0.05 were selected into multivariable regression analyses. ARR, aldosterone-to-renin ratio; BMI, body mass index; Cr, creatinine; DBP, diastolic blood pressure; EH, essential hypertension; HTN, hypertension; LDL, low-density lipoprotein cholesterol; PAC, plasma aldosterone concentration; PRA, plasma renin activity; SBP, systolic blood pressure; TG, triglyceride; TC, total cholesterol.

*P < 0.05, **P < 0.01, ***P < 0.001.

Factors Associated With Baseline Aortic Calcification

As shown in Table 4, AAC score was related to several factors including KCNJ5 mutations (P<0.001), age (P<0.001), systolic blood pressure (P=0.020), duration of hypertension (P=0.001) and number of hypertension drugs (P=0.003) in univariate analysis. In multivariable analysis, AAC score was independently associated with KCNJ5 mutations (β=-0.168, P=0.014), age (β=0.387, P<0.001), systolic blood pressure (β=0.171, P=0.010), and number of hypertension drugs (β=0.153, P=0.024).

Table 4

Multivariable regression analyses for factors associated with AAC.

UnivariateMultivariate
β coefficientP valueβ coefficientP value
KCNJ5 mutations -0.273<0.001***-0.1680.014*
Age, year 0.433<0.001***0.387<0.001***
Sex, male -0.090.232
Height, cm 0.0240.750
Weight, kg 0.0370.629
BMI, kg/m2 0.0410.588
SBP, mmHg 0.1740.020*0.1710.010*
DBP, mmHg -0.0680.369
HTN years, n 0.2430.001**-0.0260.741
HTN drugs, n 0.2230.003**0.1530.024*
Log PAC 0.0570.451
Log PRA -0.0030.966
Log ARR 0.0250.740
K, mmol/L 0.0820.274
Cr, mg/dL 0.0940.210
LDL, mg/dL -0.0180.824
TG, mg/dL 0.0630.424
TC, mg/dL 0.0120.879

Factors with P value less than 0.05 were selected into multivariable regression analyses. AAC, abdominal aortic calcification; ARR, aldosterone-to-renin ratio; BMI, body mass index; Cr, creatinine; DBP, diastolic blood pressure; EH, essential hypertension; HTN, hypertension; LDL, low-density lipoprotein cholesterol; PAC, plasma aldosterone concentration; PRA, plasma renin activity; SBP, systolic blood pressure; TG, triglyceride; TC, total cholesterol.

*P < 0.05, **P < 0.01, ***P < 0.001.

Changes in Atherosclerotic Parameters on Abdominal CT After Adrenalectomy

Twenty-six patients had post-operative CT images. After adjusting for age, sex, and follow-up examination interval in multivariable analysis, the non-carriers had higher aortic wall thickness progression after adrenalectomy at the SMA (Δthickness: -0.1 ± 0.8 mm vs. 0.9 ± 0.6 mm, P=0.024) and IMA (Δthickness: -0.1 ± 0.6 mm vs. 0.8 ± 0.7 mm, P=0.040) levels than the carriers (Table 5). The progression of AAC score was similar between the two groups (P=0.732).

Table 5

Change of aortic calcification, diameter and thickness in patient with APA before and after adrenalectomy.

KCNJ5(-) (n=15)KCNJ5(+) (n=11)Adjusted P value
SMA level
ΔDiameter, mm0.1 ± 0.80.6 ± 0.50.247
ΔThickness, mm0.9 ± 0.6-0.1 ± 0.80.024*
IMA level
ΔDiameter, mm0.1 ± 1.0-0.2 ± 1.00.195
ΔThickness, mm0.8 ± 0.7-0.1 ± 0.60.040*
ΔAAC 359.0 ± 662.8195.6 ± 384.80.732

P value was adjusted for age, sex, and exam interval.

AAC, abdominal aortic calcification; IMA, inferior mesenteric artery; SMA, superior mesenteric artery.

*P < 0.05.

