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

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.

Association between brain imaging biomarkers and continuous glucose monitoring-derived glycemic control indices in Japanese patients with type 2 diabetes mellitus.

INTRODUCTION: Although type 2 diabetes mellitus (T2DM) is associated with alterations in brain structure, the relationship between glycemic control indices and brain imaging markers remains unclear. This study aimed to investigate the association between continuous glucose monitoring (CGM)-derived glycemic control indices and brain imaging biomarkers assessed by MRI. RESEARCH DESIGN AND METHODS: This cross-sectional study included 150 patients with T2DM. The severity of cerebral white matter lesions (WMLs) was assessed using MRI for deep and subcortical white matter and periventricular hyperintensities. The degree of medial temporal lobe atrophy (MTA) was assessed using voxel-based morphometry. Each participant wore a retrospective CGM for 14 consecutive days, and glycemic control indices, such as time in range (TIR) and glycemia risk index (GRI), were calculated. RESULTS: The proportion of patients with severe WMLs showed a decreasing trend with increasing TIR (P for trend=0.006). The proportion of patients with severe WMLs showed an increasing trend with worsening GRI (P for trend=0.011). In contrast, no significant association was observed between the degree of MTA and CGM-derived glycemic control indices, including TIR (P for trend=0.325) and GRI (P for trend=0.447). CONCLUSIONS: The findings of this study indicate that the severity of WMLs is associated with TIR and GRI, which are indices of the quality of glycemic control. TRIAL REGISTRATION NUMBER: UMIN000032143.

A hyperaldosteronism subtypes predictive model using ensemble learning.

This study aimed to develop a machine-learning algorithm to diagnose aldosterone-producing adenoma (APA) for predicting APA probabilities. A retrospective cross-sectional analysis of the Japan Rare/Intractable Adrenal Diseases Study dataset was performed using the nationwide PA registry in Japan comprised of 41 centers. Patients treated between January 2006 and December 2019 were included. Forty-six features at screening and 13 features at confirmatory test were used for model development to calculate APA probability. Seven machine-learning programs were combined to develop the ensemble-learning model (ELM), which was externally validated. The strongest predictive factors for APA were serum potassium (s-K) at first visit, s-K after medication, plasma aldosterone concentration, aldosterone-to-renin ratio, and potassium supplementation dose. The average performance of the screening model had an AUC of 0.899; the confirmatory test model had an AUC of 0.913. In the external validation, the AUC was 0.964 in the screening model using an APA probability of 0.17. The clinical findings at screening predicted the diagnosis of APA with high accuracy. This novel algorithm can support the PA practice in primary care settings and prevent potentially curable APA patients from falling outside the PA diagnostic flowchart.

Primary aldosteronism with mild autonomous cortisol secretion increases renal complication risk.

Objective: In primary aldosteronism (PA), renal impairment has been identified as an important comorbidity. Excess cortisol production also may lead to renal damage; thus, concomitant mild autonomous cortisol secretion (MACS) may predispose PA patients to renal disorders. However, there is limited evidence to support this claim. Therefore, this study aimed to determine whether the concurrence of MACS and PA increases the risk of renal complications. Design: This study is a retrospective cross-sectional study. Methods: A total of 1310 patients with PA were stratified into two groups according to 1 mg dexamethasone suppression test (DST) results (cut-off post-DST serum cortisol 1.8 µg/dL): MACS (n = 340) and non-MACS (n = 970). The prevalence of renal complications was compared between the group. We also performed multiple logistic regression analysis to determine factors that increase the risk for renal complications. Results: The prevalence of lowered estimated glomerular filtration rate (eGFR) and proteinuria was nearly twice higher in the MACS group than in the non-MACS group. Not only plasma aldosterone concentration (PAC) but also the presence of MACS was selected as independent factors that were associated with the two renal outcomes. The risk of lower eGFR or proteinuria in patients who had MACS and higher levels PAC was several folds higher than in those who had an absence of MACS and lower levels of PAC. Conclusions: MACS is an independent risk factor for renal complications in patients with PA, and MACS concomitant with higher aldosterone secretion in PA patients causes an increase in the risk of developing renal complications.

Adrenal Venous Sampling-Guided Adrenalectomy Rates in Primary Aldosteronism: Results of an International Cohort (AVSTAT).

