Corticosteroid rhythms in hypoparathyroid patients.

OBJECTIVE: Previous studies indicate a possible bidirectional stimulatory relationship between parathyroid hormone (PTH) and adrenocortical hormones, but the pattern of adrenocortical secretion in hypoparathyroidism is unknown. We aimed to characterize the adrenocortical secretion in patients with postsurgical hypoparathyroidism, and whether continuous subcutaneous PTH (1-34) infusion alters secretion patterns. DESIGN: Crossover interventional study. METHODS: We recruited 10 patients with postsurgical hypoparathyroidism with very low PTH levels on stable treatment with active vitamin D and calcium. Cortisol, cortisone, and aldosterone levels were measured in microdialysate from subcutaneous tissue over 24 h, before and during continuous subcutaneous PTH (1-34) infusion. Cortisol was also assayed in serum, saliva, and urine, and aldosterone and ACTH in serum and plasma, respectively. Ten patients with primary hyperparathyroidism and 10 healthy volunteers matched for sex and age served as controls. RESULTS: Hypoparathyroid patients displayed both ultradian and circadian rhythmicity for tissue cortisol, cortisone, and aldosterone. Tissue aldosterone and cortisone levels were significantly lower in hypoparathyroid patients than in healthy controls, with no difference in tissue cortisol, but a higher cortisol to cortisone ratio. Treatment with PTH (1-34) increased tissue levels of aldosterone, cortisol, and cortisone and reduced the ratio of cortisol to cortisone. CONCLUSION: Adrenocortical hormone levels are reduced in postsurgical hypoparathyroidism, and partly restored by short-term continuous subcutaneous PTH (1-34) therapy. CLINICAL TRIAL REGISTRATION NUMBER: NCT02986607.

Nanoplastics induce molecular toxicity in earthworm: Integrated multi-omics, morphological, and intestinal microorganism analyses.

The toxicity of nanoplastics (NPs) at relatively low concentrations to soil fauna at different organismal levels is poorly understood. We investigated the responses of earthworm (Eisenia fetida) to polystyrene NPs (90-110 nm) contaminated soil at a relatively low concentration (0.02 % w:w) based on multi-omics, morphological, and intestinal microorganism analyses. Results showed that NPs accumulated in earthworms' intestinal tissues. The NPs damaged earthworms' digestive and immune systems based on injuries of the intestinal epithelium and chloragogenous tissues (tissue level) and increased the number of changed genes in the digestive and immune systems (transcriptome level). The NPs reduced gut microorganisms' diversity (Shannon index) and species richness (Chao 1 index). Proteomic, transcriptome, and histopathological analyses showed that earthworms suffered from oxidative and inflammatory stresses. Moreover, NPs influenced the osmoregulatory metabolism of earthworms as NPs damaged intestinal epithelium (tissue level), increased aldosterone-regulated sodium reabsorption (transcriptome level), inositol phosphate metabolism (proteomic level) and 2-hexyl-5-ethyl-furan-3-sulfonic acid, and decreased betaine and myo-inositol concentrations (metabolic level). Transcriptional-metabolic and transcriptional-proteomic analyses revealed that NPs disrupted earthworm carbohydrate and arachidonic acid metabolisms. Our multi-level investigation indicates that NPs at a relatively low concentration induced toxicity to earthworms and suggests that NPs pollution has significant environmental toxicity risks for soil fauna.

Heavy metals controlling cardiovascular diseases risk factors in myocardial infarction patients in critically environmentally heavy metal-polluted steel industrial town Mandi-Gobindgarh (India).