Discussion

There are several major findings in this study. First, APA patients with KCNJ5 somatic mutations had a thicker aortic wall and less aortic calcification compared to those without KCNJ5 mutations, even after matching for age, sex and blood pressure by PSM. Second, in multivariate analysis, the presence of KCNJ5 mutations was an independent factor associated with aortic wall thickness and aortic calcification. Third, after adrenalectomy, the patients with KCNJ5 mutations had less progression of aortic wall thickness compared to those without KCNJ5 somatic mutations.

The wall of the aorta is composed of tunica intima, tunica media, and tunica adventitia (28). The intima and media of the aortic wall can thicken due to adaptive collagen redistribution from aging, hypertension and pathological atherosclerosis with the formation of fat streaks and plaques (29, 30), and this has been shown to be a good marker of atherosclerosis and coronary artery disease (31, 32). Excessive aldosterone induces chronic inflammation of the vessel walls by increasing reactive oxygen species and proinflammatory transcription factors production (33). Enhanced monocytes and macrophages infiltration and adhesion on the endothelium are noted under high concentration of aldosterone (34), and the infiltrated inflammatory cells again worsen vascular inflammation (35). Aldosterone also promotes vascular remodeling of small arteries by increased collagen, fibronectin and ICAM-1 deposition in the vessel wall (36). PA is clinically associated with increased intima–media thickness of the carotid artery (37, 38), which may regress after adrenalectomy or spironolactone treatment. In this study, the APA patients with KCNJ5 somatic mutations had a thicker abdominal aorta compared to those without KCNJ5 mutations, which is probably due to higher blood pressure and more severe aldosteronism in the mutation carriers (19). In our previous study, APA patients with KCNJ5 somatic mutations had a higher degree of left ventricular hypertrophy and worse diastolic function (19). These findings may also have been due to similar reasons.

During the atherosclerotic process, atheroma or fibrous fatty plaques are formed, followed by calcium deposition in the latter stages (39). In the present study, we found more calcified plaques in those without KCNJ5 somatic mutations. The mechanism of aortic calcification formation is complex and involves multifactorial vascular inflammation (40). In our prior study we investigated serum CRP levels in PA patients, and showed that KCNJ5 mutations were associated with lower levels of pro-inflammation factors (41), metabolic syndrome and abdominal obesity (42). This may explain why the patients without KCNJ5 somatic mutations had a higher burden of aortic calcified plaques despite lower blood pressure and less severe aldosteronism compared to those with KCNJ5 somatic mutations.

Several somatic mutations including ATP1A1, ATP2B3, CACNA1D and KCNJ5 may contribute to the pathogenesis of APA (43–47). These mutations activate calcium signaling and lead to aldosterone production by increasing the expression of aldosterone synthase. In APA patient with KCNJ5 mutations, opened calcium channels and the overexpression of CYP11B2 lead to excessive aldosterone secretion from the adrenal tumor (47, 48). These mutation carriers have been found to have more severe aldosteronism compared to non-carriers (11, 12). Recently, CYP11B2 immunohistochemistry (IHC)-guided biopsy has been shown to increase the diagnostic performance of somatic mutations to around 87-94% in APA patients (49–51). One study demonstrated that an IHC-guided biopsy could increase the detection of somatic mutations in frozen adenoma tissue from 71% to 94% compared to a random biopsy by Sanger sequencing (51). In the present study, a random biopsy was used to sequence KCNJ5 mutations without the aid of CYP11B2 IHC guidance. However, an IHC-guided biopsy may have limited value in detecting KCNJ5 mutations, as they could be detected regardless of CYP11B2 expression in a random biopsy. Thus, we believe that the rate of KCNJ5 mutations identified by random biopsy is reliable in our study. Notably, the prevalence of other somatic mutations besides KCNJ5 were low (<6%) in our prior studies (13), indicating that the detection performance for other somatic mutations may be inferior by random biopsy compared to IHC-guided biopsy. As a result, the non-carriers of KCNJ5 mutations in the present study may have had various types of somatic mutations besides KCNJ5. However, we focused on the influence of KCNJ5 mutations with regards to aortic atherosclerosis in this study; therefore, our conclusions may not be affected by the lack of IHC-guided biopsy.

