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Aim Methods Results Conclusion Increasing the dietary intake of K+ in the setting of a high salt intake promotes renal Na+ excretion even though K+ concurrently enhances the secretion of aldosterone, the most effective stimulus for renal Na+ reabsorption. Here, we questioned whether in the high salt state a mechanism exists, which attenuates the aldosterone response to prevent renal Na+ reabsorption after high K+ intake.Mice were fed diets containing varying amounts of Na+ combined with KCl or KCitrate. Murine cortical connecting duct (mCCDcl1) cells were cultured in media containing normal or high [Cl−]. The response to aldosterone was analyzed by high‐resolution imaging and by biochemical approaches.The canonical cellular response to aldosterone, encompassing translocation of the mineralocorticoid receptor (MR) and activation of the epithelial Na+ channel ENaC was repressed in Na+‐replete mice fed a high KCl diet, even though plasma aldosterone concentrations were increased. The response to aldosterone was restored in Na+‐replete mice when the extracellular [Cl−] increase was prevented by feeding a high KCitrate diet. In mCCDcl1 cells, an elevated extracellular [Cl−] was sufficient to disrupt the aldosterone‐induced MR translocation.These findings indicate a pivotal role for extracellular [Cl−] in modulating renal aldosterone signaling to adapt MR activation by a high K+ intake to the NaCl balance. An impairment of [Cl−]‐mediated aldosterone resistance may contribute to excessive MR activation by aldosterone in the presence of a high salt intake characteristic of the Western diet, resulting in an inappropriate salt reabsorption and its downstream detrimental effects. [ABSTRACT FROM AUTHOR]

Key Clinical Message: In cases of primary hyperaldosteronism, the aldosterone renin ratio (ARR) is crucial for determining the need for adrenal vein sampling (AVS). Our case highlights the importance of utilizing ARR with AVS, contextual interpretation of plasma renin and aldosterone levels, and stresses that sole reliance on imaging without AVS may result in unnecessary or contralateral adrenalectomy. [ABSTRACT FROM AUTHOR]

Aims Methods Conclusion Benefits of mineralocorticoid receptor antagonists (MRAs) in heart failure with preserved and mildly reduced ejection fraction (HFpEF/HFmrEF) have not been established. Conventional randomized controlled trials are complex and expensive. The Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure with Preserved Ejection Fraction (SPIRRIT‐HFpEF) is a unique pragmatic registry‐based randomized controlled trial.SPIRRIT‐HFpEF is a multicentre, prospective, randomized, open‐label, blinded endpoint trial conducted on platforms in the Swedish Heart Failure Registry (SwedeHF) and the United States (US) Trial Innovation Network. Patients with HFpEF/HFmrEF are randomized 1:1 to spironolactone (or eplerenone) in addition to usual care, versus usual care alone. The primary outcome is total number of cardiovascular deaths and hospitalizations for heart failure. Outcomes are collected from Swedish administrative complete coverage registries and a US call centre and subsequently adjudicated. Simple eligibility criteria were based on data available in SwedeHF: heart failure as outpatient or at discharge from hospital, left ventricular ejection fraction ≥40%, N‐terminal pro‐B‐type natriuretic peptide >300 ng/L (in sinus rhythm) or >750 ng/L (in atrial fibrillation), with pre‐specified adjustment for elevated body mass index, and chronic loop diuretic use. Power and sample size assessments were based on an event‐driven design allowing enrolment over approximately 6 years, and application of hazard ratios from the TOPCAT trial, Americas subset. The final sample size is expected to be approximately 2400 patients.SPIRRIT‐HFpEF will be informative on the effectiveness of generic MRAs in HFpEF and HFmrEF, and on the feasibility of conducting pragmatic and registry‐based trials in heart failure and other chronic conditions. [ABSTRACT FROM AUTHOR]

Epithelial Na+ channels (ENaCs) are activated by proteolysis of the α and γ subunits at specific sites flanking embedded inhibitory tracts. To examine the role of α subunit proteolysis in channel activation in vivo, we generated mice lacking the distal furin cleavage site in the α subunit (αF2M mice). On a normal Na+ control diet, no differences in ENaC protein abundance in kidney or distal colon were noted between wild‐type (WT) and αF2M mice. Patch‐clamp analyses revealed similar levels of ENaC activity in kidney tubules, while no physiologically relevant differences in blood chemistry or aldosterone levels were detected. Male αF2M mice did exhibit diminished ENaC activity in the distal colon, as measured by amiloride‐sensitive short‐circuit current (ISC). Following dietary Na+ restriction, WT and αF2M mice had similar natriuretic and colonic ISC responses to amiloride. However, single‐channel activity was significantly lower in kidney tubules from Na+‐restricted αF2M mice compared with WT littermates. ENaC α and γ subunit expression in kidney and distal colon were also enhanced in Na+‐restricted αF2Mvs. WT mice, in association with higher aldosterone levels. These data provide evidence that disrupting α subunit proteolysis impairs ENaC activity in vivo, requiring compensation in response to Na+ restriction. Key points: The epithelial Na+ channel (ENaC) is activated by proteolytic cleavage in vitro, but key questions regarding the role of ENaC proteolysis in terms of whole‐animal physiology remain to be addressed.We studied the in vivo importance of this mechanism by generating a mouse model with a genetic disruption to a key cleavage site in the ENaC's α subunit (αF2M mice).We found that αF2M mice did not exhibit a physiologically relevant phenotype under normal dietary conditions, but have impaired ENaC activation (channel open probability) in the kidney during salt restriction.ENaC function at the organ level was preserved in salt‐restricted αF2M mice, but this was associated with higher aldosterone levels and increased expression of ENaC subunits, suggesting compensation was required to maintain homeostasis.These results provide the first evidence that ENaC α subunit proteolysis is a key regulator of channel activity in vivo. [ABSTRACT FROM AUTHOR]

Background: Adrenal vein sampling (AVS), integral to identifying surgically remediable unilateral primary aldosteronism (PA), is technically challenging and subject to fluctuations in cortisol and aldosterone secretion. Intra‐procedural adrenocorticotropic hormone (ACTH), conventionally administered as a 250‐μg bolus and/or 50 μg per hour infusion, increases cortisol and aldosterone secretion and can improve AVS success, but may cause discordant lateralisation compared to unstimulated AVS. Aims: To assess if AVS performed with ultra‐low dose ACTH infusion causes discordant lateralisation. Methods: Here, we describe our preliminary experience using an ultra‐low dose ACTH infusion AVS protocol. We retrospectively reviewed the results of consecutive AVS procedures (n = 37) performed with and without ultra‐low dose ACTH (1‐μg bolus followed by 1.25 μg per hour infusion). Results: Bilateral AV cannulation was successful in 70% of procedures pre‐ACTH and 89% post‐ACTH (p < 0.01). Sixty‐nine percent of studies lateralised pre‐ACTH and 55% post‐ACTH, improving to 79% when both groups were combined. Lateralisation was discordant in 11 cases, including eight in which lateralisation was present only on basal sampling, and three in which lateralisation occurred only with ACTH stimulation. Discussion: Overall, the decrease in lateralisation rates with ACTH was higher than previously reported for some protocols utilising conventional doses of ACTH. Our results suggest that AVS performed with ultra‐low dose ACTH can cause discordant lateralisation similar to AVS performed with conventional doses of ACTH. Conclusion: Prospective studies directly comparing low and conventional dose ACTH AVS protocols and long‐term patient outcomes are needed to help define the optimal ACTH dose for accurate PA subtyping. [ABSTRACT FROM AUTHOR]

Introduction: Our objective was to investigate the association between the presence of placental anastomoses and intertwin differences in renin‐angiotensin‐aldosterone activation in monochorionic twins using amniotic fluid aldosterone (AF‐ALD) levels. In addition, this study also examined the association between AF‐ALD and the ALD levels in the umbilical cord blood (UCB‐ALD) in monochorionic twins. Material and Methods: This prospective study included monochorionic diamniotic (MD) twin pregnancies that were not complicated by twin‐to‐twin transfusion syndrome (TTTS) at delivery. Amniotic fluid and umbilical cord vein blood samples were collected from each twin at delivery, and the ALD levels were measured subsequently. The MD twins were divided into two groups: those with placental anastomoses and those without anastomoses owing to fetoscopic laser surgery. The differences in the AF‐ALD levels between the larger and smaller twins were analyzed. Results: The AF‐ALD levels showed a strong and significant positive correlation with UCB‐ALD levels in 131 MD twins (r = 0.804, p < 0.001). Intertwin differences were examined in 41 and 28 pairs of MD twins with and without placental anastomoses, respectively. The AF‐ALD levels in the smaller twins were significantly higher than those in the larger twins among the pairs of MD twins with placental anastomoses (p = 0.003); however, no statistically significant intertwin differences were observed among the twins without placental anastomoses (p > 0.05). Conclusions: The AF‐ALD levels reflect the UCB‐ALD levels in MD twins. The presence of placental anastomoses led to intertwin discordance in the ALD levels in MD twins even uncomplicated with TTTS. It was considered that monochorionic twins have this clinical background, and it leads to the development of TTTS. [ABSTRACT FROM AUTHOR]