Heavy metals (HMs) have a very significant clinical role in the pathogenesis, progression and management of cardiovascular diseases (CVDs). The prevalence of CVDs was reported to be higher in critically environmentally HM-polluted (EHMP) steel industrial town Mandi-Gobindgarh (India) for the last more than a decade. To ascertain the role of HMs in the onset of CVDs, the present study was chosen to investigate HMs content in myocardial infarction (MI) patients from EHMP steel industrial town Mandi-Gobindgarh. Total of 110 MI patients along with number- and age-matched healthy volunteers were recruited in the present investigation. The CVDs risk factors estimated in MI patients were overweight (higher body mass index), hypertension (higher systolic and diastolic blood pressures), dyslipidaemia (higher serum cholesterol, triglycerides and lower HDL cholesterol), inflammation (higher-serum C reactive protein and aldosterone) and elevated oxidative stress (higher urinary 8-hydroxydeoxyguanosine). An imbalance of serum electrolyte concentrations including Na (hypernatremia), Ca (hypercalcaemia) and K (hypokalaemia) was also observed in MI patients in which CVDs risk factors were found to correlate positively with serum Na and Ca and negatively with serum K, respectively. Hair HM analysis was used as a bio-indicator for monitoring body HM status from past environmental HM exposure in which CVDs risk factors were observed to correlate positively with higher hair concentrations of Zn, Fe, Mo, Pb, As, Ca and Na and negatively with lower hair concentrations of Cu, Mg, Mn and K in MI patients, respectively. Thus, higher hair concentrations of Zn and Pb indicate their higher environmental exposure and possible cause of higher CVDs risk factors in MI patients from Mandi-Gobindgarh.

Reference intervals and values for fecal cortisol, aldosterone, and the ratio of cortisol to dehydroepiandrosterone metabolites in four species of cetaceans.

The goal of the current study was to create reference intervals and values for several common and one potential novel physiological indicators of animal welfare for four species of cetaceans. The subjects included 189 bottlenose dolphins (Tursiops truncatus), 27 Indo-Pacific bottlenose dolphins (Tursiops aduncus), eight Pacific white-sided dolphins (Lagenorhynchus obliquidens), and 13 beluga whales (Delphinapterus leucas) at Alliance of Marine Mammal Parks and Aquariums and/or Association of Zoos and Aquariums accredited facilities. During two sampling time periods between July and November of 2018 and between January and April of 2019, fecal samples were collected weekly for five weeks from all animals. Samples were processed and analyzed using enzyme immunoassay for fecal cortisol, aldosterone, and dehydroepiandrosterone (DHEA) metabolites. Linear mixed models were used to examine demographic and time factors impacting hormone metabolite concentrations. Age, sex, and time of year were all significant predictors for some of the models (p < 0.01). An iOS mobile application ZooPhysioTrak was created for easy access to species-specific reference intervals and values accounting for significant predictors. For facilities without access to this application, additional reference intervals and values were constructed without accounting for significant predictors. Information gained from this study and the use of the application can provide reference intervals and values to make informed management decisions for cetaceans in zoological facilities.

ACTH Stimulation Maximizes the Accuracy of Peripheral Steroid Profiling in Primary Aldosteronism Subtyping.

CONTEXT: Adrenocorticotropic hormone (ACTH) can contribute to aldosterone excess in primary aldosteronism (PA) via increased melanocortin type 2 receptor expression. Dynamic manipulation of the hypothalamic-pituitary-adrenal (HPA) axis could assist PA subtyping, but a direct comparison of dynamic tests is lacking. OBJECTIVE: To investigate plasma steroid differences between aldosterone-producing adenoma (APA) and bilateral PA (BPA) relative to ACTH variations. METHODS: We conducted comprehensive dynamic testing in 80 patients: 40 with APA and 40 with BPA. Peripheral plasma was collected from each patient at 6 time points: morning; midnight; after 1 mg dexamethasone suppression; and 15, 30, and 60 minutes after ACTH stimulation. We quantified 17 steroids by mass spectrometry in response to ACTH variations in all patients and compared their discriminative power between the 2 PA subtypes. RESULTS: Patients with APA had higher morning and midnight concentrations of 18-hydroxycortisol, 18-oxocortisol, aldosterone, and 18-hydroxycorticosterone than those with BPA (P < 0.001 for all). In response to cosyntropin stimulation, the APA group had larger increments of aldosterone, 18-oxocortisol, 11-deoxycorticosterone, corticosterone, and 11-deoxycortisol (P < 0.05 for all). Following dexamethasone suppression, the APA group had larger decrements of aldosterone, 18-hydroxycortisol, and 18-oxocortisol (P < 0.05 for all), but their concentrations remained higher than in the BPA group (P < 0.01 for all). The highest discriminatory performance between the PA subtypes was achieved using steroids measured 15 minutes post-ACTH stimulation (area under receiver operating characteristic curve 0.957). CONCLUSION: Steroid differences between APA and BPA are enhanced by dynamic HPA testing; such noninvasive tests could circumvent the need for adrenal vein sampling in a subset of patients with PA.