There are several limitations to this study. First, somatic mutations besides KCNJ5 such as ATP1A1, ATP2B3, CACNA1D and other new genes were not evaluated in this study, and the patients were grouped as being non-carriers of KCNJ5 mutations (44, 46, 52, 53). In addition, we did not use CYP11B2 IHC-guided biopsy to detect somatic mutations, which may have performed better than random biopsy. Second, despite the use of PSM to ameliorate imbalances in age, sex, BMI and LDL between the two groups of APA patients, other unknown discrepancies may have contributed to the increased aortic calcification in the non-carriers, and we do not have pathological data regarding the atherosclerotic burden of resected adrenal samples. Third, the number of patients with available follow-up abdominal CT was relatively small (n=26). However, the progression of aortic wall thickness remained significant after adjusting for age, sex and examination interval, indicating that small number of patients only had a limited impact. Finally, the CT images used to generate AAC and aortic wall thickness used 5.0 mm slice reconstruction. Although the correlation between the measured AAC from 2.5mm and 5.0mm slice thickness was almost perfect (r = 0.999, P < 0.0001), a 10% underestimation of AAC maybe expected due to partial volume effect (54, 55).

In conclusion, APA patients with KCNJ5 somatic mutations had a thicker abdominal aortic wall but less atherosclerotic calcification compared to those without KCNJ5 mutations. After surgery, the APA patients with KCNJ5 somatic mutations had less wall thickness progression than the non-carriers.

Data Availability Statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethics Statement

The studies involving human participants were reviewed and approved by Institutional Review Board of NTUH. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

Author Contributions

B-CL: project concept and design, data collection, imaging analysis, data analysis, and write up. VK: data collection, imaging analysis, and write up. C-CC project concept and design. J-ZH: data collection, imaging analysis. Y-YC: project concept and design. C-HT: project concept and design. Z-WC: project concept and design. Y-LL: project concept and design. C-HC: critical revisions. C-WL: critical revisions. C-TP: critical revisions. C-SH: critical revisions. V-CW: project concept and design, data collection, and critical revisions. Y-HL: project concept and design, data collection, imaging analysis, and critical revisions. All authors contributed to the article and approved the submitted version.

Appendix

Membership of the Taiwan Primary Aldosteronism Investigation (TAIPAI) Study Group: Che-Hsiung Wu, MD (Chi-Taz Hospital, PI of Committee); V-CW, MD (NTUH, PI of Committee); Y-HL, MD (NTUH, PI of Committee); Hung-Wei Chang, MD, PhD (Far Eastern Clinics, PI of Committee); Lian-Yu Lin MD, PhD (NTUH, PI of Committee); Fu-Chang Hu, MS, ScD, (Harvard Statistics, Site Investigator); Kao-Lang Liu, MD (NTUH, PI of Committee); Shuo-Meng Wang, MD (NTUH, PI of Committee); Kuo-How Huang, MD (NTUH, PI of Committee); Yung-Ming Chen, MD (NTUH, PI of Committee); C-CC, MD (NTUH, PI of Committee); Shih-Cheng Liao, MD (NTUH, PI of Committee); Ruoh-Fang Yen, MD, PhD (NTUH, PI of Committee); and Kwan-Dun Wu, MD, PhD (NTUH, Director of Coordinating Center).

Funding

This study was supported by National Taiwan University Hospital (NTUH 108-A141), Ministry of Science and Technology (MOST 106-2314-B-002-169-MY3), and Department of Health, Executive Yuan, R.O.C. (PTH10744). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Acknowledgments

We thank the staff of the Second Core Lab of the Department of Medical Research at National Taiwan University Hospital for technical assistance.

