Cardiovascular Outcomes of KCNJ5 Mutated Aldosterone-Producing Adenoma: A Systematic Review.

BACKGROUND: While clinical features of KCNJ5-mutated aldosterone-producing adenoma (APA) have been reported, evidence of its clinical outcomes is lacking. We aimed to synthesize available literature about the associations between KCNJ5 mutation with cardiovascular and metabolic outcomes among patients with APA. METHODS: In this systematic review of observational studies, MEDLINE and Embase were searched through August 2022. Two independent authors screened the search results and extracted data from eligible observational studies investigating cardiovascular or metabolic outcomes between KCNJ5-mutated APAs and KCNJ5-non-mutated APAs. Risk of Bias In Non-randomized Studies of Interventions was used to assess the quality of the included studies. RESULTS: A total of 573 titles/abstracts were screened and after the expert opinion of the literature, full text was read in 20 titles/abstracts, of which 12 studies were included. Across 3 studies comparing the baseline or change in the cardiac function between KCNJ5-mutated APAs and KCNJ5-non-mutated APAs, all studies reported the association between impaired cardiac functions and KCNJ5 mutation status. Among 6 studies evaluating the cure of hypertension after surgery, all studies showed that KCNJ5 mutation was significantly associated with the cure of hypertension. In quality assessment, 7 studies were at serious risk of bias, while the remaining studies were at moderate risk of bias. CONCLUSIONS: This systematic review provided evidence of the significant association between KCNJ5 mutation and unfavorable cardiovascular outcomes in patients with primary aldosteronism. Further research is needed to improve the quality of evidence on this topic and elucidate the underlying mechanisms of the potential burden of KCNJ5 mutation.

Effectiveness of DialBetesPlus, a self-management support system for diabetic kidney disease: Randomized controlled trial.

We evaluated the effectiveness of a mobile health (mHealth) intervention for diabetic kidney disease patients by conducting a 12-month randomized controlled trial among 126 type 2 diabetes mellitus patients with moderately increased albuminuria (urinary albumin-to-creatinine ratio (UACR): 30-299 mg/g creatinine) recruited from eight clinical sites in Japan. Using a Theory of Planned Behavior (TPB) behavior change theory framework, the intervention provides patients detailed information in order to improve patient control over exercise and dietary behaviors. In addition to standard care, the intervention group received DialBetesPlus, a self-management support system allowing patients to monitor exercise, blood glucose, diet, blood pressure, and body weight via a smartphone application. The primary outcome, change in UACR after 12 months (used as a surrogate measure of renal function), was 28.8% better than the control group's change (P = 0.029). Secondary outcomes also improved in the intervention group, including a 0.32-point better change in HbA1c percentage (P = 0.041). These improvements persisted when models were adjusted to account for the impacts of coadministration of drugs targeting albuminuria (GLP-1 receptor agonists, SGLT-2 inhibitors, ACE inhibitors, and ARBs) (UACR: -32.3% [95% CI: -49.2%, -9.8%] between-group difference in change, P = 0.008). Exploratory multivariate regression analysis suggests that the improvements were primarily due to levels of exercise. This is the first trial to show that a lifestyle intervention via mHealth achieved a clinically-significant improvement in moderately increased albuminuria.

Adrenal venous sampling criteria for chemiluminescent enzyme immunoassay as a preferable alternative to radioimmunoassay in primary aldosteronism.