Dysregulation of the mineralocorticoid hormone aldosterone is an increasingly prevalent cause of hypertension. Aldosterone synthase (CYP11B2) shares 93% homology to 11β‐hydroxylase (CYP11B1), which produces cortisol. Lorundrostat, a highly selective inhibitor of CYP11B2, is a potential safe and effective treatment for aldosterone‐dependent, uncontrolled hypertension, including treatment‐resistant hypertension. Lorundrostat showed highly selective inhibition of CYP11B2 in vitro, with 374‐fold selectivity for CYP11B2 vs. CYP11B1. A first‐in‐human study of single ascending doses ranging from 5 to 800 mg and multiple ascending doses ranging from 40 to 360 mg once daily was conducted in healthy participants. After single‐ and multiple‐dose administration, lorundrostat plasma levels peaked 1–3 h after administration with a t1/2 of 10–12 h. Plasma aldosterone decreased up to 40% with single 100‐mg to 200‐mg doses and up to 70% with single 400 to 800‐mg doses. Plasma aldosterone returned to baseline within 16 h after single 100‐mg doses and multiple once‐daily 120‐mg doses. Lorundrostat demonstrated a favorable safety profile in healthy participants. Dose‐ and exposure‐dependent inhibition of renal tubular sodium reabsorption was observed across a clinically relevant dose range with no suppression of basal or cosyntropin‐stimulated cortisol production and only a modest increase in mean serum potassium. [ABSTRACT FROM AUTHOR]

Renin‐secreting tumours are rare causes of secondary hypertension and hypokalaemia. They are usually surgically curable, hence proper diagnostic work‐up and tumour localisation is essential. In this paper, we present three Swedish patients recently diagnosed with renin secreting tumours, two with reninomas and one with an extrarenal renin‐producing tumour, to illustrate diagnostic challenges. We also discuss the biochemical work‐up, the pros and cons of different imaging techniques (computer tomography [CT], magnetic resonance imaging and [18F]fluorodeoxyglucose‐positron emission tomography‐CT), as well as how renal vein sampling (RVC) may contribute to localisation of the tumour. [ABSTRACT FROM AUTHOR]

Aim: This Phase I study evaluated the safety and early efficacy of an aldosterone synthase inhibitor (BI 690517) in people with diabetes and albuminuric chronic kidney disease. Methods: Double‐blind, placebo‐controlled study (NCT03165240) at 40 sites across Europe. Eligible participants [estimated glomerular filtration rate ≥20 and <75 ml/min/1.73 m2; urine albumin/creatinine ratio (UACR) ≥200 and <3500 mg/g] were randomized 6:1 to receive once‐daily oral BI 690517 3, 10 or 40 mg, or eplerenone 25‐50 mg, or placebo, for 28 days. The primary endpoint was the proportion of participants with drug‐related adverse events (AEs). Secondary endpoints included changes from baseline in the UACR. Results: Fifty‐eight participants were randomized and treated from 27 November 2017 to 16 April 2020 (BI 690517: 3 mg, n = 18; 10 mg, n = 13; 40 mg, n = 14; eplerenone, n = 4; placebo, n = 9) for 28 days. Eight (13.8%) participants experienced drug‐related AEs [BI 690517: 3 mg (two of 18); 10 mg (four of 13); 40 mg (two of 14)], most frequently constipation [10 mg (one of 13); 40 mg (one of 14)] and hyperkalaemia [3 mg (one of 18); 10 mg (one of 13)]. Most AEs were mild to moderate; one participant experienced severe hyperkalaemia (serum potassium 6.9 mmol/L; BI 690517 10 mg). UACR responses [≥20% decrease from baseline (first morning void urine) after 28 days] were observed for 80.0% receiving BI 690517 40 mg (eight of 10) versus 37.5% receiving placebo (three of eight). Aldosterone levels were suppressed by BI 690517, but not eplerenone or placebo. Conclusions: BI 690517 was generally well tolerated, reduced plasma aldosterone and may decrease albuminuria in participants with diabetes and albuminuric chronic kidney disease. [ABSTRACT FROM AUTHOR]

Introduction: Calcineurin inhibitors (CNIs) are widely used in transplantation. Although CNI‐related hyperkalemia is common (10%–60.6%), the underlying pathogenetic mechanism is not well‐elucidated and may lead to dose adjustment or treatment withdrawal. Objective: The aim of this study is to describe CNI‐related hyperkalemia due to hyporeninemic hypoaldosteronism in pediatric transplant recipients who were successfully treated with fludrocortisone. Method: In a total of 55 hematopoietic stem cell (HSCT) and 35 kidney transplant recipients followed according to institutional immunosuppression protocols, recipients diagnosed with CNI‐related hyperkalemia were reviewed. Recipients who were receiving intravenous fluid, potassium, or were diagnosed with hemolysis, acute graft rejection, or had an eGFR < 30 mL/min/1.73m2, were excluded. A detailed analysis of clinical history as well as biochemical studies was carried out to reveal possible pathophysiology. Results: Three pediatric transplant recipients (one HSCT, two kidney transplantation) with findings of hyperkalemia, hyponatremia, and a mild elevation in blood urea nitrogen while on CNIs were recruited. Urinary potassium excretion was diminished while sodium excretion was increased. Plasma aldosterone levels were low, and renin was not increased in response. Primary adrenal insufficiency was ruled out, and hyporeninemic hypoaldosteronism was diagnosed. CNI‐related hyperkalemia was detected earlier in case 1, who had HSCT (22 days), than in the second and third cases, who had kidney transplantation (24 and 30 months post‐transplantation, respectively). The discrepancy was hypothesized to be explained by higher overall CNI dose due to higher serum target CNI used in HSCT than kidney transplantation. Electrolyte imbalance was reversed upon administration of physiologic dose fludrocortisone (0.05 mg, daily), while fludrocortisone was ceased after CNI withdrawal in case 1, which is additional evidence for the etiological association of CNIs and hyporeninemic hypoaldosteronism. Conclusion: Our three cases strengthen the premise that CNI‐related hyperkalemia may be due to hyporeninemic hypoaldosteronism, and the timing and severity may be related to CNI dose. Fludrocortisone is a safe and effective treatment in CNI‐related hyperkalemia, providing maintenance of CNIs, which are one of the essential therapeutic agents for pediatric transplantation. [ABSTRACT FROM AUTHOR]

Perfluorotetradecanoic acid (PFTeDA) is a novel perfluoroalkyl substance that ubiquitously exists in the environment. However, whether PFTeDA affects adrenal cortex function remains unclear. Male Sprague–Dawley rats (age of 60 days) were daily administered with PFTeDA (0, 1, 5, and 10 mg/kg body weight) through gavage for 28 days. PFTeDA did not change body and adrenal gland weights. PFTeDA markedly elevated serum corticosterone level at 10 mg/kg but lowering serum aldosterone level at this dosage without influencing serum adrenocorticotropic hormone level. PFTeDA thickened zona fasciculata without affecting zona glomerulosa. PFTeDA remarkably upregulated the expression of corticosterone biosynthetic genes (Mc2r, Scarb1, Star, Cyp21, Cyp11b1, and Hsd11b1) and their proteins, whereas downregulating aldosterone biosynthetic enzyme Cyp11b2 and its protein, thereby distinctly altering their serum levels. PFTeDA markedly downregulated the expression of antioxidant genes (Sod1 and Sod2) and their proteins at 10 mg/kg. PFTeDA significantly decreased SIRT1/PGC1α and AMPK signaling while stimulating AKT1/mTOR signaling. Corticosterone significantly inhibited testosterone production by adult Leydig cells at >0.1 μM in vitro; however aldosterone significantly stimulated testosterone production at 0.1 nM. In conclusion, exposure to PFTeDA at male rat adulthood causes corticosterone excess and aldosterone deficiency via SIRT1/PGC1α, AMPK, and AKT1/mTOR signals, which in turn additively leads to testosterone deficiency. [ABSTRACT FROM AUTHOR]