References

1. Rossi GP, Bernini G, Caliumi C, Desideri G, Fabris B, Ferri C, et al. . A Prospective Study of the Prevalence of Primary Aldosteronism in 1,125 Hypertensive Patients. J Am Coll Cardiol (2006) 48:2293–300. 10.1016/j.jacc.2006.07.059 [Abstract] [CrossRef] [Google Scholar]
2. Douma S, Petidis K, Doumas M, Papaefthimiou P, Triantafyllou A, Kartali N, et al. . Prevalence of Primary Hyperaldosteronism in Resistant Hypertension: A Retrospective Observational Study. Lancet (2008) 371:1921–6. 10.1016/S0140-6736(08)60834-X [Abstract] [CrossRef] [Google Scholar]
3. Hundemer GL, Curhan GC, Yozamp N, Wang M, Vaidya A. Cardiometabolic Outcomes and Mortality in Medically Treated Primary Aldosteronism: A Retrospective Cohort Study. Lancet Diabetes Endocrinol (2018) 6:51–9. 10.1016/S2213-8587(17)30367-4 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
4. Milliez P, Girerd X, Plouin PF, Blacher J, Safar ME, Mourad JJ. Evidence for an Increased Rate of Cardiovascular Events in Patients With Primary Aldosteronism. J Am Coll Cardiol (2005) 45:1243–8. 10.1016/j.jacc.2005.01.015 [Abstract] [CrossRef] [Google Scholar]
5. Lacolley P, Labat C, Pujol A, Delcayre C, Benetos A, Safar M. Increased Carotid Wall Elastic Modulus and Fibronectin in Aldosterone-Salt-Treated Rats: Effects of Eplerenone. Circulation (2002) 106:2848–53. 10.1161/01.CIR.0000039328.33137.6C [Abstract] [CrossRef] [Google Scholar]
6. Strauch B, Petrak O, Zelinka T, Wichterle D, Holaj R, Kasalicky M, et al. . Adrenalectomy improves arterial stiffness in primary aldosteronism. Am J Hypertens (2008) 21:1086–92. 10.1038/ajh.2008.243 [Abstract] [CrossRef] [Google Scholar]
7. Lin YH, Lin LY, Chen A, Wu XM, Lee JK, Su TC, et al. . Adrenalectomy Improves Increased Carotid Intima-Media Thickness and Arterial Stiffness in Patients With Aldosterone Producing Adenoma. Atherosclerosis (2012) 221:154–9. 10.1016/j.atherosclerosis.2011.12.003 [Abstract] [CrossRef] [Google Scholar]
8. Liao CW, Lin LY, Hung CS, Lin YT, Chang YY, Wang SM, et al. . Time Course and Factors Predicting Arterial Stiffness Reversal in Patients With Aldosterone-Producing Adenoma After Adrenalectomy: Prospective Study of 102 Patients. Sci Rep (2016) 6:20862. 10.1038/srep20862 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
9. Amar L, Plouin PF, Steichen O. Aldosterone-Producing Adenoma and Other Surgically Correctable Forms of Primary Aldosteronism. Orphanet J Rare Dis (2010) 5:9. 10.1186/1750-1172-5-9 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
10. Fernandes-Rosa FL, Williams TA, Riester A, Steichen O, Beuschlein F, Boulkroun S, et al. . Genetic Spectrum and Clinical Correlates of Somatic Mutations in Aldosterone-Producing Adenoma. Hypertension (2014) 64:354–61. 10.1161/HYPERTENSIONAHA.114.03419 [Abstract] [CrossRef] [Google Scholar]
11. Boulkroun S, Beuschlein F, Rossi GP, Golib-Dzib JF, Fischer E, Amar L, et al. . Prevalence, Clinical, and Molecular Correlates of KCNJ5 Mutations in Primary Aldosteronism. Hypertension (2012) 59:592–8. 10.1161/HYPERTENSIONAHA.111.186478 [Abstract] [CrossRef] [Google Scholar]
12. Lenzini L, Rossitto G, Maiolino G, Letizia C, Funder JW, Rossi GP. A Meta-Analysis of Somatic KCNJ5 K(+) Channel Mutations In 1636 Patients With an Aldosterone-Producing Adenoma. J Clin Endocrinol Metab (2015) 100:E1089–95. 10.1210/jc.2015-2149 [Abstract] [CrossRef] [Google Scholar]