Variability of Aldosterone Measurements During Adrenal Venous Sampling for Primary Aldosteronism.

BACKGROUND: Variability of aldosterone concentrations has been described in patients with primary aldosteronism. METHODS: We performed a retrospective cohort study of 340 patients with primary aldosteronism who underwent adrenal venous sampling (AVS) at a tertiary referral center, 116 of whom also had a peripheral venous aldosterone measured hours before the procedure. AVS was performed by the same interventional radiologist using bilateral, simultaneous sampling, under unstimulated and then stimulated conditions, and each sample was obtained in triplicate. Main outcome measures were: (i) change in day of AVS venous aldosterone from pre-AVS to intra-AVS and (ii) variability of triplicate adrenal venous aldosterone concentrations during AVS. RESULTS: Within an average duration of 131 minutes, 81% of patients had a decline in circulating aldosterone concentrations (relative decrease of 51% and median decrease of 7.0 ng/dl). More than a quarter (26%) of all patients had an inferior vena cava aldosterone of ≤5 ng/dl at AVS initiation. The mean coefficient of variation of triplicate adrenal aldosterone concentrations was 30% and 39%, in the left and right veins, respectively (corresponding to a percentage difference of 57% and 73%), resulting in lateralization discordance in up to 17% of patients if the lateralization index were calculated using only one unstimulated aldosterone-to-cortisol ratio rather than the average of triplicate measures. CONCLUSIONS: Circulating aldosterone levels can reach nadirs conventionally considered incompatible with the primary aldosteronism diagnosis, and adrenal venous aldosterone concentrations exhibit acute variability that can confound AVS interpretation. A single venous aldosterone measurement lacks precision and reproducibility in primary aldosteronism.

Repeat Adrenal Vein Sampling in Aldosteronism: Reproducibility and Interpretation of Persistently Discordant Results.

CONTEXT: The reproducibility of adrenal vein sampling (AVS) is unknown. OBJECTIVE: This work aimed to determine reproducibility of biochemical results and diagnostic lateralization in patients undergoing repeat AVS. METHODS: A retrospective chart review was conducted of single-center, single-operator AVS procedures at a tertiary care center. Included were patients with confirmed primary aldosteronism (PA) undergoing repeat AVS because of concerns about technical success or discordant diagnostic results. Simultaneous AVS was performed by an experienced operator using a consistent protocol of precosyntropin and postcosyntropin infusion. Among successfully catheterized adrenal veins (selectivity index ≥ 2), the correlation of the adrenalaldosterone/cortisol (A/C) ratio was measured between the first and second AVS. The secondary outcome measure was diagnostic agreement on repeat AVS lateralization (lateralization index ≥ 3). RESULTS: There were 46 sets of AVS from 23 patients at a median of 3 months apart. There was moderate correlation in A/C ratios in the adrenal veins and inferior vena cava (Spearman r = 0.49-0.59, P < .05) pre cosyntropin. Post cosyntropin, the correlation was better (Spearman r = 0.67-0.76, P < .05). In technically successful AVS, there was moderate correlation between the repeated lateralization indices (Spearman r = 0.53, P < .05). In 15 patients in whom repeat AVS was performed because of apparent lateralization discordance with computed tomography imaging, the final diagnosis was the same in the second AVS procedure. Initial failed AVS was successful 75% of the time on repeat attempt. CONCLUSION: Repeat AVS was feasible and usually successful when an initial attempt failed. There was modest correlation between individual repeat adrenal A/C ratios and lateralization indices when AVS was performed twice. The final lateralization diagnosis was identical in all cases. This demonstrates that AVS is a reliable and reproducible localizing test in PA.

Significance of Discordant Results Between Confirmatory Tests in Diagnosis of Primary Aldosteronism.