Baxdrostat is a selective small‐molecule aldosterone synthase inhibitor in development for treatment of hypertension and chronic kidney disease. This phase 1, open‐label, parallel‐group study assessed the safety and pharmacokinetics (PK) of baxdrostat in participants with varying degrees of renal function. Participants were enrolled into control (estimated glomerular filtration rate [eGFR] ≥60 mL/min), moderate to severe renal impairment (eGFR 15‐59 mL/min), or kidney failure (eGFR <15 mL/min) groups and received a single 10‐mg baxdrostat dose followed by 7 days of inpatient PK blood and urine sampling. Safety was assessed by adverse events, clinical laboratory evaluations, vital signs, physical examinations, and electrocardiograms (ECGs). Thirty‐2 participants completed the study. There were no deaths and only 1 mild drug‐related adverse event (diarrhea). No clinically meaningful changes in laboratory values, vital signs, physical examinations, or ECGs occurred. Plasma concentration‐time curves of baxdrostat were similar among all groups. Urine PK parameters were similar (approximately 12% excreted) in the moderate to severe renal impairment and control groups. Inadequate urine production in the kidney failure group resulted in minimal urinary baxdrostat excretion. Renal impairment had no significant impact on systemic exposure or clearance of baxdrostat, suggesting that dose adjustment due to PK differences in patients with kidney disease is unnecessary. [ABSTRACT FROM AUTHOR]

Aldosterone has been suggested to be involved in the microvascular complications observed in type 2 diabetes. We aimed to investigate the effect of mineralocorticoid receptor (MR) blockade on endothelial function in individuals with type 2 diabetes compared to healthy controls. We included 12 participants with type 2 diabetes and 14 controls. We measured leg hemodynamics at baseline and during femoral arterial infusion of acetylcholine and sodium nitroprusside before and 8 weeks into treatment with MR blockade (eplerenone). Acetylcholine infusion was repeated with concomitant n‐acetylcysteine (antioxidant) infusion. No difference in leg blood flow or vascular conductance was detected before or after the treatment with MR blockade in both groups and there was no difference between groups. Infusion of n‐acetylcysteine increased baseline blood flow and vascular conductance, but did not change the vascular response to acetylcholine before or after treatment with MR blockade. Skeletal muscle eNOS content was unaltered by MR blockade and no difference between groups was detected. In conclusion, we found no effect of MR blockade endothelial function in individuals with and without type 2 diabetes. As the individuals with type 2 diabetes did not have vascular dysfunction, these results might not apply to individuals with vascular dysfunction. [ABSTRACT FROM AUTHOR]

Aldosterone is responsible for maintaining volume and potassium homeostasis. Although high salt consumption should suppress aldosterone production, individuals with hyperaldosteronism lose this regulation, leading to a state of high aldosterone despite dietary sodium consumption. The present study examines the effects of elevated aldosterone, with or without high salt consumption, on the expression of key Na+ transporters and remodelling in the distal nephron. Epithelial sodium channel (ENaC) α‐subunit expression was increased with aldosterone regardless of Na+ intake. However, ENaC β‐ and γ‐subunits unexpectedly increased at both a transcript and protein level with aldosterone when high salt was present. Expression of total and phosphorylated Na+Cl− cotransporter (NCC) significantly increased with aldosterone, in association with decreased blood [K+], but the addition of high salt markedly attenuated the aldosterone‐dependent NCC increase, despite equally severe hypokalaemia. We hypothesized this was a result of differences in distal convoluted tubule length when salt was given with aldosterone. Imaging and measurement of the entire pNCC‐positive tubule revealed that aldosterone alone caused a shortening of this segment, although the tubule had a larger cross‐sectional diameter. This was not true when salt was given with aldosterone because the combination was associated with a lengthening of the tubule in addition to increased diameter, suggesting that differences in the pNCC‐positive area are not responsible for differences in NCC expression. Together, our results suggest the actions of aldosterone, and the subsequent changes related to hypokalaemia, are altered in the presence of high dietary Na+. Key points: Aldosterone regulates volume and potassium homeostasis through effects on transporters in the kidney; its production can be dysregulated, preventing its suppression by high dietary sodium intake.Here, we examined how chronic high sodium consumption affects aldosterone's regulation of sodium transporters in the distal nephron.Our results suggest that high sodium consumption with aldosterone is associated with increased expression of all three epithelial sodium channel subunits, rather than just the alpha subunit.Aldosterone and its associated decrease in blood [K+] lead to an increased expression of Na‐Cl cotransporter (NCC); the addition of high sodium consumption with aldosterone partially attenuates this NCC expression, despite similarly low blood [K+].Upstream kinase regulators and tubule remodelling do not explain these results. [ABSTRACT FROM AUTHOR]

The prevailing model of steroid hormone nuclear receptor function assumes ligand‐induced homodimer formation followed by binding to DNA hormone response elements (HREs). This model has been challenged by evidence showing that the glucocorticoid receptor (GR) forms tetramers upon ligand and DNA binding, which then drive receptor‐mediated gene transactivation and transrepression. GR and the closely‐related mineralocorticoid receptors (MR) interact to transduce corticosteroid hormone signaling, but whether they share the same quaternary arrangement is unknown. Here, we used a fluorescence imaging technique, Number & Brightness, to study oligomerization in a cell system allowing real‐time analysis of receptor‐DNA interactions. Agonist‐bound MR forms tetramers in the nucleoplasm and higher order oligomers upon binding to HREs. Antagonists form intermediate‐size quaternary arrangements, suggesting that large oligomers are essential for function. Divergence between MR and GR quaternary structure is driven by different functionality of known and new multimerization interfaces, which does not preclude formation of heteromers. Thus, influencing oligomerization may be important to selectively modulate corticosteroid signaling. [ABSTRACT FROM AUTHOR]

This document summarizes a study on the clinical outcomes of surgical management for primary aldosteronism (PA) when adrenal vein sampling (AVS) results are inconclusive. AVS is the preferred method for subtyping PA, but it can be challenging to successfully cannulate both adrenal veins. The study found that patients who had successful AVS and underwent unilateral adrenalectomy achieved clinical and biochemical remission. Patients with inconclusive AVS results were managed either surgically or with medical therapy, and the majority of those who underwent surgery achieved biochemical remission. The study suggests that inconclusive AVS results, along with imaging findings, can help guide surgical decision-making, but further research is needed to validate these findings. It also emphasizes that patients who are not candidates for surgery should not undergo AVS. [Extracted from the article]

Resistant hypertension, a severe condition affecting about 10 % of people with high blood pressure, significantly increases the risk of heart, brain, and kidney issues. This study investigates the potential of baxdrostat and its derivatives (1–22) as aldosterone synthase inhibitors for resistant hypertension using in silico methods. The study employed various computational methods, including molecular dynamics simulation (MD), molecular docking, frontier molecular orbital (FMO) analysis, and global chemical descriptors, to evaluate the interactions between the compounds and the target proteins. The docking results showed that compounds 2, 5, 7, and baxdrostat had binding affinities of −7.8 kcal/mol, −10.9 kcal/mol, −10.6 kcal/mol, and −9.3 kcal/mol, respectively. Additionally, molecular dynamics simulations revealed that ligands 2, 5, and baxdrostat formed the most stable protein‐ligand complexes with aldosterone synthase. The complex of the 4FDH‐baxdrostat remained highly stable across all tested temperatures (300 K, 305 K, 310 K, and 320 K), consistently displaying low RMSD values, with the minimum observed at 305 K. Baxdrostat emerges as the most promising candidate among the compounds examined, showcasing notable potential when considering a combination of in vitro, in vivo, and now in silico data. While baxdrostat remains the primary candidate based on comprehensive in vitro, in vivo, and in silico studies, further analysis using FMO theory suggests that ligands 2 and 5 have promising potential due to their smaller Egap. To validate these findings, further clinical investigations are warranted. [ABSTRACT FROM AUTHOR]

Aims: Whether aldosterone levels after myocardial infarction (MI) are associated with mid‐ and long‐term left ventricular (LV) remodelling in the era of systematic use of renin–angiotensin system inhibitors is uncertain. We prospectively investigated the relationship between aldosterone levels and mid‐ and long‐term LV remodelling in patients with acute MI. Methods and results: Plasma aldosterone was measured in 119 patients successfully treated by primary percutaneous coronary angioplasty for a first acute ST‐elevation MI (STEMI) 2–4 days after the acute event. LV volumes were assessed by cardiac magnetic resonance (CMR) and transthoracic echocardiography (TTE) in the same timeframe and 6 months later. LV assessment was repeated by TTE 3–9 years after MI (n = 80). The median aldosterone level at baseline was 23.1 [16.8; 33.1] pg/ml. In the multivariable model, higher post‐MI aldosterone concentration was significantly associated with more pronounced increase in LV end‐diastolic volume index (TTE: β ± standard error [SE]: 0.113 ± 0.046, p = 0.015; CMR: β ± SE: 0.098 ± 0.040, p = 0.015) and LV end‐systolic volume index (TTE: β ± SE: 0.083 ± 0.030, p = 0.008; CMR: β ± SE: 0.064 ± 0.032, p = 0.048) at 6‐month follow‐up, regardless of the method of assessment. This result was consistent also in patients with a LV ejection fraction (LVEF) >40%. The association between baseline plasma aldosterone and adverse LV remodelling did not persist at the 3–9‐year follow‐up evaluation. Conclusion: Aldosterone concentration in the acute phase was associated with adverse LV remodelling in the medium term, even in the subgroup of patients with LVEF >40%, suggesting a potential role of the mineralocorticoid system in post‐MI adverse remodelling. Plasma aldosterone was no longer associated with LV remodelling in the long term (NCT01109225). [ABSTRACT FROM AUTHOR]