13. Wu VC, Wang SM, Chueh SJ, Yang SY, Huang KH, Lin YH, et al. . The Prevalence of CTNNB1 Mutations in Primary Aldosteronism and Consequences for Clinical Outcomes. Sci Rep (2017) 7:39121. 10.1038/srep39121 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
14. Taguchi R, Yamada M, Nakajima Y, Satoh T, Hashimoto K, Shibusawa N, et al. . Expression and Mutations of KCNJ5 mRNA in Japanese Patients With Aldosterone-Producing Adenomas. J Clin Endocrinol Metab (2012) 97:1311–9. 10.1210/jc.2011-2885 [Abstract] [CrossRef] [Google Scholar]
15. Zheng FF, Zhu LM, Nie AF, Li XY, Lin JR, Zhang K, et al. . Clinical Characteristics of Somatic Mutations in Chinese Patients With Aldosterone-Producing Adenoma. Hypertension (2015) 65:622–8. 10.1161/HYPERTENSIONAHA.114.03346 [Abstract] [CrossRef] [Google Scholar]
16. Hong AR, Kim JH, Song YS, Lee KE, Seo SH, Seong MW, et al. . Genetics of Aldosterone-Producing Adenoma in Korean Patients. PloS One (2016) 11:e0147590. 10.1371/journal.pone.0147590 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
17. Vilela LAP, Rassi-Cruz M, Guimaraes AG, Moises CCS, Freitas TC, Alencar NP, et al. . KCNJ5 Somatic Mutation Is a Predictor of Hypertension Remission After Adrenalectomy for Unilateral Primary Aldosteronism. J Clin Endocrinol Metab (2019) 104:4695–702. 10.1210/jc.2019-00531 [Abstract] [CrossRef] [Google Scholar]
18. Rossi GP, Cesari M, Letizia C, Seccia TM, Cicala MV, Zinnamosca L, et al. . KCNJ5 Gene Somatic Mutations Affect Cardiac Remodelling But do Not Preclude Cure of High Blood Pressure and Regression of Left Ventricular Hypertrophy in Primary Aldosteronism. J Hypertens (2014) 32:1514–21; discussion 1522. 10.1097/HJH.0000000000000186 [Abstract] [CrossRef] [Google Scholar]
19. Chang YY, Tsai CH, Peng SY, Chen ZW, Chang CC, Lee BC, et al. . KCNJ5 Somatic Mutations in Aldosterone-Producing Adenoma Are Associated With a Worse Baseline Status and Better Recovery of Left Ventricular Remodeling and Diastolic Function. Hypertension (2021) 77:114–25. 10.1161/HYPERTENSIONAHA.120.15679 [Abstract] [CrossRef] [Google Scholar]
20. Kitamoto T, Suematsu S, Matsuzawa Y, Saito J, Omura M, Nishikawa T. Comparison of Cardiovascular Complications in Patients With and Without KCNJ5 Gene Mutations Harboring Aldosterone-Producing Adenomas. J Atheroscler Thromb (2015) 22:191–200. 10.5551/jat.24455 [Abstract] [CrossRef] [Google Scholar]
21. Budoff MJ, Shaw LJ, Liu ST, Weinstein SR, Mosler TP, Tseng PH, et al. . Long-Term Prognosis Associated With Coronary Calcification: Observations From a Registry of 25,253 Patients. J Am Coll Cardiol (2007) 49:1860–70. 10.1016/j.jacc.2006.10.079 [Abstract] [CrossRef] [Google Scholar]
22. Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of Clinical Cardiovascular Events With Carotid Intima-Media Thickness: A Systematic Review and Meta-Analysis. Circulation (2007) 115:459–67. 10.1161/CIRCULATIONAHA.106.628875 [Abstract] [CrossRef] [Google Scholar]
23. Rosero EB, Peshock RM, Khera A, Clagett P, Lo H, Timaran CH. Sex, Race, and Age Distributions of Mean Aortic Wall Thickness in a Multiethnic Population-Based Sample. J Vasc Surg (2011) 53:950–7. 10.1016/j.jvs.2010.10.073 [Abstract] [CrossRef] [Google Scholar]