Plasma aldosterone concentration (PAC) was routinely measured using radioimmunoassay (RIA); however, the RIA kit was discontinued in March 2021 in Japan. This study examined PAC conversion in adrenal venous sampling (AVS) and AVS criteria when measured using chemiluminescent enzyme immunoassay (CLEIA). PAC of 415 adrenal venous blood samples from AVS (including segmental AVS) of 63 patients with primary aldosteronism was measured using RIA (Spac-S aldosterone kit; Fujirebio Inc.) and CLEIA (Lumipulse Presto Aldosterone; Fujirebio Inc.). PAC of 70 AVS samples was also measured using liquid chromatography-mass spectrometry (LC-MS/MS, ASKA Pharma Medical Co., Ltd.). PAC conversion formulas were determined for each AVS sample assay. PAC measured using CLEIA was significantly correlated with that measured using RIA (correlation coefficient = 0.971). The PAC conversion formula was PAC (CLEIA) = PAC (RIA) × 0.772 - 1,199 pg/mL. The PAC of 14,000 pg/mL in RIA was equivalent to 9,613 pg/mL in CLEIA. PAC measured using CLEIA was also correlated with that measured using LC-MS/MS, and the PAC conversion formula was PAC (CLEIA, pg/mL) = 0.97 × PAC (LC-MS/MS, pg/mL) + 211. The inter-assay coefficient of variability (CV) was 1.1-1.3% and intra-assay CV was 1.0-1.7%, measured using CLEIA. The PAC conversion formula for AVS samples was obtained using CLEIA and RIA, and the conversion formula was different from that for peripheral blood. PAC values measured by CLEIA showed preferable accuracy and high concordance with those measured by LC-MS/MS, even in AVS samples. The study outcomes are useful for interpreting AVS results using non-RIA measurement methods.

Efficacy of StepAdd, a Personalized mHealth Intervention Based on Social Cognitive Theory to Increase Physical Activity Among Patients With Type 2 Diabetes Mellitus: Protocol for a Randomized Controlled Trial.

BACKGROUND: Increasing physical activity improves glycemic control in patients with type 2 diabetes (T2D). Mobile health (mHealth) interventions have been proven to increase exercise, but engagement often fades with time. As the use of health behavior theory in mHealth design can increase effectiveness, we developed StepAdd, an mHealth intervention based on the constructs of social cognitive theory (SCT). StepAdd improves exercise behavior self-efficacy and self-regulation through the use of goal-setting, barrier-identifying, and barrier-coping strategies, as well as automatic feedback functions. A single-arm pilot study of StepAdd among 33 patients with T2D showed a large increase in step count (mean change of 4714, SD 3638 daily steps or +86.7%), along with strong improvements in BMI (mean change of -0.3 kg/m2) and hemoglobin A1c level (mean change of -0.79 percentage points). OBJECTIVE: In this study, we aim to investigate the efficacy and safety of StepAdd, an mHealth exercise support system for patients with T2D, via a large, long, and controlled follow-up to the pilot study. METHODS: This is a randomized, open-label, multicenter study targeting 160 patients with T2D from 5 institutions in Japan with a 24-week intervention. The intervention group will record daily step counts, body weight, and blood pressure using the SCT-based mobile app, StepAdd, and receive feedback about these measurements. In addition, they will set weekly step count goals, identify personal barriers to walking, and define strategies to overcome these barriers. The control group will record daily step counts, body weight, and blood pressure using a non-SCT-based placebo app. Both groups will receive monthly consultations with a physician who will advise patients regarding lifestyle modifications and use of the app. The 24-week intervention period will be followed by a 12-week observational period to investigate the sustainability of the intervention's effects. The primary outcome is between-group difference in the change in hemoglobin A1c values at 24 weeks. The secondary outcomes include other health measures, measurements of steps, measurements of other behavior changes, and assessments of app use. The trial began in January 2023 and is intended to be completed in December 2025. RESULTS: As of September 5, 2023, we had recruited 44 patients. We expect the trial to be completed by October 8, 2025, with the follow-up observation period being completed by December 31, 2025. CONCLUSIONS: This trial will provide important evidence about the efficacy of an SCT-based mHealth intervention in improving physical activities and glycemic control in patients with T2D. If this study proves the intervention to be effective and safe, it could be a key step toward the integration of mHealth as part of the standard treatment received by patients with T2D in Japan. TRIAL REGISTRATION: Japan Registry of Clinical Trials (JRCT) jRCT2032220603; https://rctportal.niph.go.jp/en/detail?trial_id=jRCT2032220603. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/53514.

Identifying primary aldosteronism patients who require adrenal venous sampling: a multi-center study.