Recently, we described local aldosterone production in the murine large intestine. Upregulated local aldosterone synthesis in different tissues has been linked with inflammatory conditions, which have been attenuated by the aldosterone synthase (CYP11B2) inhibitor, fadrozole (FAD286). Therefore, we investigated the effect of inhibition of intestinal aldosterone synthesis on the development of intestinal inflammation. Sprague‐Dawley rats were administered 5% (v/w) dextran sodium sulphate (DSS) for 7 days with or without daily FAD286 (30 mg/kg/d) subcutaneous injections on 3 days before, during and one day after DSS. Tissue aldosterone concentrations were evaluated by ELISA, CYP11B2 by Western blot and RT‐qPCR. FAD286 halved adrenal aldosterone production but, intriguingly, increased the colonic aldosterone concentration. The lack of inhibitory effect of FAD286 in the colon might have been affected by the smaller size of colonic vs. adrenal CYP11B2, as seen in Western blot. When combined with DSS, FAD286 aggravated the macroscopic and histological signs of intestinal inflammation, lowered the animals' body weight gain and increased the incidence of gastrointestinal bleeding and the permeability to iohexol in comparison to DSS‐animals. To conclude, FAD286 exerted harmful effects during intestinal inflammation. Local intestinal aldosterone did not seem to play any role in the inflammatory pathogenesis occurring in the intestine. [ABSTRACT FROM AUTHOR]

Aldosterone (ALD) is excreted in urine mainly as glucuronide conjugates of ALD and tetrahydroaldosterone. Measuring these urinary metabolites might be an alternative screening test to plasma ALD for primary aldosteronism. We report a validated LC–MS/MS method to measure both analytes simultaneously. Urine samples underwent enzymatic hydrolysis to release the analytes from their glucuronide conjugates followed by organic solvent extraction and LC–MS/MS. The analytical performance of this method was evaluated. The within‐batch and between‐batch coefficients of variation for urine ALD and urine THA were all ≤5.2 and ≤3.7%. The lower limit of quantification was 0.5 nmol/L, and the linearity was up to at least 2770 nmol/L for both analytes. No significant matrix interference and carryover were observed. Both analytes in urine were stable for at least 48 h at 10°C and at least 18 months at −80°C. Local reference intervals were established from 126 healthy normotensive Chinese subjects (53% women, age: 20–65 years). Reference intervals for urine ALD and tetrahydroaldosterone were 2–38 and 9–139 nmol/day, respectively. This validated method can be applied to screening and diagnosing primary aldosteronism. [ABSTRACT FROM AUTHOR]

Aims: High aldosterone is a key driver of hypertension and long‐term negative sequelae. We evaluated the safety and efficacy of dexfadrostat phosphate (DP13), a novel aldosterone synthase (CYP11B2) inhibitor, in healthy participants. Methods: This randomized, double‐blind, placebo‐controlled study was conducted in two parts. In part A, a single‐ascending dose escalation, 16 participants received oral DP13 1–16 mg. Part B was a multiple‐ascending dose, sequential group study in which 32 participants received oral DP13 4, 8 or 16 mg once daily for 8 days. Safety and tolerability were monitored throughout. An adrenocorticotropic hormone (ACTH) stimulation test at maximal blood drug concentrations defined the dose range for multiple dosing. Results: DP13 was well tolerated at all doses, with no serious adverse events. In part B, all DP13 doses (4, 8 and 16 mg) over 8 days effectively suppressed aldosterone production, increased the urinary sodium/potassium ratio, decreased plasma sodium and increased plasma potassium and renin levels compared with placebo, resulting in potent suppression of the aldosterone‐to‐renin ratio (ARR). Endocrine counter‐regulation resulted in the 4 mg dose no longer sustaining 24‐h aldosterone suppression after 8 days of treatment, unlike the 8‐ and 16 mg doses. There was no evidence of drug‐induced adrenal insufficiency (ACTH stress challenge). Conclusions: In patients with excess aldosterone and ensuing sodium retention driving hypertension, managing sodium balance is critical. A CYP11B2 inhibitor like DP13, whose effectiveness can be monitored by a reduction in ARR, may prove valuable in managing aldosterone‐dependent hypertension and primary aldosteronism. [ABSTRACT FROM AUTHOR]

Background: Primary hyperaldosteronism (PHA) is an underdiagnosed cause of secondary hypertension, with an increased risk of cardiovascular and renal complications compared with those with essential hypertension alone. Distinguishing between unilateral and bilateral aldosterone secretion is important as management differs. Adrenal vein sampling (AVS) is the gold standard for determining lateralisation. Current international guidelines suggest AVS may be omitted in those aged <35 years with PHA and a unilateral adrenal adenoma on imaging. Aim: To characterise all patients referred for AVS at Waitematā District Health Board (WDHB), review the success rate of AVS and compare concordance of AVS with imaging. Methods: All patients who underwent AVS in WDHB from January 2015 to September 2020 were retrospectively assessed. Clinical records, laboratory data and radiological findings were reviewed. Results: Ninety‐six patients underwent AVS, with four excluded as private records were unable to be obtained. Of the 92 patients included, age ranged from 22 to 79 years. AVS was successful on first attempt in 89 (96.7%) patients. AVS and imaging findings were concordant in 62.2% of patients. One (14.3%) of seven aged <35 years had discordant results, and 16 (47%) of 34 patients with a unilateral adenoma on imaging had discordant results to AVS. Conclusions: AVS at WDHB is successful on first attempt in most patients. AVS is essential in the management of PHA for those deemed to be surgical candidates, regardless of age. [ABSTRACT FROM AUTHOR]

Background: In a previous study, telmisartan suppressed aldosterone secretion in healthy cats but not in cats with primary hyperaldosteronism (PHA). Hypotheses: Telmisartan suppresses aldosterone secretion in middle‐aged healthy cat and cats with diseases that may result in secondary hyperaldosteronism, but not in those with PHA. Animals: Thirty‐eight cats: 5 with PHA; 16 with chronic kidney disease (CKD), subclassified as hypertensive (CKD‐H) or non‐hypertensive (CKD‐NH); 9 with hyperthyroidism (HTH); 2 with idiopathic systemic arterial hypertension (ISH); and 6 healthy middle‐aged cats. Methods: Prospective, cross‐sectional study. Serum aldosterone concentration, potassium concentration, and systolic blood pressure were measured before and 1 and 1.5 hours after PO administration of 2 mg/kg of telmisartan. The aldosterone variation rate (AVR) was calculated for each cat. Results: No significant difference in the minimum AVR was observed among groups (median [quartile 1 (Q1); quartile 3 (Q3)]: 25 [0; 30]; 5 [−27; −75]; 10 [−6; −95]; 53 [19; 86]; 29 [5; 78]) for PHA, CKD, HTH, ISH, and healthy cats, respectively (P =.05). Basal serum aldosterone concentration (pmol/L) was significantly higher in PHA cats (median [Q1; Q3]: 2914 [2789; 4600]) than in CKD‐H cats (median [Q1; Q3]: 239 [189; 577], corrected P value =.003) and CKD‐NH cats (median [Q1; Q3]: 353 [136; 1371], corrected P value =.004). Conclusions and Clinical Importance: The oral telmisartan suppression test using a single dose of 2 mg/kg telmisartan did not discriminate cats with PHA from healthy middle‐aged cats or cats with diseases that may result in secondary hyperaldosteronism. [ABSTRACT FROM AUTHOR]