24. Rossi GP, Belfiore A, Bernini G, Desideri G, Fabris B, Ferri C, et al. . Comparison of the Captopril and the Saline Infusion Test for Excluding Aldosterone-Producing Adenoma. Hypertension (2007) 50:424–31. 10.1161/HYPERTENSIONAHA.107.091827 [Abstract] [CrossRef] [Google Scholar]
25. Wu VC, Chang HW, Liu KL, Lin YH, Chueh SC, Lin WC, et al. . Primary Aldosteronism: Diagnostic Accuracy of the Losartan and Captopril Tests. Am J Hypertens (2009) 22:821–7. 10.1038/ajh.2009.89 [Abstract] [CrossRef] [Google Scholar]
26. Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M, Jr., Detrano R. Quantification of Coronary Artery Calcium Using Ultrafast Computed Tomography. J Am Coll Cardiol (1990) 15:827–32. 10.1016/0735-1097(90)90282-T [Abstract] [CrossRef] [Google Scholar]
27. Azizan EA, Murthy M, Stowasser M, Gordon R, Kowalski B, Xu S, et al. . Somatic Mutations Affecting the Selectivity Filter of KCNJ5 are Frequent in 2 Large Unselected Collections of Adrenal Aldosteronomas. Hypertension (2012) 59:587–91. 10.1161/HYPERTENSIONAHA.111.186239 [Abstract] [CrossRef] [Google Scholar]
28. Jana S, Hu M, Shen M, Kassiri Z. Extracellular Matrix, Regional Heterogeneity of the Aorta, and Aortic Aneurysm. Exp Mol Med (2019) 51:1–15. 10.1038/s12276-019-0286-3 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
29. Gasser TC, Ogden RW, Holzapfel GA. Hyperelastic Modelling of Arterial Layers With Distributed Collagen Fibre Orientations. J R Soc Interface (2006) 3:15–35. 10.1098/rsif.2005.0073 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
30. Finn AV, Kolodgie FD, Virmani R. Correlation Between Carotid Intimal/Medial Thickness and Atherosclerosis: A Point of View From Pathology. Arterioscler Thromb Vasc Biol (2010) 30:177–81. 10.1161/ATVBAHA.108.173609 [Abstract] [CrossRef] [Google Scholar]
31. Fazio GP, Redberg RF, Winslow T, Schiller NB. Transesophageal Echocardiographically Detected Atherosclerotic Aortic Plaque Is a Marker for Coronary Artery Disease. J Am Coll Cardiol (1993) 21:144–50. 10.1016/0735-1097(93)90729-K [Abstract] [CrossRef] [Google Scholar]
32. Nishino M, Masugata H, Yamada Y, Abe H, Hori M, Kamada T. Evaluation of Thoracic Aortic Atherosclerosis by Transesophageal Echocardiography. Am Heart J (1994) 127:336–44. 10.1016/0002-8703(94)90122-8 [Abstract] [CrossRef] [Google Scholar]
33. Fiebeler A, Schmidt F, Muller DN, Park JK, Dechend R, Bieringer M, et al. . Mineralocorticoid Receptor Affects AP-1 and Nuclear Factor-Kappab Activation in Angiotensin II-Induced Cardiac Injury. Hypertension (2001) 37:787–93. 10.1161/01.HYP.37.2.787 [Abstract] [CrossRef] [Google Scholar]
34. Caprio M, Newfell BG, la Sala A, Baur W, Fabbri A, Rosano G, et al. . Functional Mineralocorticoid Receptors in Human Vascular Endothelial Cells Regulate Intercellular Adhesion Molecule-1 Expression and Promote Leukocyte Adhesion. Circ Res (2008) 102:1359–67. 10.1161/CIRCRESAHA.108.174235 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
35. Cathcart MK. Regulation of Superoxide Anion Production by NADPH Oxidase in Monocytes/Macrophages: Contributions to Atherosclerosis. Arterioscler Thromb Vasc Biol (2004) 24:23–8. 10.1161/01.ATV.0000097769.47306.12 [Abstract] [CrossRef] [Google Scholar]
36. Pu Q, Neves MF, Virdis A, Touyz RM, Schiffrin EL. Endothelin Antagonism on Aldosterone-Induced Oxidative Stress and Vascular Remodeling. Hypertension (2003) 42:49–55. 10.1161/01.HYP.0000078357.92682.EC [Abstract] [CrossRef] [Google Scholar]