Adrenal venous sampling (AVS) is crucial for subtyping primary aldosteronism (PA) to explore the possibility of curing hypertension. Because AVS availability is limited, efforts have been made to develop strategies to bypass it. However, it has so far proven unsuccessful in applying clinical practice, partly due to heterogeneity and missing values of the cohorts. For this purpose, we retrospectively assessed 210 PA cases from three institutions where segment-selective AVS, which is more accurate and sensitive for detecting PA cases with surgical indications, was available. A machine learning-based classification model featuring a new cross-center domain adaptation capability was developed. The model identified 102 patients with PA who benefited from surgery in the present cohort. A new data imputation technique was used to address cross-center heterogeneity, making a common prediction model applicable across multiple cohorts. Logistic regression demonstrated higher accuracy than Random Forest and Deep Learning [(0.89, 0.86) vs. (0.84, 0.84), (0.82, 0.84) for surgical or medical indications in terms of f-score]. A derived integrated flowchart revealed that 35.2% of PA cases required AVS with 94.1% accuracy. The present model enabled us to reduce the burden of AVS on patients who would benefit the most.

Segmental low-density area on contrast-enhanced CT is a possible clue to diagnosing branch artery fibromuscular dysplasia.

Summary: Fibromuscular dysplasia can cause renovascular hypertension. Since fibromuscular dysplasia may be underdiagnosed, precise diagnosis and management are crucial, especially for young women. A 20-year-old woman with hypertension and hypokalemia was referred to our hospital for further evaluation of secondary hypertension. At the previous hospital, her blood pressure was 160/110 mmHg and the serum potassium level was 2.9 mEq/L. The equilibrium phase on contrast-enhanced computed tomography revealed a low-density area in the upper median portion of the right kidney. On admission to our hospital, her blood pressure was 141/96 mmHg under 5 mg of amlodipine. Laboratory tests revealed plasma renin activity of 11.3 ng/mL/h and plasma aldosterone concentration of 117.1 pg/mL. Renal venous sampling of active renin concentration showed a right-to-left renin ratio of 3.13, confirming a significant increase in renin secretion from the right kidney. Selective reno-angiography detected focal stenosis with adjacent aneurysmal dilation and tortuosity in the proximal branch of the right renal artery. She was diagnosed with branch artery fibromuscular dysplasia and successfully treated with percutaneous transluminal angioplasty. After the treatment, she was free from hypertension and hypokalemia without any medications. Since branch artery fibromuscular dysplasia is sometimes difficult to diagnose, contrast-enhanced computed tomography can be a promising diagnostic tool as shown in this case. Concerning treatment, our patient was treated with percutaneous transluminal angioplasty, which should be considered for women of reproductive age because recommended antihypertensive medications can be teratogenic even in the first trimester of pregnancy. Learning points: Although branch artery fibromuscular dysplasia (FMD) is sometimes difficult to diagnose, it should be considered in patients with high-renin, high-aldosterone hypertension. Branch artery FMD can present with a low-density area of the kidney on contrast-enhanced computed tomography, as shown in this case. Percutaneous transluminal angioplasty (PTA) can be an appropriate treatment for branch artery FMD, especially in young female patients. PTA may immediately improve hypertension and hypokalemia without the need for medications.

Lethal Arrhythmia Induced by Severe Hypokalemia with Primary Aldosteronism: A Case Report and Literature Review.

A 26-year-old woman experienced sudden loss of consciousness with respiratory arrest while engaged in a heated conversation shortly after consuming a carbohydrate-rich meal; she was resuscitated immediately. Severe hypokalemia became evident and was deemed to have caused lethal arrhythmia. She was diagnosed with a left aldosterone-producing adenoma and achieved remission following partial adrenalectomy. Primary aldosteronism is frequently complicated by hypokalemia; however, hypokalemia-induced lethal arrhythmias are rare. Clinicians should recognize that primary aldosteronism can potentially cause sudden death in apparently healthy individuals; hence, an early diagnosis and proper treatment are critical.

Differences between left adrenal vein sampling sites revealed with segmental sampling in primary aldosteronism.