Background: Primary aldosteronism (PA) is a frequent cause of hypertension. Aldosterone excess together with high dietary salt intake aggravates cardiovascular damage, despite guideline‐recommended mineralocorticoid receptor antagonist (MRA) treatment. Objectives: To investigate the antihypertensive impact of a moderate dietary salt restriction and associated physiological changes, including mental well‐being. Methods: A total of 41 patients with PA on a stable antihypertensive regimen—including MRA—followed a dietary salt restriction for 12 weeks with structured nutritional training and consolidation by a mobile health app. Salt intake and adherence were monitored every 4 weeks using 24‐h urinary sodium excretion and nutrition protocols. Body composition was assessed by bioimpedance analysis and mental well‐being by validated questionnaires. Results: Dietary salt intake significantly decreased from 9.1 to 5.2 g/d at the end of the study. In parallel, systolic (130 vs. 121 mm Hg) and diastolic blood pressure (BP) (84 vs. 81 mm Hg) improved significantly. Patients' aptitude of estimating dietary salt content was refined significantly (underestimation by 2.4 vs. 1.4 g/d). Salt restriction entailed a significant weight loss of 1.4 kg, improvement in pulse pressure (46 vs. 40 mm Hg) and normalization of depressive symptoms (PHQD scale, p < 0.05). Salt restriction, cortisol after dexamethasone suppression test and dosage of renin‐angiotensin‐aldosterone‐system (RAAS) blockers were independently associated with BP reduction. Conclusion: A moderate restriction of dietary salt intake in patients with PA substantially reduces BP and depressive symptoms. Moreover, the findings underline that a sufficient RAAS blockade seems to augment the effects of salt restriction on BP and cardiovascular risk. [ABSTRACT FROM AUTHOR]

Minerals provide micronutrients that function in various ways in the body, and they are necessary for the survival of animals. In this study, we first compared the mineral content of foods of wild Japanese macaques in lowland Yakushima with that of monkey chow used for many years to feed captive macaques and specifically formulated to obtain good health in captive macaques (National Research Council [NRC] recommendations). Second, we clarified the mineral balance in captive individuals when feeding them monkey chow to clarify the digestibility/bioavailability of the minerals. Third, we investigated the physiological response when we experimentally increased sodium intake. In the lowland of Yakushima, which is in the vicinity (<800 m) of the coast, animals, fungi, and mature leaves had high sodium contents compared with NRC recommendations. The calcium contents of mature leaves and animals were higher than the NRC recommendations. The overall mineral intake in this population was lower than that in the captive animals for calcium, phosphorus, sodium, and iron, while similar for magnesium and higher in potassium. Patterns in the intake and excretion of minerals indicated that excretion was mostly from urine and not from feces, and apparent digestibility was high for sodium. This tendency was opposite for calcium, magnesium, and phosphorus and intermediate for potassium. A sodium‐provisioning experiment showed that fecal aldosterone concentration remained low in both control and sodium‐provisioning conditions so the macaques do not need reabsorb sodium in the kidneys. Therefore, sodium content in the monkey chow, which is slightly lower than the NRC recommendation, seemed high enough so that the macaques could avoid the need to reabsorb sodium in the kidneys. We advocate similar studies for other primate populations or species to better understand the role of mineral concentrations on food selection and to identify potential mineral deficiencies. Highlights: We revealed the major mineral contents of foods of wild Japanese macaques in lowland Yakushima, which is in the vicinity of the coast.Sodium‐provisioning experiments on captive individuals suggest that sodium content of monkey chow, which slightly lower than the recommendations, is sufficient to fulfill the sodium requirements. [ABSTRACT FROM AUTHOR]

Background: Primary aldosteronism (PA) is the most common endocrine cause of hypertension. It is associated with higher cardio‐metabolic risk than essential hypertension. Hypertension is common in patients with type 2 diabetes who carry increased cardiovascular risk; however, it is unknown how frequently they are tested for PA. Aim: To assess the extent to which the Endocrine Society's 2016 PA screening guidelines have been applied in a tertiary diabetes care setting and evaluate the demographic, clinical and biochemical characteristics of patients who met screening criteria compared with those who did not. Methods: This is a retrospective cohort study. Data were collected from 272 patients who attended tertiary diabetes clinics and had two or more blood pressure measurements from January to December 2018. Results: Of 272 patients, 60 (22.1%) had indication(s) for PA screening, but only 14 (23.3%) of 60 were screened using the aldosterone‐to‐renin ratio (ARR). Five patients who did not meet screening criteria were screened. Only one of 19 patients screened had an abnormal ARR; however, 16 were taking medications known to affect aldosterone and/or renin production. Conclusions: In a tertiary diabetes outpatient setting, only a minority of patients who fulfilled the Endocrine Society criteria for PA screening were actually screened. Appropriate screening for PA in the diabetic hypertensive population is necessary for the diagnosis and targeted treatment of a highly modifiable cardiovascular risk factor. Further studies are needed to develop feasible strategies to identify patients with PA in this population. [ABSTRACT FROM AUTHOR]

Di‐n‐pentyl phthalate (DPeP) is an endocrine‐disrupting phthalate plasticizer. The objective of this study was to investigate the effect of DPeP on adrenocortical function in adult male rats following in utero exposure. DPeP (0, 10, 50, 100, and 500 mg/kg/day) was administered by gavage to pregnant Sprague–Dawley rats from gestational day 14 to 21. The morphology and function of the adrenal cortex in 56‐day‐old male offspring were studied. DPeP at 100 and 500 mg/kg/day significantly reduced serum aldosterone levels and at 500 mg/kg/day markedly reduced corticosterone and adrenocorticotropic hormone levels. DPeP at 10–500 mg/kg markedly reduced the thickness of zona glomerulosa without affecting the thickness of zona fasciculata. DPeP significantly downregulated the expression of Agtr1a, Mc2r, Scarb1, Cyp11a1, Hsd3b1, Cyp21, Cyp11b1, Cyp11b2, Nr5a1, Nr4a2, and Bcl2 genes as well as their proteins. DPeP at 500 mg/kg/day significantly increased phosphorylated AMPK, while DPeP at 100 mg/kg/day and higher doses reduced phosphorylated AKT1 and total SIRT1 level. DPeP at 100 and 500 μM markedly induced reactive oxygen species and apoptosis in H295R cells after 24 h of culture. In conclusion, in utero exposure to DPeP disrupts adrenocortical function of the adult male offspring by (1) increasing AMPK phosphorylation and decreasing AKT1 phosphorylation and SIRT1 levels, (2) reducing adrenocorticotropic hormone levels, and (3) possibly inducing oxidative stress and apoptosis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Summary: Obstructive sleep apnea is a chronic, sleep‐related breathing disorder, which is an independent risk factor for cardiovascular disease. The renin–angiotensin–aldosterone system regulates salt and water homeostasis, blood pressure, and cardiovascular remodelling. Elevated aldosterone levels are associated with excess morbidity and mortality. We aimed to analyse the influence and implications of renin–angiotensin–aldosterone system derangement in individuals with and without obstructive sleep apnea. We pooled data from 20 relevant studies involving 2828 participants (1554 with obstructive sleep apnea, 1274 without obstructive sleep apnea). The study outcomes were the levels of renin–angiotensin–aldosterone system hormones, blood pressure and heart rate. Patients with obstructive sleep apnea had higher levels of plasma renin activity (pooled wmd+ 0.25 [95% confidence interval 0.04–0.46], p = 0.0219), plasma aldosterone (pooled wmd+ 30.79 [95% confidence interval 1.05–60.53], p = 0.0424), angiotensin II (pooled wmd+ 5.19 [95% confidence interval 3.11–7.27], p < 0.001), systolic (pooled wmd+ 5.87 [95% confidence interval 1.42–10.32], p = 0.0098) and diastolic (pooled wmd+ 3.40 [95% confidence interval 0.86–5.94], p = 0.0086) blood pressure, and heart rate (pooled wmd+ 3.83 [95% confidence interval 1.57–6.01], p = 0.0009) compared with those without obstructive sleep apnea. The elevation remained significant (except for renin levels) when studies involving patients with resistant hypertension were removed. Sub‐group analysis demonstrated that levels of angiotensin II were significantly higher only among the Asian population with obstructive sleep apnea compared with those without obstructive sleep apnea. Body mass index accounted for less than 10% of the between‐study variance in elevation of the renin–angiotensin–aldosterone system parameters. Patients with obstructive sleep apnea have higher levels of renin–angiotensin–aldosterone system hormones, blood pressure and heart rate compared with those without obstructive sleep apnea, which remains significant even among patients without resistant hypertension. [ABSTRACT FROM AUTHOR]