37. Holaj R, Zelinka T, Wichterle D, Petrak O, Strauch B, Widimsky J., Jr. Increased Intima-Media Thickness of the Common Carotid Artery in Primary Aldosteronism in Comparison With Essential Hypertension. J Hypertens (2007) 25:1451–7. 10.1097/HJH.0b013e3281268532 [Abstract] [CrossRef] [Google Scholar]
38. Holaj R, Rosa J, Zelinka T, Strauch B, Petrak O, Indra T, et al. . Long-Term Effect of Specific Treatment of Primary Aldosteronism on Carotid Intima-Media Thickness. J Hypertens (2015) 33:874–82; discussion 882. 10.1097/HJH.0000000000000464 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
39. Rudelli S, Viriato SP, Meireles TL, Frederico TN. Treatment of Displaced Neck Fractures of the Femur With Total Hip Arthroplasty. J Arthroplasty (2012) 27:246–52. 10.1016/j.arth.2011.04.041 [Abstract] [CrossRef] [Google Scholar]
40. Chen NC, Hsu CY, Chen CL. The Strategy to Prevent and Regress the Vascular Calcification in Dialysis Patients. BioMed Res Int (2017) 2017:9035193. 10.1155/2017/9035193 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
41. Wu VC, Huang KH, Peng KY, Tsai YC, Wu CH, Wang SM, et al. . Prevalence and Clinical Correlates of Somatic Mutation in Aldosterone Producing Adenoma-Taiwanese Population. Sci Rep (2015) 5:11396. 10.1038/srep11396 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
42. Chen KM, Chang YL, Wu TH, Lee BC, Chen PT, Liu KL, et al. . Aldosterone-Producing Adenoma-Harbouring KCNJ5 Mutations Is Associated With Lower Prevalence of Metabolic Disorders and Abdominal Obesity. J Hypertens (2021) 39(12):2353–60. 10.1097/HJH.0000000000002948 [Abstract] [CrossRef] [Google Scholar]
43. Stowasser M, Gordon RD. Primary Aldosteronism: Changing Definitions and New Concepts of Physiology and Pathophysiology Both Inside and Outside the Kidney. Physiol Rev (2016) 96:1327–84. 10.1152/physrev.00026.2015 [Abstract] [CrossRef] [Google Scholar]
44. Beuschlein F, Boulkroun S, Osswald A, Wieland T, Nielsen HN, Lichtenauer UD, et al. . Somatic Mutations in ATP1A1 and ATP2B3 Lead to Aldosterone-Producing Adenomas and Secondary Hypertension. Nat Genet (2013) 45:440–4, 444e1-2. 10.1038/ng.2550 [Abstract] [CrossRef] [Google Scholar]
45. Azizan EA, Poulsen H, Tuluc P, Zhou J, Clausen MV, Lieb A, et al. . Somatic Mutations in ATP1A1 and CACNA1D Underlie a Common Subtype of Adrenal Hypertension. Nat Genet (2013) 45:1055–60. 10.1038/ng.2716 [Abstract] [CrossRef] [Google Scholar]
46. Scholl UI, Goh G, Stolting G, de Oliveira RC, Choi M, Overton JD, et al. . Somatic and Germline CACNA1D Calcium Channel Mutations in Aldosterone-Producing Adenomas and Primary Aldosteronism. Nat Genet (2013) 45:1050–4. 10.1038/ng.2695 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
47. Choi M, Scholl UI, Yue P, Bjorklund P, Zhao B, Nelson-Williams C, et al. . K+ Channel Mutations in Adrenal Aldosterone-Producing Adenomas and Hereditary Hypertension. Science (2011) 331:768–72. 10.1126/science.1198785 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
48. Oki K, Plonczynski MW, Luis Lam M, Gomez-Sanchez EP, Gomez-Sanchez CE. Potassium Channel Mutant KCNJ5 T158A Expression in HAC-15 Cells Increases Aldosterone Synthesis. Endocrinology (2012) 153:1774–82. 10.1210/en.2011-1733 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