OBJECTIVES: To clarify the differences between two left sampling sites (left adrenal central vein [LCV] and common trunk [CMT], conjunction with LCV and inferior phrenic vein) and their impact on adrenal venous sampling (AVS) in primary aldosteronism by analyzing the results of segmental AVS (sAVS). METHODS: We retrospectively analyzed a final cohort of 432 patients who underwent cosyntropin-stimulated sAVS from 2017 to 2020. Hormone levels in the LCV and the CMT were compared. Subtype diagnosis was based on the lateralization index with LCV and CMT sampling (a cutoff value of 4) and sAVS after excluding patients with a selectivity index (SI) <3. RESULTS: Compared with the LCV, CMT sampling showed significantly lower aldosterone and cortisol levels and a higher proportion of cases with an SI of <3 (2.8% vs 0.5%, p = 0.025) and <5 (6.9% vs 0.5%, p < 0.001), while the aldosterone-to-cortisol ratio and the lateralization index were not significantly different. Subtyping of both sites was concordant in 94.7% (393/415) and discordant in the remainder, which included left and right aldosterone-producing adenoma and idiopathic hyperaldosteronism cases referring to the sAVS. There was no significant difference between the concordance rate of the two sampling sites based on the sAVS diagnosis. CONCLUSIONS: LCV sampling meets the SI criteria for successful AVS more frequently compared with CMT sampling, but neither was better than the other in terms of diagnosis under conditions of meeting the criteria. ADVANCES IN KNOWLEDGE: LCV sampling would decrease the number of cases judged as AVS failure.

Association of Reversal of Renin Suppression With Long-Term Renal Outcome in Medically Treated Primary Aldosteronism.

BACKGROUND: Renin suppression in primary aldosteronism indicates mineralocorticoid receptor activation via excessive aldosterone secretion, inducing renal damage. We investigated whether the reversal of renin suppression after the initiation of mineralocorticoid receptor antagonist therapy was associated with long-term renal outcomes in medically treated patients with primary aldosteronism. METHODS: This retrospective cohort study included 318 patients with primary aldosteronism treated with mineralocorticoid receptor antagonist between 2008 and 2020 at the Yokohama Rosai Hospital in Japan. The posttreatment renin status was defined as unsuppressed (ie, reversal of renin suppression) when individual plasma renin activity after the initiation of mineralocorticoid receptor antagonist (post-plasma renin activity) was ≥1.0 ng/mL per hour; otherwise, it was defined as suppressed. We analyzed the association of posttreatment renin status with subsequent longitudinal estimated glomerular filtration rate changes using linear mixed-effects models for repeated measurements, adjusting for potential confounders. RESULTS: The posttreatment renin status of 119 patients was unsuppressed (median post-plasma renin activity, 1.7 ng/mL per hour) and that of 199 patients was suppressed (median post-PRA, 0.5 ng/mL per hour). Through the median follow-up period of 3.1 years, the decline in estimated glomerular filtration rate was milder among patients with the unsuppressed posttreatment renin (-0.46 [95% CI, -0.63 to -0.28] mL/min per 1.73 m2 per year) than those with suppressed posttreatment renin (-1.41 [95% CI, -1.56 to -1.27] mL/min per 1.73 m2 per year; difference, 0.96 [95% CI, 0.72-1.20] mL/min per 1.73 m2 per year). CONCLUSIONS: Our findings may highlight the importance of reversing renin suppression with optimal mineralocorticoid receptor antagonist titration in medically treated primary aldosteronism, which could mitigate adverse renal outcomes.

Feasibility of single-port laparoscopic partial adrenalectomy with selective adrenal venous sampling and high-resolution ultrasound for unilateral aldosterone-producing adenomas.

BACKGROUND: The surgical and endocrinological outcomes of single-port laparoscopic partial adrenalectomy for patients with aldosterone-producing adenomas are unknown. Precise diagnosis of intra-adrenal aldosterone activity and a precise surgical procedure may improve outcomes. In this study, we aimed to determine the surgical and endocrinological outcomes of single-port laparoscopic partial adrenalectomy with preoperative segmental selective adrenal venous sampling and intraoperative high-resolution laparoscopic ultrasound in patients with unilateral aldosterone-producing adenomas. We identified 53 patients with partial adrenalectomy and 29 patients with laparoscopic total adrenalectomy. Single-port surgery was performed for 37 and 19 patients, respectively. METHODS: A single-center, retrospective cohort study. All patients with unilateral aldosterone-producing adenomas diagnosed by selective adrenal venous sampling and treated surgically between January 2012 and February 2015 were included. Follow-up with biochemical and clinical assessments was set at 1 year after surgery for short-term outcomes and was performed every 3 months after surgery. RESULTS: We identified 53 patients with partial adrenalectomy and 29 patients with laparoscopic total adrenalectomy. Single-port surgery was performed for 37 and 19 patients, respectively. Single-port surgery was associated with shorter operative and laparoscopic times (odds ratio, 0.14; 95% confidence interval, 0.039-0.49; P = .002 and odds ratio, 0.13; 95% confidence interval, 0.032-0.57; P = .006, respectively). All single-port and multi-port partial adrenalectomy cases showed complete short-term (median 1 year) biochemical success, and 92.9% (26 of 28 patients) who underwent single-port partial adrenalectomy and 100% (13 of 13 patients) who underwent multi-port partial adrenalectomy showed complete long-term (median 5.5 years) biochemical success. No complications were observed with single-port adrenalectomy. CONCLUSION: Single-port partial adrenalectomy is feasible after selective adrenal venous sampling for unilateral aldosterone-producing adenomas, with shorter operative and laparoscopic times and a high rate of complete biochemical success.