CONTEXT: Current clinical guidelines recommend confirmation of a positive result in at least one confirmatory test in the diagnosis of primary aldosteronism (PA). Clinical implication of multiple confirmatory tests has not been established, especially when patients show discordant results. OBJECTIVE: The aim of the present study was to explore the role of 2 confirmatory tests in subtype diagnosis of PA. DESIGN AND SETTING: A retrospective cross-sectional study was conducted at two referral centers. PARTICIPANTS AND METHODS: We identified 360 hypertensive patients who underwent both a captopril challenge test (CCT) and a saline infusion test (SIT) and exhibited at least one positive result. Among them, we studied 193 patients with PA whose data were available for subtype diagnosis based on adrenal vein sampling (AVS). MAIN OUTCOME MEASURE: The prevalence of bilateral subtype on AVS according to the results of the confirmatory tests was measured. RESULTS: Of patients studied, 127 were positive for both CCT and SIT (double-positive), whereas 66 were positive for either CCT or SIT (single-positive) (n = 34 and n = 32, respectively). Altogether, 135 were diagnosed with bilateral subtype on AVS. The single-positive patients had milder clinical features of PA than the double-positive patients. The prevalence of bilateral subtype on AVS was significantly higher in the single-positive patients than in the double-positive patients. (63/66 [95.5%] vs 72/127 [56.7%], P < .01). Several clinical parameters were different between CCT single-positive and SIT single-positive patients. CONCLUSION: Patients with discordant results between CCT and SIT have a high probability of bilateral subtype of PA on AVS.

Approach to the Patient with Primary Aldosteronism: Utility and Limitations of Adrenal Vein Sampling.

Several studies over the past 3 decades document a higher prevalence of primary aldosteronism (PA) among hypertensive patients than generally presumed. PA exists as a spectrum from mild to severe aldosterone excess. Although a variety of PA subtypes exist, the 2 most common are aldosterone-producing adenomas (APAs) and bilateral hyperaldosteronism (BHA). The distinction is important, because APA-and other subtypes, with aldosterone production mostly from 1 adrenal-can be cured surgically, and BHA should be treated medically with mineralocorticoid-receptor antagonists (MRAs). The major shortcomings in the tailored management of patients with possible PA are the low rates of screening for case identification and the expensive and technically challenging imaging and interventional procedures required to distinguish APA from BHA, especially adrenal vein sampling (AVS). When AVS identifies an APA and allows the patient to be cured surgically, the procedure is of great value. In contrast, the patient with BHA is treated with MRA whether AVS is performed or not. Consequently, it is prudent to gauge how likely it is to benefit from imaging and AVS in each case prior to embarking on these studies. The explosion of information about PA in the past decade, including predictors of APA and of surgical benefit, are useful in limiting the evaluation for some patients with a positive PA screening test. This article will review our suggestions for approaching these patients in a pragmatic style, recognizing the limitations to even the best resources and facilities.

Prediction of unilateral hyperaldosteronism on adrenal vein sampling using captopril challenge test in patients with primary aldosteronism.

Captopril challenge test (CCT) is a simple and safe confirmatory test for primary aldosteronism (PA). We investigated the effectiveness of the indices after captopril administration for prediction of unilateral hyperaldosteronism (UHA) on adrenal vein sampling (AVS). We studied 238 patients with PA who had CCT and successful AVS between July 2007 and December 2019 in Sapporo City General Hospital. Receiver operating characteristic (ROC) curve analysis showed that the diagnostic performance for prediction of UHA on AVS in regard to the reduction rate of plasma aldosterone concentration (PAC) after captopril administration was inferior to aldosterone to renin ratio (ARR) and PAC (area under the ROC curve 0.72 vs. 0.84, 0.72 vs. 0.89, respectively, both p < 0.01). Based on the optimal cut-off values in ARR (897 pg/mL/ng/mL/h, sensitivity 64.6%, specificity 93.0%) and PAC (203 pg/mL, sensitivity 73.9%, specificity 93.0%) after captopril administration, the patients were divided into three groups: (1) both positive, (2) one positive, and (3) both negative. The prevalence of UHA on AVS in the three groups were 90.0%, 52.9%, and 7.3%, respectively. In the first group, 31 of 32 patients with unilateral nodular lesion on CT had an ipsilateral unilateral AVS. In conclusion, the combination of post-captopril ARR and PAC is useful for prediction of laterality diagnosis on AVS. AVS is strongly recommended in patients with both positive or one positive results for the optimal cut-off values of post-captopril ARR and PAC and is weakly recommended in patients with both negative results.