CONTEXT: Adrenal venous sampling (AVS) is the current criterion standard lateralization technique in primary aldosteronism (PA). Japanese registry data found that 30% of patients with unilateral PA did not undergo adrenalectomy, but the reasons for this and whether the same pattern is seen internationally are unknown. OBJECTIVE: To assess the rate of AVS-guided adrenalectomy across an international cohort and identify factors that resulted in adrenalectomy not being performed in otherwise eligible patients. DESIGN, SETTING, AND PARTICIPANTS: Retrospective, multinational, multicenter questionnaire-based survey of management of PA patients from 16 centers between 2006 and 2018. MAIN OUTCOME MEASURES: Rates of AVS implementation, AVS success rate, diagnosis of unilateral PA, adrenalectomy rate, and reasons why adrenalectomy was not undertaken in patients with unilateral PA. RESULTS: Rates of AVS implementation, successful AVS, and unilateral disease were 66.3%, 89.3% and 36.9% respectively in 4818 patients with PA. Unilateral PA and adrenalectomy rate in unilateral PA were lower in Japanese than in European centers (24.0% vs 47.6% and 78.2% vs 91.4% respectively). The clinical reasoning for not performing adrenalectomy in unilateral PA were more likely to be physician-derived in Japan and patient-derived in Europe. Physician-derived factors included non-AVS factors, such as good blood pressure control, normokalemia, and the absence of adrenal lesions on imaging, which were present before AVS. CONCLUSION: Considering the various unfavorable aspects of AVS, stricter implementation and consideration of surgical candidacy prior to AVS will increase its diagnostic efficiency and utility.

Diabetes Mellitus Itself Increases Cardio-Cerebrovascular Risk and Renal Complications in Primary Aldosteronism.

CONTEXT: The prevalence of diabetes mellitus (DM) in patients with primary aldosteronism (PA) is higher than in those with essential hypertension and the general population. Although DM is a common major risk factor for cardio-cerebrovascular (CCV) diseases and renal complications, details of its effects in PA have not been demonstrated. OBJECTIVE: The aim of this study was to determine the effects of coexistent DM on the risk of CCV events and progression of renal complications in PA patients. DESIGN: A multi-institutional, cross-sectional study was conducted. PATIENTS AND METHODS: PA patients experienced between January 2006 and October 2016 and with available data of CCV events and DM were enrolled from the Japan PA registry of the Japan Primary Aldosteronism Study/Japan Rare Intractable Adrenal Diseases Study (n = 2524). CCV events and renal complications were compared between a DM group and a non-DM group by logistic and liner-regression analysis. RESULTS: DM significantly increased the odds ratio (OR) of CCV events (OR 1.59, 95% CI: 1.05-2.41) and that of proteinuria (OR 2.25, 95% CI: 1.59-3.16). DM correlated significantly with declines in estimated glomerular filtration rate (ß = .05, P = .02). CONCLUSIONS: This the first report to demonstrate the presence of DM as an independent risk factor for CCV events and renal complications, even in PA patients. Management of DM should be considered in addition to the specific treatment of PA.

Obesity predicts persistence of resistant hypertension after surgery in patients with primary aldosteronism.

OBJECTIVE: Primary aldosteronism (PA) is considered a major cause of resistant hypertension (RHT). The prevalence of RHT has been recently reported to reach 18% in general hypertension. However, little is known about the prevalence and the outcomes after adrenalectomy of RHT in PA. Therefore, we aimed to clarify the prevalence and surgical outcomes in patients with both PA and RHT. PATIENTS AND DESIGN: Among 550 patients who underwent adrenalectomy for unilateral PA in the Japan PA Study, RHT was defined as an uncontrolled blood pressure (≥140/90 mm Hg) despite treatment with at least any three antihypertensives or hypertension controlled with at least four drugs. Surgical outcome was assessed by the biochemical and clinical outcome. RESULTS: Although 40 (7.3%) patients fulfilled the criteria for preoperative RHT, this should be underestimated because only 36% of patients with postoperative RHT were classified as having preoperative RHT. The prevalence of preoperative RHT was approximately 20% when estimated using the total number of patients with postoperative RHT and the ratio of postoperative RHT in patients with preoperative RHT. Although an improvement in hypertension was achieved in approximately 80% of patients with preoperative RHT, 20% of these exhibited persistent RHT. These patients were more obese than those for whom RHT improved after surgery. Notably, body mass index of ≥25 kg/m2 was an independent predictor of postoperative RHT. CONCLUSIONS: The prevalence of RHT in PA was lower than expected even with the adjustment for underestimation. Furthermore, obesity is an independent factor predicting the postoperative persistence of RHT.