Aldosterone has hypertrophic and profibrotic effects on the heart. This study aims to determine the relationship between serum aldosterone concentration (SAC) and aldosterone‐to‐renin ratio (ARR) with left ventricular (LV) geometry and diastolic function in essential hypertension (EH). We investigated 213 EH patients (50.3 ± 12.6 years; 57.7% male). SAC, ARR measurements, and echocardiographic analysis were performed for participants. Overall, stepwise multiple regression analysis showed significant associations between SAC and interventricular septum, LV posterior wall thickness, LV amass, LV mass index, e′ velocity, a′ velocity, and E/e′ ratio after adjustment of potentially confounding covariates. When patients were divided into three SAC tertiles, multivariate‐adjusted analysis of covariance (ANCOVA) demonstrated a significant increase in LV mass (P ˂ 0.001), LV mass index (P ˂ 0.001), relative wall thickness (P = 0.003), interventricular septum (P = 0.001), LV posterior wall thickness (P = 0.001) and E/e′ ratio (P ˂ 0.001), but a decrease in e′ velocity (P = 0.002) from the first to third tertile of SAC. In logistic regression analysis, increased SAC was independently associated with concentric LV hypertrophy [OR: 1.21, 95% CI: 1.11–1.33, P ˂ 0.001]. No significant associations were found between ARR and echocardiographic parameters of LV structure or diastolic function. In conclusion, SAC, but not ARR, is independently associated with echocardiographic indices of LV structure and diastolic function and is also related to concentric LV hypertrophy. Our findings suggest that aldosterone's pro‐hypertrophic and myocardial fibrosis effects contribute to alterations in LV structure and diastolic function in EH beyond blood pressure. [ABSTRACT FROM AUTHOR]

Diabetic ketoacidosis (DKA), a frequent complication of type 1 diabetes (T1D), is characterized by hyperosmolar hypovolemia. The response of water‐regulating hormones arginine vasopressin (AVP; antidiuretic hormone) and aldosterone to DKA treatment in children is not well understood, although they may have potential as future diagnostic, prognostic, and/or treatment monitoring markers in diabetic patients. We aimed to characterize the dynamics of the response in copeptin (marker for AVP) and aldosterone secretion to rehydration treatment in pediatric patients with DKA. Data originated from a prospective, observational, multicenter study including 28 pediatric T1D patients treated for DKA (median age, 11.5 years; weight, 35 kg). Serial measurements of hormone levels were obtained during 72 h following rehydration start. Semimechanistic pharmacometric modeling was used to analyze the kinetic/dynamic relationship of copeptin and aldosterone secretion in response to the correction of hyperosmolality and hypovolemia, respectively. Modeling revealed different sensitivities for osmolality‐dependent copeptin secretion during the first 72 h of rehydration, possibly explained by an osmotic shift introduced by hypovolemia. Response in aldosterone secretion to the correction of hypovolemia seemed to be delayed, which was well described by an extra upstream turnover compartment, possibly representing chronic upregulation of aldosterone synthase (cytochrome P450 11B2). In conclusion, semimechanistic modeling provided novel physiological insights in hormonal water regulation in pediatric patients during DKA treatment, providing rationale to further evaluate the potential of monitoring copeptin, but not aldosterone due to its delayed response, for future optimization of rehydration treatment to reduce the risk of acute complications such as cerebral edema. [ABSTRACT FROM AUTHOR]

An abundance of knowledge has been collected describing the involvement of neuroendocrine parameters in major depression. The hypothalamic–pituitary–adrenocortical (HPA) axis regulating cortisol release has been extensively studied; however, attempts to target the HPA axis pharmacologically to treat major depression have failed. This review focuses on the importance of the adrenocortical stress hormone aldosterone, which is released by adrenocorticotropic hormone and angiotensin, and the mineralocorticoid receptor (MR) in depression. Depressed patients, in particular those with atypical depression, have signs of central hyperactivation of the aldosterone sensitive MR, potentially as a consequence of a reactive aldosterone release induced by low blood pressure and as a result of low sensitivity of peripheral MR. This is reflected in reduced heart rate variability, increased salt appetite and sleep changes in this group of patients. In addition, enlarged brain ventricles, compressed corpus callosum and changes of the choroid plexus are associated with increased aldosterone (in relation to cortisol). Furthermore, subjects with these features often show obesity. These characteristics are related to a worse antidepressant treatment outcome. Alterations in choroid plexus function as a consequence of increased aldosterone levels, autonomic dysregulation, metabolic changes and/or inflammation may be involved. The characterization of this regulatory system is in its early days but may identify new targets for therapeutic interventions. [ABSTRACT FROM AUTHOR]

Aim: The kaliuretic action of the renin–angiotensin–aldosterone system (RAAS) is well established as highlighted by hyperkalemia side effect of RAAS inhibitors but such action is usually ascribed to systemic RAAS. The present study addresses the involvement of intrarenal RAAS in K+ homeostasis with emphasis on locally generated renin within the collecting duct (CD). Methods: Wild‐type (Floxed) and CD‐specific deletion of renin (CD renin KO) mice were treated for 7 days with a high K+ (HK) diet to investigate the role of CD renin in kaliuresis regulation and further define the underlying mechanism with emphasis on analysis of intrarenal aldosterone biosynthesis. Results: In floxed mice, renin levels were elevated in the renal medulla and urine following a 1‐week HK diet, indicating activation of the intrarenal renin. CD renin KO mice had blunted HK‐induced intrarenal renin response and developed impaired kaliuresis and elevated plasma K+ level (4.45 ± 0.14 vs. 3.89 ± 0.04 mM, p < 0.01). In parallel, HK‐induced intrarenal aldosterone and CYP11B2 expression along with expression of renal outer medullary K+ channel (ROMK), calcium‐activated potassium channel subunit alpha‐1 (α‐BK), α‐Na+‐K+‐ATPase, and epithelial sodium channel (β‐ENaC and cleaved‐γ‐ENaC) expression were all significantly blunted in CD renin KO mice in contrast to the unaltered responses of plasma aldosterone and adrenal CYP11B2. Conclusion: Taken together, these results support a kaliuretic action of CD renin during HK intake. [ABSTRACT FROM AUTHOR]

Aims: The effects of adding a sodium–glucose cotransporter 2 (SGLT2) inhibitor to a mineralocorticoid receptor antagonist (MRA) or an angiotensin receptor–neprilysin inhibitor (ARNI) in patients with heart failure (HF) and mildly reduced ejection fraction (HFmrEF) and preserved ejection fraction (HFpEF) are uncertain, even though the use of all three drugs is recommended in recent guidelines. Methods and results: The efficacy and safety of dapagliflozin added to background MRA or ARNI therapy was examined in patients with HFmrEF/HFpEF enrolled in the DELIVER trial. The primary outcome was the composite of worsening HF or cardiovascular death. Of 6263 patients, 2667 (42.6%) were treated with an MRA and 301 (4.8%) with an ARNI at baseline. Patients taking either were younger, more often men and had lower systolic blood pressure and ejection fraction; they were also more likely to have prior HF hospitalization. The benefit of dapagliflozin was similar whether patients were receiving these therapies. The hazard ratio for the effect of dapagliflozin compared to placebo on the primary outcome was 0.86 (95% confidence interval [CI] 0.74–1.01) for MRA non‐users versus 0.76 (95% CI 0.64–0.91) for MRA users (pinteraction = 0.30). The corresponding values for ARNI non‐users and users were 0.82 (95% CI 0.73–0.92) and 0.74 (95% CI 0.45–1.22), respectively (pinteraction = 0.75). None of the adverse events examined was more common with dapagliflozin compared to placebo overall or in the MRA and ARNI subgroups. Conclusions: The efficacy and safety of dapagliflozin were similar, regardless of background treatment with an MRA or ARNI. SGLT2 inhibitors may be added to other treatments recommended in recent guidelines for HFmrEF/HFpEF. [ABSTRACT FROM AUTHOR]

Background: The influence of aldosterone breakthrough (ABT) on proteinuria reduction during renin‐angiotensin system (RAS) inhibition for spontaneous proteinuric chronic kidney disease (CKDP) has not been determined in dogs. Objectives: Determine whether ABT occurs in dogs with CKDP and if it is associated with decreased efficacy in proteinuria reduction during RAS inhibitor treatment. Animals: Fifty‐six client‐owned dogs with CKDP and 31 healthy client‐owned dogs. Methods: Prospective, multicenter, open‐label clinical trial. Dogs were treated with an angiotensin‐converting enzyme inhibitor or angiotensin receptor blocker alone or in combination at the attending clinician's discretion and evaluated at 5 time points over 6 months. Healthy dogs were used to determine the urine aldosterone‐to‐creatinine ratio cutoff that defined ABT. The relationship of ABT (present at ≥50% of visits) and proteinuria outcome (≥50% reduction in urine protein‐to‐creatinine ratio from baseline at ≥50% of subsequent visits) was evaluated. Mixed effects logistic regression was used to evaluate the relationship between clinical variables and outcomes (either successful proteinuria reduction or ABT). Results: Thirty‐six percent (20/56) of dogs had successful proteinuria reduction. Between 34% and 59% of dogs had ABT, depending on the definition used. Aldosterone breakthrough was not associated with proteinuria outcome. Longer duration in the study was associated with greater likelihood of successful proteinuria reduction (P =.002; odds ratio, 1.6; 95% confidence interval [CI], 1.2‐2.2). Conclusions and Clinical Importance: Aldosterone breakthrough was common in dogs receiving RAS inhibitors for CKDp but was not associated with proteinuria outcome. [ABSTRACT FROM AUTHOR]