Confirmatory testing of primary aldosteronism with saline infusion test and LC-MS/MS.

OBJECTIVE: Saline infusion testing (SIT) for confirmation of primary aldosteronism (PA) is based on impaired aldosterone suppression in PA compared to essential hypertension (EH). In the past, aldosterone was quantified using immunoassays (IA). Liquid chromatography tandem mass spectrometry (LC-MS/MS) is increasingly used in clinical routine. We aimed at a method-specific aldosterone threshold for the diagnosis of PA during SIT and explored the diagnostic utility of steroid panel analysis. DESIGN: Retrospective cohort study of 187 paired SIT samples (2009-2018). Diagnosis of PA (n = 103) and EH (n = 84) was established based on clinical routine workup without using LC-MS/MS values. SETTING: Tertiary care center. METHODS: LC-MS/MS using a commercial steroid panel. Receiver operator characteristics analysis was used to determine method-specific cut-offs using a positive predictive value (PPV) of 90% as criterion. RESULTS: Aldosterone measured by IA was on average 31 ng/L higher than with LC-MS/MS. The cut-offs for PA confirmation were 54 ng/L for IA (sensitivity: 95%, 95% CI: 89.0-98.4; specificity: 87%, 95% CI: 77.8-93.3; area under the curve (AUC): 0.955, 95% CI: 0.924-0.986; PPV: 90%, 95% CI: 83.7-93.9) and 69 ng/L for LC-MS/MS (79%, 95% CI: 69.5-86.1; 89%, 95% CI: 80.6-95.0; 0.902, 95% CI: 0.857-0.947; 90%, 95% CI: 82.8-94.4). Other steroids did not improve SIT. CONCLUSIONS: Aldosterone quantification with LC-MS/MS and IA yields comparable SIT-cut-offs. Lower AUC for LC-MS/MS is likely due to the spectrum of disease in PA and previous decision making based on IA results. Until data of a prospective trial with clinical endpoints are available, the suggested cut-off can be used in clinical routine.

Ultrafiltration in Acute Heart Failure: Implications of Ejection Fraction and Early Response to Treatment From CARRESS-HF.

Background Ultrafiltration is not commonly used because of higher incidence of worsening renal function without improved decongestion. We examined differential outcomes of high versus low fluid removal and preserved versus reduced ejection fraction (EF) in CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure). Methods and Results Baseline characteristics in the ultrafiltration arm were compared according to 24-hour ultrafiltration-based fluid removal above versus below the median. Patients were stratified by EF (≤40% or >40%). We compared clinical parameters of clinical decongestion during the hospitalization based on initial (≤24 hours) response to ultrafiltration. Cox-proportional hazards models were used to identify associations between fluid removal <24 hours and composite of death, hospitalization, or unscheduled outpatient/emergency department visit during study follow-up. The intention-to-treat analysis included 93 patients. Within 24 hours, median fluid removal was 1.89 L (Q1, Q3: 1.22, 3.16). The high fluid removal group had a greater urine output (9.08 versus 6.23 L, P=0.027) after 96 hours. Creatinine change from baseline to 96 hours was similar in both groups (0.10 mg/dL increase, P=0.610). The EF >40% group demonstrated larger increases of change in creatinine (P=0.023) and aldosterone (P=0.038) from baseline to 96 hours. Among patients with EF >40%, those with above median fluid removal (n=17) when compared with below median (n=17) had an increased rate of the combined end point (87.5% versus 47.1%, P=0.014). Conclusions In patients with acute heart failure, higher initial fluid removal with ultrafiltration had no association with worsening renal function. In patients with EF >40%, ultrafiltration was associated with worsening renal function irrespective of fluid removal rate and higher initial fluid removal was associated with higher rates of adverse clinical outcomes, highlighting variable responses to decongestive therapy.