Basal Plasma Aldosterone Concentration Predicts Therapeutic Outcomes in Primary Aldosteronism.

PURPOSE: Normal basal plasma aldosterone concentration (PAC) reflects mild aldosterone excess compared to high basal PAC. We previously reported lower risk for cardiovascular and cerebrovascular events in patients with primary aldosteronism (PA) and normal basal PAC (nPA) than in those with high basal PAC (hPA). However, the differences in therapeutic outcomes between nPA and hPA are unclear. The aim of this multi-institutional, retrospective cohort study was to determine the clinical significance of nPA to therapeutic outcomes, including adrenalectomy (ADX) and treatment with mineralocorticoid receptor antagonists (MRAs). METHODS: A total of 1146 patients with PA who were diagnosed and underwent adrenal venous sampling (AVS) between January 2006 and October 2016 were enrolled. The clinical parameters at baseline and after ADX or treatment with MRA were compared between the nPA and hPA groups. RESULTS: Significantly higher rates of absent clinical success (36.6 vs. 21.9%, P = 0.01) and absent biochemical success (26.4 vs. 5.2%, P < 0.01) were found for the nPA group than for the hPA group, respectively. Logistic regression analysis identified baseline PAC as a significant independent predictor of absent clinical success of ADX and MRAs. CONCLUSIONS: Plasma aldosterone concentration at baseline was a significant and independent predictor of absent clinical success of ADX and MRA. Mineralocorticoid receptor antagonist treatment appeared to be a better therapeutic choice than ADX in the nPA group.

Overestimation of glomerular filtration rate calculated from serum creatinine as compared with cystatin C in patients with subclinical hypercortisolism: Hyogo Adrenal Metabolic Registry.

The skeletal muscle mass are decreased in the patients with hypercortisolism. Glomerular filtration rate (eGFR) is not accurately evaluated by calculation from serum creatinine (eGFRcre) in these patients. However, it is not known whether it applies to patients with subclinical hypercortisolism. We investigated the dissociation between eGFRcre and eGFR calculated from cystatin C (eGFRcys) in patients with subclinical hypercortisolism and its association with the skeletal muscle mass. This cross-sectional study includes 23 patients with overt Cushing's syndrome (CS), 84 patients with possible autonomous cortisol secretion (pACS) and 232 patients with non-functioning adenomas (NFA). eGFRcre, eGFRcys, the ratio of eGFRcre to eGFRcys (eGFRcre/eGFRcys) were calculated. Skeletal muscle index (SMI) was measured by a direct segmental multi-frequency bioelectrical impedance body composition analyzer. eGFRcre/eGFRcys was significantly higher (p < 0.01) in pACS (mean ± standard error: 1.15 ± 0.02) than NFA (1.06 ± 0.01). In multiple linear regression analysis, the presence of pACS (ß = 0.162, p < 0.01), and post 1 mg-DST cortisol levels (ß = 0.190, p < 0.01) were significantly associated with eGFRcre/eGFRcys independent of age, gender, BMI and diabetes. eGFRcre/eGFRcys was significantly and inversely associated with SMI (r = -0.164, p = 0.02). Furthermore, post 1 mg-DST cortisol levels was significantly associated with SMI in simple (r = -0.177, p = 0.01) and multiple (ß = -0.089, p = 0.01) regression analyses. In conclusion, dissociation between eGFRcre and eGFRcys was observed in patients with subclinical hypercortisolism at least partly explained by muscle mass. Our findings raise an important clinical point that eGFRcre value should be carefully evaluated even in the phase of subclinical hypercortisolism.

Association between nighttime sleep duration, midday naps, and glycemic levels in Japanese patients with type 2 diabetes.