Node-by-node diagnosis for multiple ipsilateral nodules by segmental adrenal venous sampling in primary aldosteronism.

OBJECTIVES: In patients with primary aldosteronism (PA), multiple adrenocortical nodules may be present on the surgical side. The aim of this study was to clarify the pathological diagnosis and the node-by-node diagnostic capability of segmental adrenal venous sampling (sAVS). DESIGN: Retrospective study. PATIENTS: A total of 162 patients who underwent adrenalectomy following sAVS were studied. MEASUREMENTS: Multiple nodules on the surgical side were extracted while referring to contrast-enhanced computed tomography images. We also performed a detailed histopathological analysis of the resected specimens from patients undergoing sAVS, which included immunohistochemistry for CYP11B2. RESULTS: In 11 (6.8%) patients, two to three nodules were detected on the surgical side. All patients were diagnosed by sAVS with at least one aldosterone-producing adenoma (APA) for localized aldosterone elevation in tributaries. Seven patients showed a lateralization index value of ≥4 after ACTH stimulation. Histopathologically and clinically, two patients had two or three CYP11B2-positive APAs, and the other nine patients both APAs and non-APAs. The positive predictive value of the most suspected APA, that is, the drainer that showed the highest aldosterone level by sAVS, was 11/11 (100%, 95% confidence interval [CI]: 71.5%-100%), while that for the second and third suspected APA was 3/7 (42.9%, 95% CI: 9.9%-81.6%), and they were significantly different (p = .01). Further, the positive predictive value of non-APA was 4/4 (100%, 95% CI: 39.8%-100%). CONCLUSIONS: The sAVS could correctly diagnose the aldosterone production in multiple ipsilateral adrenal nodules.

Association Between Aldosterone and Hypertension Among Patients With Overt and Subclinical Hypercortisolism.

Introduction: Hypertension is one of the most common clinical features of patients with overt and subclinical hypercortisolism. Although previous studies have shown the coexistence of autonomous cortisol and aldosterone secretion, it is unclear whether aldosterone plays a role in hypertension among patients with hypercortisolism. Therefore, we examined the associations of plasma aldosterone concentrations (PACs) with hypertension among patients with overt and subclinical hypercortisolism. Methods: This single-center retrospective cohort study included patients with adrenal tumor and serum cortisol levels after 1-mg dexamethasone suppression test >1.8 µg/dL (50 nmol/L). Using multivariable regression models adjusting for baseline characteristics, we investigated the association of PACs with systolic blood pressure and postoperative improvement of hypertension after the adrenalectomy. Results: Among 89 patients enrolled in this study (median age, 51 years), 21 showed clinical signs of Cushing syndrome (overt hypercortisolism) and 68 did not show clinical presentations (subclinical hypercortisolism). We found that higher PACs were significantly associated with elevated systolic blood pressure among patients with subclinical hypercortisolism (adjusted difference [95% CI] = +0.59 [0.19-0.99], P = 0.008) but not among those with overt hypercortisolism. Among 33 patients with subclinical hypercortisolism and hypertension who underwent adrenalectomy, the postoperative improvement of hypertension was significantly associated with higher PACs at baseline (adjusted risk difference [95% CI] = +1.45% [0.35-2.55], P = 0.01). Conclusion: These findings indicate that aldosterone may contribute to hypertension among patients with subclinical hypercortisolism. Further multi-institutional and population-based studies are required to validate our findings and examine the clinical effectiveness of the intervention targeting aldosterone for such patients.