Low-grade Cortisol Cosecretion Has Limited Impact on ACTH-stimulated AVS Parameters in Primary Aldosteronism.

CONTEXT: In primary aldosteronism, cosecretion of cortisol may alter cortisol-derived adrenal venous sampling indices. OBJECTIVE: To identify whether cortisol cosecretion in primary aldosteronism alters adrenal venous sampling parameters and interpretation. DESIGN: Retrospective case-control study. SETTING: A tertiary referral center. PATIENTS: 144 adult patients with primary aldosteronism who had undergone both adrenocorticotropic hormone-stimulated adrenal venous sampling and dexamethasone suppression testing between 2004 and 2018. MAIN OUTCOME MEASURES: Adrenal venous sampling indices including adrenal vein aldosterone/cortisol ratios and the selectivity, lateralization, and contralateral suppression indices. RESULTS: 21 (14.6%) patients had evidence of cortisol cosecretion (defined as a failure to suppress cortisol to ≤50 nmol/L post dexamethasone). Patients with evidence of cortisol cosecretion had a higher inferior vena cava cortisol concentration (P = .01) than those without. No difference was observed between the groups in terms of selectivity index, lateralization index, lateralization of aldosterone excess, or adrenal vein cannulation rate. CONCLUSIONS: Cortisol cosecretion alters some parameters in adrenocorticotrophic hormone-stimulated adrenal venous sampling but does not result in alterations in patient management.

Basal contralateral aldosterone suppression is rare in lateralized primary aldosteronism.

CONTEXT: Unilateral aldosteronomas should suppress renin and contralateral aldosterone secretion. Complete aldosterone suppression in contralateral adrenal vein sample (AVS) could predict surgical outcomes. OBJECTIVES: To retrospectively evaluate the prevalence of basal contralateral suppression using Aldosterone (A)contralateral(CL)/Aperipheral(P) as compared to (A/Cortisol(C)CL)/(A/C)P ratio in primary aldosteronism (PA) patients studied in two Canadian centers. To determine the best cut-off to predict clinical and biochemical surgical cure. To compare the accuracy of ACL/AP to the basal and post-ACTH lateralization index (LI) in predicting surgical cure. METHODS: In total, 330 patients with PA and successful AVS were included; 124 lateralizing patients underwent surgery. Clinical and biochemical cure at 3 and 12 months were evaluated using the PASO criteria. RESULTS: Using ACL/AP and (A/C)CL/(A/C)P at the cut-off of 1, the prevalence of contralateral suppression was 6 and 45%, respectively. Using ROC curves, the ACL/AP ratio is associated with clinical cure at 3 and 12 months and biochemical cure at 12 months. (A/C)CL/(A/C)P is associated with biochemical cure only. The cut-offs for ACL/AP offering the best sensitivity (Se) and specificity (Sp) for clinical and biochemical cures at 12 months are 2.15 (Se: 63% and Sp: 71%) and 6.15 (Se: 84% and Sp: 77%), respectively. Basal LI and post-ACTH LI are associated with clinical cure but only the post-ACTH LI is associated with biochemical cure. CONCLUSIONS: In lateralized PA, basal contralateral suppression defined by ACL/AP is rare and incomplete compared to the (A/C)CL/(A/C)P ratio and is associated with clinical and biochemical postoperative outcome, but with modest accuracy.

Adrenocortical tumorigenesis: Lessons from genetics.