OBJECTIVES: To clarify the relationship between nighttime sleep duration, midday naps, and glycemic control in Japanese patients diagnosed with type 2 diabetes (n = 355) or impaired glucose tolerance (n = 43). METHODS: A total of 398 patients completed a self-administered questionnaire on sleep duration/quality and were divided into five groups according to their self-reported nighttime sleep duration: <5 h, 5-6 h, 6-7 h, 7-8 h, and >8 h. Each group was further divided into two subgroups each according to the presence or absence of midday naps. Poor glycemic control was defined as HbA1c ≥ 7.0%. RESULTS: Short nighttime sleep (<5 h), poor sleep induction, daytime sleepiness, and low sleep satisfaction were associated with high HbA1c levels. HbA1c was higher in the short nighttime sleep/no nap group than in non-nappers with different nighttime sleep duration, whereas the short nighttime sleep/nap group showed similar HbA1c levels to the other nap subgroups. In multivariate logistic regression models, after adjusting for a number of potential confounders, short (<5 h) nighttime sleep without nap was significantly associated with poor glycemic control compared with 6-7 h nighttime sleep without nap (OR [95% CI]: 7.14 [2.20-23.20]). However, taking naps reduced this risk for poor glycemic control in short sleepers. Other risk factors for poor glycemic control were low sleep satisfaction (1.73 [1.10-2.70]) and poor sleep induction (1.69 [1.14-2.50]). CONCLUSIONS: Poor sleep quality and quantity could aggravate glycemic control in type 2 diabetes. Midday naps could mitigate the deleterious effects of short nighttime sleep on glycemic control. CLINICAL TRIALS REGISTRATION: UMIN 000017887.

Serum Macro TSH Level is Associated with Sleep Quality in Patients with Cardiovascular Risks - HSCAA Study.

Macro thyroid-stimulating hormone (TSH) has been reported to be associated with seasonality and regulated by changes in day length in rodents, different from free TSH. In the present study, we investigated structural differences between macro TSH and free TSH levels in human serum, as well as the association of macro TSH with sleep quality. We enrolled 314 patients registered in the Hyogo Sleep Cardio-Autonomic Atherosclerosis (HSCAA) study. Sleep quality shown by actigraphy, sleep physical activity, and percent sleep in all and TSH closely matched subjects were significantly associated with high macro TSH levels. Macro and free TSH were similarly increased following thyrotropin-releasing hormone (TRH) stimulation, while circadian changes associated with those were distinct. To further analyze the structure of macro TSH, serum samples were separated by gel filtration chromatography. Although treatment with glycosidase did not affect morbidity, the macro TSH fraction had a markedly low affinity to the Con A column as compared with free TSH, indicating a distinct glycosylation structure. In conclusion, an increase in serum macro TSH is associated with low sleep quality and regulated in a manner distinct from free TSH, potentially due to an altered glycosylation structure.

Associations of Sleep Quality and Awake Physical Activity with Fluctuations in Nocturnal Blood Pressure in Patients with Cardiovascular Risk Factors.

BACKGROUND: Sleep quality and awake physical activity are important behavioral factors involved in the occurrence of cardiovascular diseases, potentially through nocturnal blood pressure (BP) changes. However, the impacts of quantitatively measured sleep quality and awake physical activity on BP fluctuation, and their relationships with several candidate causal factors for nocturnal hypertension are not well elucidated. METHODS: This cross-sectional study included 303 patients registered in the HSCAA study. Measurements included quantitatively determined sleep quality parameters and awake physical activity obtained by actigraph, nocturnal systolic BP (SBP) fall [100 × (1- sleep SBP/awake SBP ratio)], apnea hypopnea index, urinary sodium and cortisol secretion, plasma aldosterone concentration and renin activity, insulin resistance index, parameters of heart rate variability (HRV), and plasma brain-derived neurotrophic factor (BDNF). RESULTS: Simple regression analysis showed that time awake after sleep onset (r = -0.150), a parameter of sleep quality, and awake physical activity (r = 0.164) were significantly correlated with nocturnal SBP fall. Among those, time awake after sleep onset (ß = -0.179) and awake physical activity (ß = 0.190) were significantly and independently associated with nocturnal SBP fall in multiple regression analysis. In a subgroup of patients without taking anti-hypertensive medications, both time awake after sleep onset (ß = -0.336) and awake physical activity (ß = 0.489) were more strongly and independently associated with nocturnal SBP falls. CONCLUSION: Sleep quality and awake physical activity were found to be significantly associated with nocturnal SBP fall, and that relationship was not necessarily confounded by candidate causal factors for nocturnal hypertension.