Aldosterone exerts some of its effects not by binding to mineralocorticoid receptors, but rather by acting via G protein-coupled estrogen receptors (GPER). To determine if aldosterone binds directly to GPER, we studied the ability of aldosterone to compete for the binding of [³H] 2-methoxyestradiol ([³H] 2-ME), a high potency GPER-selective agonist. We used GPER gene transfer to engineer Sf9-cultured insect cells to express GPER. We chose insect cells to avoid interactions with any intrinsic mammalian receptors for aldosterone. [³H] 2-ME binding was saturable and reversible to a high-affinity population of receptors with Kd = 3.7 nM and Bmax = 2.2 pmol/mg. Consistent with agonist binding to G Protein-coupled receptors, [³H] 2-ME high- affinity state binding was reduced in the presence of the hydrolysis-resistant GTP analog, GppNHp. [³H] 2-ME binding was competed for by the GPER agonist G1, the GPER antagonist G15, estradiol (E2), as well as aldosterone (Aldo). The order of potency for competing for [³H] 2-ME binding, namely 2ME > Aldo > E2 ≥ G1, paralleled the orders of potency for inhibition of cell proliferation and inhibition of ERK phosphorylation by ligands acting at GPER. These data confirm the ability of aldosterone to interact with the GPER, consistent with the interpretation that aldosterone likely mediates its GPER-dependent effects by direct binding to the GPER. Significance statement: Despite the growing evidence for aldosterone's actions via G protein-coupled estrogen receptors (GPER), there remains significant skepticism that aldosterone can directly interact with GPER. The current studies are the first to demonstrate directly that aldosterone indeed is capable of binding to the GPER and thus likely mediates its GPER-dependent effects by direct binding to the receptor. [ABSTRACT FROM AUTHOR]

Sudden death is a devastating complication of heart failure (HF). Current guidelines recommend an implantable cardioverter-defibrillator (ICD) for prevention of sudden death in patients with HF and reduced ejection fraction (HFrEF) specifically those with a left ventricular ejection fraction ≤35% after at least 3 months of optimized HF treatment. The benefit of ICD in patients with symptomatic HFrEF caused by coronary artery disease has been well documented; however, the evidence for a benefit of prophylactic ICD implantation in patients with HFrEF of non-ischaemic aetiology is less strong. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, beta-blockers (BB), and mineralocorticoid receptor antagonists (MRA) block the deleterious actions of angiotensin II, norepinephrine, and aldosterone, respectively. Neprilysin inhibition potentiates the actions of endogenous natriuretic peptides that mitigate adverse ventricular remodelling. BB, MRA, angiotensin receptor-neprilysin inhibitor (ARNI) have a favourable effect on reduction of sudden cardiac death in HFrEF. Recent data suggest a beneficial effect of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in reducing serious ventricular arrhythmias and sudden cardiac death in patients with HFrEF. So, in the current era of new drugs for HFrEF and with the optimal use of disease-modifying therapies (BB, MRA, ARNI and SGLT2i), we might need to reconsider the need and timing for use of ICD as primary prevention of sudden death, especially in HF of non-ischaemic aetiology. [ABSTRACT FROM AUTHOR]

Background: Chronic kidney disease (CKD) leads to low serum concentrations of vitamin D metabolites. Thus, hypovitaminosis D associated with CKD might contribute to disease progression via increased concentration of renin angiotensin aldosterone system (RAAS) mediators. Objectives: To evaluate whether supplementation with calcifediol affects equilibrium concentrations of selected mediators of the RAAS. We hypothesized that vitamin D supplementation will decrease concentration of circulating RAAS mediators in dogs with CKD. Animals: Six client‐owned adult dogs with IRIS Stage 2 and 3 CKD. Methods: Prospective study. Serum 25‐hydroxyvitamin D (25[OH]D), 1,25‐dihydroxyvitamin D (1,25[OH]2D), 24,25‐dihydroxyvitamin D (24,25[OH]2D), RAAS mediators (angiotensin I/II/III/IV/1‐5/1‐7, and aldosterone), and surrogate angiotensin converting enzyme (ACE) activity (calculated by the ratio of angiotensin II to angiotensin I) were evaluated at baseline, after 3 months of calcifediol supplementation, and 2 months after discontinuing administration of supplement. Results: All serum vitamin D metabolite concentrations increased significantly by month 3 (P <.001): 25(OH)D (median 250 ng/mL; range, 204‐310), compared to baseline (median 43.2 ng/mL; range, 33.8‐58.3 ng/mL); 1,25(OH)2D (median 66.1 pg/mL; range, 57.3‐88.1 pg/mL) compared to baseline (median 35.2 pg/mL; range, 29.3‐56.7 pg/mL); 24,25(OH)2D (median 68.4 ng/mL; range, 22.1‐142.0 ng/mL) compared to baseline (median 14.4 ng/mL; range, 9.0‐21.3 ng/mL). Calculated ACE activity was significantly lower at month 3 (median 0.5; range, 0.4‐1.0) compared to baseline (median 0.7; range, 0.6‐1.3; P =.01). There were no significant differences in any of the evaluated RAAS variables at any other time‐point. Conclusions and Clinical Importance: Short‐term calcifediol supplementation in this small group of CKD dogs appeared to decrease ACE activity. [ABSTRACT FROM AUTHOR]

Arterial hypertension is a major risk factor for cardiovascular disease. The prevalence of primary aldosteronism (PA) ranges from 5% to 10% in the general hypertensive population and is regarded as one of the most common causes of secondary hypertension. There are two major causes of PA: bilateral adrenal hyperplasia and aldosterone-producing adenoma. The diagnosis of PA comprises screening, confirmatory testing, and subtype differentiation. The Endocrine Society Practice Guidelines for the diagnosis and treatment of PA recommends screening of patients at an increased risk of PA. These categories include patients with stage 2 and 3 hypertension, drug-resistant hypertension, hypertensive with spontaneous or diuretic-induced hypokalemia, hypertension with adrenal incidentaloma, hypertensive with a family history of early onset hypertension or cerebrovascular accident at a young age, and all hypertensive first-degree relatives of patients with PA. Recently, several studies have linked PA with obstructive sleep apnea and atrial fibrillation unexplained by structural heart defects and/or other conditions known to cause the arrhythmia, which may be partly responsible for the higher rates of cardiovascular and cerebrovascular accidents in patients with PA. The aim of this review is to discuss which patients should be screened for PA, focusing not only on well-established guidelines but also on additional groups of patients with a potentially higher prevalence of PA, as has been reported in recent research. [ABSTRACT FROM AUTHOR]

Central serous chorioretinopathy (CSC) is a vision‐threatening disease with no validated treatment and unclear pathogenesis. It is characterized by dilation and leakage of choroidal vasculature, resulting in the accumulation of subretinal fluid, and serous detachment of the neurosensory retina. Numerous studies have demonstrated that melatonin had multiple protective effects against endothelial dysfunction, vascular inflammation, and blood–retinal barrier (BRB) breakdown. However, the effect of melatonin on CSC, and its exact pathogenesis, is not well understood thus far. In this study, an experimental model was established by intravitreal injection of aldosterone in rats, which mimicked the features of CSC. Our results found that melatonin administration in advance significantly inhibited aldosterone‐induced choroidal thickening and vasodilation by reducing the expression of calcium‐activated potassium channel KCa2.3, and attenuated tortuosity of choroid vessels. Moreover, melatonin protected the BRB integrity and prevented the decrease in tight junction protein (ZO‐1, occludin, and claudin‐1) levels in the rat model induced by aldosterone. Additionally, the data also showed that intraperitoneal injection of melatonin in advance inhibited aldosterone‐induced macrophage/microglia infiltration, and remarkably diminished the levels of inflammatory cytokines (interleukin‐6 [IL‐6], IL‐1β, and cyclooxygenase‐2), chemokines (chemokine C–C motif ligand 3, and C–X–C motif ligand 1), and matrix metalloproteinases (MMP‐2 and MMP‐9). Luzindole, as the nonselective MT1 and MT2 antagonist, and 4‐phenyl‐2‐propionamidotetraline, as the selective MT2 antagonist, neutralized the melatonin‐induced inhibition of choroidal thickening and choroidal vasodilation, indicating that melatonin might exert the effects via binding to its receptors. Furthermore, the IL‐17A/nuclear factor‐κB signaling pathway was activated by intravitreal administration of aldosterone, while it was suppressed in melatonin‐treated in advance rat eyes. This study indicates that melatonin could serve as a promising safe therapeutic strategy for CSC patients. [ABSTRACT FROM AUTHOR]