Aldosterone-Producing Adenomas of Increased Size Are Associated With Higher Steroidogenic Activity.

CONTEXT: There are inconsistent results and insufficient evidence as to whether an association exists between the size and aldosterone-producing ability of aldosterone-producing adenomas. OBJECTIVE: We further investigated this possible association retrospectively. METHODS: A total of 142 cases of primary aldosteronism diagnosed as unilateral by adrenal venous sampling at 2 referral centers between 2009 and 2019 were included. We classified these individuals into small and large tumor groups using a diameter of 14 mm as a cutoff. This size was the median diameter of the tumor on the affected side of the adrenal gland. We compared plasma aldosterone concentration (PAC), plasma renin activity (PRA), PAC to PRA ratio, PAC from a saline infusion test (SIT), urinary aldosterone secretion (uAld), and serum potassium as indices of aldosterone-producing ability between the 2 groups. In some cases, we conducted histopathological evaluations and detection of the KCNJ5 mutation. RESULTS: PAC, PAC to PRA ratio, PAC from SIT, and uAld were higher and serum potassium was lower in the large tumor group. PAC, PAC from SIT, uAld, and serum potassium significantly correlated with tumor diameter. PRA was not associated with tumor diameter. Clear cell-dominant cases were more common in the large tumor group, while cases showing a strong expression of CYP11B2 were not significantly different between the groups. KCNJ5 mutations tended to be more common in the large tumor group. CONCLUSION: The higher aldosterone-producing ability in larger adenomas can be used to infer the responsible lesion and disease type.

A Case of 123I-Metaiodobenzylguanidine Scintigraphy-Negative Pheochromocytoma with a Tumor-Developing Mutation in the RET Gene.

Pheochromocytoma (PCC) is rare catecholamine-producing endocrine tumor that metastasizes in approximately 10% of cases. As a functional imaging of PCC, 123I-metaiodobenzylguanidine (MIBG) scintigraphy was established, and some cases of PCC exhibit negative accumulation on MIBG scintigraphy, indicating a high risk of metastasis. Additionally, germline genetic variants of PCC are evident in approximately 30% of cases, although the genotype-phenotype correlation in PCC, especially the association between genetic mutations and MIBG scintigraphy, remains unclear. A 33-year-old man was admitted to our hospital for further examination for hypertension. He was diagnosed with sporadic PCC, and left adrenalectomy was performed. The adrenal tumor was negative on MIBG scintigraphy. Histology of the tumor revealed a moderately differentiated PCC. Target gene testing revealed a mutation in RET (c.2071G > A). This mutation has been reported to be a tumor-developing gene involved in the pathogenesis of PCC. Moreover, the RET mutation is the only gene mutation reported in a previous study of PCC with negative results on MIBG scintigraphy, except for the SDHB gene mutation, which is a common mutation in metastatic PCC. Correctively, the present RET gene mutation may be associated to MIBG-scintigraphy negative PCC and its pathophysiology. Clinicians should follow such cases more cautiously in clinical practice.

Comparison of Echocardiographic Changes Between Surgery and Medication Treatment in Patients With Primary Aldosteronism.

Background Primary aldosteronism can cause cardiac dysfunction, including left ventricular hypertrophy, left ventricular diastolic dysfunction, and left atrial enlargement. A few studies have compared the cardioprotective effects between surgery and medication for primary aldosteronism, although most have not adjusted for baseline disease status. In this study, we investigated the difference in cardiovascular outcomes between surgery and medication treatment for primary aldosteronism after adjusting for baseline clinical characteristics, including aldosterone level and pretreatment echocardiographic information. Methods and Results We retrospectively analyzed 220 patients diagnosed with primary aldosteronism who underwent adrenalectomy (n=144) or medication treatment (n=76) between 2009 and 2019. Echocardiographic changes were evaluated pretreatment and 1 year posttreatment. The surgery group had lower potassium, lower plasma renin activity, and higher plasma aldosterone concentration than the medication group, indicating a severe primary aldosteronism phenotype in the former. The decrease in left ventricular mass index after treatment was significantly greater in the surgery group than in the medication group (P=0.047). However, this relationship was not noted after multivariable regression analysis (standard ß=-0.08, P=0.17). Additionally, decreased parameter values related to left ventricular diastolic dysfunction and left atrial enlargement were not different between the groups. Pretreatment echocardiographic values were most associated with changes in all echocardiographic parameters. The findings were consistent in the propensity score-matched analysis. Conclusions This study's findings suggest that there is no difference in cardioprotective efficacy between surgical and medication treatment under similar disease severity; however, it should be considered that several study participants with severe hyperaldosteronism were managed surgically.