Advances in genomics over the past two decades have allowed for elucidation of the genetic alterations leading to the development of adrenocortical tumors and/or hyperplasias. These molecular changes were initially discovered through the study of rare familial tumor syndromes such as McCune-Albright Syndrome, Carney complex, Li-Fraumeni syndrome, and Beckwith-Wiedemann syndrome, with the identification of alterations in genes and molecular pathways that subsequently led to the discovery of aberrations in these or related genes and pathways in sporadic tumors. Genetic alterations in GNAS, PRKAR1A, PRKACA, PRKACB, PDE11A, and PDE8B, that lead to aberrant cyclic adenosine monophosphate-protein (cAMP) kinase A signaling, were found to play a major role in the development of benign cortisol-producing adrenocortical tumors and/or hyperplasias, whereas genetic defects in KCNJ5, ATP1A1, ATP2B3, CACNA1D, CACNA1H, and CLCN2 were implicated in the development of benign aldosterone-producing tumors and/or hyperplasias through modification of intracellular calcium signaling. Germline ARMC5 defects were found to cause the development of primary bilateral macronodular adrenocortical hyperplasia with glucocorticoid and/or mineralocorticoid oversecretion. Adrenocortical carcinoma was linked primarily to aberrant p53 signaling and/or Wnt-ß-catenin signaling, as well as IGF2 overexpression, with frequent genetic alterations in TP53, ZNRF3, CTNNB1, and 11p15. This review focuses on the genetic underpinnings of benign cortisol- and aldosterone-producing adrenocortical tumors/hyperplasias and adrenocortical carcinoma.

Precise Mapping of Intra-Adrenal Aldosterone Activities Provides a Novel Surgical Strategy for Primary Aldosteronism.

Segmental selective adrenal venous sampling (sAVS) elucidates an intraadrenal aldosterone activity map (IAMap), which allows us to design a novel surgical treatment strategy for patients with primary aldosteronism. We evaluated the usefulness of sAVS by analyzing 278 patients with whom we had prospectively used IAMap using the criteria of sAVS for surgical indication between 2009 and 2015. We evaluated its diagnostic accuracy using pathological and postsurgical biochemical and clinical outcomes. One hundred twenty and 158 patients were diagnosed with unilateral and bilateral disease, respectively, through sAVS. The concordance of lateralization diagnosis with computed tomography imaging was 66.6%. Among the unilateral patients, we performed partial adrenalectomy in 68 patients whose IAMap showed focal aldosterone hypersecretion from computed tomography-detectable tumor in the affected adrenal gland. All of them achieved complete biochemical success 1 year after surgery. Furthermore, 25 of 158 bilateral disease patients underwent surgical resection because they were preoperatively diagnosed as bilateral aldosterone-producing adenomas by IAMap. These cases showed complete or partial biochemical success (28.0% and 72.0%, respectively); 36.0% showed complete clinical success. Pathological studies demonstrated that all 145 resected specimens possessed aldosterone-producing adenoma or multiple nodules (132 and 13 cases, respectively), and none showed diffuse hyperplasia. IAMap accurately diagnosed both bilateral and unilateral aldosterone-producing adenomas and diffuse hyperplasia before surgery. sAVS allows a novel surgical strategy for selected PA patients with favorable outcomes.

Controversies and advances in adrenal venous sampling in the diagnostic workup of primary aldosteronism.

Adrenal venous sampling (AVS) is a key part of the diagnostic workup of primary aldosteronism, distinguishing unilateral from bilateral disease and determining treatment options. Although AVS is a well-established procedure, many aspects remain controversial, including optimal patient selection for the procedure and exactly how AVS is performed and interpreted. Despite the controversies, a growing body of evidence supports the use of AVS in most patients with primary aldosteronism, though some specific patient groups may be able to forego AVS and proceed directly to treatment. Although AVS remains a difficult procedure, success rates may be improved with the use of advanced CT imaging techniques and/or rapid cortisol assays. New advances in nuclear imaging and steroid profiling may also offer alternatives or adjuncts to AVS in the future.

Historical changes and between-facility differences in adrenal venous sampling for primary aldosteronism in Japan.

Primary aldosteronism (PA) is a common curable cause of hypertension. Adrenal venous sampling (AVS) is recommended for subtype diagnosis but is a difficult procedure. Recently, an increased prevalence of PA was reported, creating a greater demand for treatment of the condition in clinical facilities. The aim of the present study was to identify the historical changes over time and the differences between facilities in the success rate and subtype diagnosis of PA. The database of the PA registry developed by the Japan PA Study (JPAS) was used. A total of 2599 patients with PA who underwent AVS were evaluated. The overall success rate of AVS was 88%. The bilateral subtype was the dominant subtype, comprising 69% of cases. During the period 2004-2011 to 2011-2017, there were significant changes in the total number of AVS procedures (from 562 to 1732), ratio of ACTH administration with AVS (75 to 97%), success rate (79 to 90%), and proportion with bilateral subtype diagnosis (53 to 72%). There were also significant inter-facility differences in the number of AVS procedures (6 to 322), success rate (59 to 97%), and proportion with the bilateral subtype (44 to 86%). The principal enrolled department was Endocrinology (86%), and the ratio of unilateral PA was significantly higher in this department than in others (32% vs. 25%). In conclusion, the number of AVS procedures performed, the success rate, and the proportion with the bilateral subtype increased over time after normalizing the centre difference. Significant differences were observed between the centres.