49. Nanba K, Omata K, Else T, Beck PCC, Nanba AT, Turcu AF, et al. . Targeted Molecular Characterization of Aldosterone-Producing Adenomas in White Americans. J Clin Endocrinol Metab (2018) 103:3869–76. 10.1210/jc.2018-01004 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
50. Nanba K, Omata K, Gomez-Sanchez CE, Stratakis CA, Demidowich AP, Suzuki M, et al. . Genetic Characteristics of Aldosterone-Producing Adenomas in Blacks. Hypertension (2019) 73:885–92. 10.1161/HYPERTENSIONAHA.118.12070 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
51. De Sousa K, Boulkroun S, Baron S, Nanba K, Wack M, Rainey WE, et al. . Genetic, Cellular, and Molecular Heterogeneity in Adrenals With Aldosterone-Producing Adenoma. Hypertension (2020) 75:1034–44. 10.1161/HYPERTENSIONAHA.119.14177 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
52. Scholl UI, Healy JM, Thiel A, Fonseca AL, Brown TC, Kunstman JW, et al. . Novel Somatic Mutations in Primary Hyperaldosteronism are Related to the Clinical, Radiological and Pathological Phenotype. Clin Endocrinol (Oxf) (2015) 83:779–89. 10.1111/cen.12873 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
53. Prada ETA, Burrello J, Reincke M, Williams TA. Old and New Concepts in the Molecular Pathogenesis of Primary Aldosteronism. Hypertension (2017) 70:875–81. 10.1161/HYPERTENSIONAHA.117.10111 [Abstract] [CrossRef] [Google Scholar]
54. van der Bijl N, de Bruin PW, Geleijns J, Bax JJ, Schuijf JD, de Roos A, et al. . Assessment of Coronary Artery Calcium by Using Volumetric 320-Row Multi-Detector Computed Tomography: Comparison of 0.5 Mm With 3.0 Mm Slice Reconstructions. Int J Cardiovasc Imaging (2010) 26:473–82. 10.1007/s10554-010-9581-8 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
55. Zweig BM, Sheth M, Simpson S, Al-Mallah MH. Association of Abdominal Aortic Calcium With Coronary Artery Calcium and Obstructive Coronary Artery Disease: A Pilot Study. Int J Cardiovasc Imaging (2012) 28:399–404. 10.1007/s10554-011-9818-1 [Abstract] [CrossRef] [Google Scholar]
Articles from Frontiers in Endocrinology are provided here courtesy of Frontiers Media SA

Full text links 

Read article at publisher's site: https://doi.org/10.3389/fendo.2022.830130

Read article for free, from open access legal sources, via Unpaywall: https://www.frontiersin.org/articles/10.3389/fendo.2022.830130/pdfUnpaywall

Citations & impact 

Impact metrics

2
Citations
Jump to Citations
6
Data citations
Jump to Data

Alternative metrics

Altmetric item for https://www.altmetric.com/details/123916517
Altmetric
Discover the attention surrounding your research
https://www.altmetric.com/details/123916517

Smart citations by scite.ai
Smart citations by scite.ai include citation statements extracted from the full text of the citing article. The number of the statements may be higher than the number of citations provided by EuropePMC if one paper cites another multiple times or lower if scite has not yet processed some of the citing articles.
Explore citation contexts and check if this article has been supported or disputed.
https://scite.ai/reports/10.3389/fendo.2022.830130

Supporting
Mentioning
Contrasting
0
1
0

Article citations

Data 

Similar Articles 

To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation.

Funding 

Funders who supported this work.

Ministry of Health and Welfare

    Ministry of Science and Technology, Taiwan

      National Taiwan University Hospital (1)