Phenotypic Variability in a Family with Carney Complex Accompanied by a Novel Mutation Involving PRKAR1A.

Carney complex is a rare, autosomal dominant disease accompanied by multiple endocrine neoplastic syndromes. Mutations in the PRKAR1A gene have recently been reported as a cause of Carney complex, but genotype-phenotype correlations vary widely. A 15-year-old Japanese man (Case 1) with short stature visited our hospital with suspected Cushing's syndrome. Biochemical investigations suggested corticotropin-independent Cushing's syndrome. Computed tomography revealed multiple bilateral adrenal tumors, and a two-staged partial adrenalectomy was performed. Pathological findings revealed primary pigmented nodular adrenocortical disease (PPNAD). The patient also exhibited distinctive spotty skin pigmentation. Based on these features, the patient was diagnosed as Carney complex. Cascade screening of family members was performed, and the mother (Case 2) and elder brother (Case 3) were diagnosed as Carney complex. Case 2 showed cardiac myxoma, acromegaly, spotty skin pigmentation, and mammary myxoid fibroadenoma. Case 3 exhibited gigantism, spotty skin pigmentation, and thyroid nodules. Target gene testing in Case 1 and 2 revealed the same novel mutation in PRKAR1A gene (c.503G>T, p.Gly168Val). This mutation was predicted as a pathogenic variant by multiple in silico analyses. Here, we present a family of Carney complex cases with a novel PRKAR1A pathogenic variant exhibiting varied clinical phenotypes within each case. In these cases, some specific phenotypes of Carney complex, such as pigmentary disorders, myxomas, and PPNAD are important as clues for diagnosis and prognostic factors. Clinicians should consider further examination in patients with Carney complex-specific phenotypes.

Characteristics of aldosterone-producing adenomas in patients without plasma renin activity suppression.

Primary aldosteronism (PA) usually accompanies suppressed plasma renin activity (PRA) through a negative feedback mechanism. While some cases of PA with unsuppressed PRA were reported, there have been no studies about the characteristics of PA with unsuppressed PRA; thus, these characteristics were examined herein. Nine patients with unsuppressed PRA and 86 patients with suppressed PRA were examined. All patients underwent segmental adrenal venous sampling (sAVS) and adrenalectomy, and were pathologically confirmed to have cytochrome P450 11B2 (CYP11B2)-positive aldosterone-producing adenoma according to international histopathology consensus criteria. Unsuppressed and suppressed PRA were defined as PRA levels of > 1.0 and ≤ 1.0 ng/mL/hr, respectively, in multiple blood samples obtained in the resting position. The unsuppressed PRA group had higher morning cortisol levels (12.6 [8.5, 13.5] vs. 8.5 [7.1, 11.0] µg/dL, P = 0.03) and higher cortisol levels after a 1 mg dexamethasone suppression test (DST) (2.2 [1.6, 2.5] vs. 1.3 [1.0, 1.9] µ g/dL, P = 0.004) than the suppressed PRA group. The unsuppressed PRA group also showed higher aldosterone levels on the non-surgical side during sAVS (P = 0.02 before adrenocorticotropic hormone (ACTH) stimulation, P = 0.002 after ACTH stimulation), a higher intensity of CYP17 expression in the resected adrenal gland (P = 0.02), and a lower clinical complete success rate 1 year after surgery (P = 0.04) compared with those in the suppressed PRA group. These findings suggest that PA should not be ruled out by unsuppressed PRA among patients with hypertension, particularly when their cortisol levels remain unsuppressed in the 1 mg DST. Meanwhile, it should be acknowledged that patients with unsuppressed PRA have higher aldosterone levels on the non-surgical side, and a lower likelihood of postoperative complete clinical success is to be expected.