Kinetics and Interrelations of the Renin Aldosterone Response to Acute Psychosocial Stress: A Neglected Stress System.

CONTEXT: The renin-angiotensin-aldosterone system (RAAS) plays an important role in cardiovascular homeostasis and its dysfunction relates to negative health consequences. Acute psychosocial stress seems to activate the RAAS in humans, but stress kinetics and interrelations of RAAS parameters compared with a nonstress control group remain inconclusive. OBJECTIVE: We systematically investigated in a randomized placebo-controlled design stress kinetics and interrelations of the reactivity of RAAS parameters measured in plasma and saliva to standardized acute psychosocial stress induction. METHODS: 58 healthy young men were assigned to either a stress or a placebo control group. The stress group underwent the Trier Social Stress Test (TSST), while the control group underwent the placebo TSST. We repeatedly assessed plasma renin, and plasma and salivary aldosterone before and up to 3 hours after stress/placebo. We simultaneously assessed salivary cortisol to validate successful stress induction and to test for interrelations. RESULTS: Acute psychosocial stress induced significant increases in all endocrine measures compared with placebo-stress (all P ≤ .041). Highest renin levels were observed 1 minute after stress, and highest aldosterone and cortisol levels 10 and 20 minutes after stress, with salivary aldosterone starting earlier at 1 minute after stress. Renin completed recovery at 10 minutes, cortisol at 60 minutes, salivary aldosterone at 90 minutes, and plasma aldosterone at 180 minutes after stress. Stress increase scores of all endocrine measures related to each other, as did renin and cortisol areas under the curve with respect to increase (AUCi) and salivary and plasma aldosterone AUCi (all P ≤ .047). CONCLUSIONS: Our findings suggest that in humans acute psychosocial stress induces a differential and interrelated RAAS parameter activation pattern. Potential implications for stress-related cardiovascular risk remain to be elucidated.

Neuroprotective Biomarkers and Cognitive Function in a Long-Term Prospective Population-based Study of Aging US Adults.

BACKGROUND: Relationships between brain-derived neurotrophic factor (BDNF), insulin-like growth factor (IGF-1), aldosterone, and cognition in aging were evaluated in the population-based Epidemiology of Hearing Loss Study (1993 to present). METHODS: Beginning in 1998 to 2000, cognitive impairment was assessed by report of physician diagnoses and the Mini-Mental State Examination. In 2009 to 2010 and 2013 to 2016, information was collected on diagnosis of mild cognitive impairment/dementia. Decline in cognitive function was assessed by principal component analysis from additional tests administered during 2009 to 2010 and 2013 to 2016. BDNF, IGF-1, and aldosterone were measured in serum collected in 1998 to 2000. RESULTS: There were 1970 participants (mean age=66.9 y; 59.1% female) without cognitive impairment at baseline. Among women, low BDNF was associated with 16-year incident cognitive impairment [hazard ratio=1.76; 95% confidence interval (CI)=1.04, 2.98]. Among men, increasing IGF-1 was associated with decreased risk [per SD: relative risk (RR)=0.57; 95% CI=0.35, 0.92], whereas increasing aldosterone levels were associated with increased risk (per SD: RR=1.28; 95% CI=1.01, 1.62) for 5-year incident mild cognitive impairment/dementia. Overall, low BDNF was associated with increased risk (RR=1.52; 95% CI=1.02, 2.26) for 5-year cognitive decline. CONCLUSION: Low levels of serum BDNF and IGF-1 were associated with poorer cognition during aging. There may be differential biomarker effects by sex.