Liver diseases are the fourth common death in Europe responsible for about 2 million death per year worldwide. Among the known detrimental causes for liver dysfunction are virus infections, intoxications and obesity. The mineralocorticoid receptor (MR) is a ligand‐dependent transcription factor activated by aldosterone or glucocorticoids but also by pathological milieu factors. Canonical actions of the MR take place in epithelial cells of kidney, colon and sweat glands and contribute to sodium reabsorption, potassium secretion and extracellular volume homeostasis. The non‐canonical functions can be initiated by inflammation or an altered micro‐milieu leading to fibrosis, hypertrophy and remodelling in various tissues. This narrative review summarizes the evidence regarding the role of MR in portal hypertension, non‐alcoholic fatty liver disease, liver fibrosis and cirrhosis, demonstrating that inhibition of the MR in vivo seems to be beneficial for liver function and not just for volume regulation. Unfortunately, the underlying molecular mechanisms are still not completely understood. LINKED ARTICLES: This article is part of a themed issue on Emerging Fields for Therapeutic Targeting of the Aldosterone‐Mineralocorticoid Receptor Signaling Pathway. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.13/issuetoc [ABSTRACT FROM AUTHOR]

During the past decades, the mineralocorticoid receptor (MR) has evolved from a much-overlooked member of the steroid hormone receptor family to an important player, not only in volume and electrolyte homeostasis but also in pathological changes occurring in an increasing number of tissues, especially the renal and cardiovascular systems. Simultaneously, a wealth of information about the structure, interaction partners and chromatin requirements for genomic signalling of steroid hormone receptors became available. However, much of the information for the MR has been deduced from studies of other family members and there is still a lack of knowledge about MR-specific features in ligand binding, chromatin remodelling, co-factor interactions and general MR specificity-conferring mechanisms that can completely explain the differences in pathophysiological function between MR and its closest relative, the glucocorticoid receptor. This review aims to give an overview of the current knowledge of MR structure, signalling and co-factors modulating its activity. LINKED ARTICLES: This article is part of a themed issue on Emerging Fields for Therapeutic Targeting of the Aldosterone-Mineralocorticoid Receptor Signaling Pathway. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.13/issuetoc. [ABSTRACT FROM AUTHOR]

Mineralocorticoid receptor antagonists (MRAs) are key agents in guideline‐oriented drug therapy for cardiovascular diseases such as chronic heart failure with reduced ejection fraction and resistant hypertension. Currently available steroidal MRAs are efficacious in reducing morbidity and mortality; however, they can be associated with intolerable side effects including hyperkalaemia in everyday clinical practice. Recently, a new class of non‐steroidal MRAs (including esaxerenone, AZD9977, apararenone, KBP‐5074 and finerenone) have been developed with an improved benefit–risk profile and a novel indication for finerenone for diabetic kidney disease. To better understand the non‐steroidal MRAs, this review provides information on the molecular pharmacology as well as relevant current preclinical and clinical data on cardiorenal outcomes. A comparative review of all compounds in the class is discussed with regard to clinical efficacy and safety as well as a perspective outlining their future use in clinical practice. LINKED ARTICLES: This article is part of a themed issue on Emerging Fields for Therapeutic Targeting of the Aldosterone‐Mineralocorticoid Receptor Signaling Pathway. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.13/issuetoc [ABSTRACT FROM AUTHOR]

Chronic low‐grade inflammation and immune cell activation are important mechanisms in the pathophysiology of cardiovascular disease (CVD). Therefore, targeted immunosuppression is a promising novel therapy to reduce cardiovascular risk. In this review, we identify the mineralocorticoid receptor (MR) on immune cells as a potential target to modulate inflammation. The MR is present in almost all cells of the cardiovascular system, including immune cells. Activation of the MRs in innate and adaptive immune cells induces inflammation which can contribute to CVD, by inducing endothelial dysfunction and hypertension. Moreover, it accelerates atherosclerotic plaque formation and destabilization and impairs tissue regeneration after ischaemic events. Identifying the molecular targets for these non‐renal actions of the MR provides promising novel cardiovascular drug targets for mineralocorticoid receptor antagonists (MRAs), which are currently mainly applied in hypertension and heart failure. LINKED ARTICLES: This article is part of a themed issue on Emerging Fields for Therapeutic Targeting of the Aldosterone‐Mineralocorticoid Receptor Signaling Pathway. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.13/issuetoc [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is a major public health concern, affecting approximately 10% of the population worldwide. CKD of glomerular or tubular origin leads to the activation of stress mechanisms, including the renin–angiotensin–aldosterone system and mineralocorticoid receptor (MR) activation. Over the last two decades, blockade of the MR has arisen as a potential therapeutic approach against various forms of kidney disease. In this review, we summarize the experimental studies that have shown a protective effect of MR antagonists (MRAs) in nondiabetic and diabetic CKD animal models. Moreover, we review the main clinical trials that have shown the clinical application of MRAs to reduce albuminuria and, importantly, to slow CKD progression. Recent evidence from the FIDELIO trial showed that the MRA finerenone can reduce hard kidney outcomes when added to the standard of care in CKD associated with type 2 diabetes. Finally, we discuss the effects of MRAs relative to those of SGLT2 inhibitors, as well as the potential benefit of combination therapy to maximize organ protection. LINKED ARTICLES: This article is part of a themed issue on Emerging Fields for Therapeutic Targeting of the Aldosterone‐Mineralocorticoid Receptor Signaling Pathway. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.13/issuetoc [ABSTRACT FROM AUTHOR]

Aims: This prespecified analysis of the FIDELIO‐DKD trial compared the effects of finerenone, a selective non‐steroidal mineralocorticoid receptor antagonist, on cardiorenal outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) by history of heart failure (HF). Methods and results: Patients with T2D and CKD (urine albumin‐to‐creatinine ratio ≥30–5000 mg/g and estimated glomerular filtration rate [eGFR] ≥25–<75 ml/min/1.73 m2), without symptomatic HF with reduced ejection fraction (New York Heart Association II–IV) and treated with optimized renin–angiotensin system blockade were randomized to finerenone or placebo. The composite cardiovascular (CV) outcome (CV death, non‐fatal myocardial infarction, non‐fatal stroke, or hospitalization for HF) and composite kidney outcome (kidney failure, sustained ≥40% decrease in eGFR from baseline, or renal death) were analysed by investigator‐reported medical history of HF. Of 5674 patients, 436 (7.7%) had a history of HF. Over a median follow‐up of 2.6 years, the effect of finerenone compared with placebo on the composite CV outcome was consistent in patients with and without a history of HF (hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.50–1.06 and HR 0.90, 95% CI 0.77–1.04, respectively; interaction p = 0.33). The effect of finerenone on the composite kidney outcome did not differ by history of HF (HR 0.79, 95% CI 0.52–1.20 and HR 0.83, 95% CI 0.73–0.94, respectively; interaction p = 0.83). Conclusion: In FIDELIO‐DKD, finerenone improved cardiorenal outcome in patients with CKD and T2D irrespective of baseline HF history. [ABSTRACT FROM AUTHOR]

Objective: The central nucleus of the amygdala (CeA) has dense downward fiber projections towards the nucleus tractus solitary (NTS) and can modulate the activity of NTS taste neurons. However, whether CeA affects the nongenomic role of aldosterone (ALD) in regulating sodium intake at the NTS level remains unclear. Methods: First, 40 adult male Sprague Dawley rats were divided into five groups, referring to different concentrations of ALD, to observe the sodium intake pattern compared with the vehicle (n = 8). ALD, the mineralocorticoid receptor antagonist spironolactone (SPI), and ALD + SPI were injected into the NTS. Then, the rats were divided into four groups (n = 16): bilateral/unilateral CeA electrolytic lesions, bilateral/unilateral CeA sham lesions. After recovery, one stainless steel 23‐gauge cannula with two tubes was implanted into the rat NTS, and all rats underwent a recovery period of 7 days. Then, each group was divided into two subgroups that received aldosterone or control solution injection, and the cumulative intake of 0.3 mol/L NaCl solution was recorded within 30 min. Results: Bilateral CeA lesion eliminated the increased 0.3 mol/L NaCl intake induced by aldosterone microinjected into the NTS (CeA lesion: 0.3 ± 0.04 ml/30 min vs. sham lesion: 1.3 ± 0.3 ml/30 min). Unilateral CeA lesion reduced the increased NaCl intake induced by aldosterone microinjected into the NTS compared with the control group (p <.05) in the first 15 min but not in 15–30 min (p >.05). In sham lesion rats, aldosterone (5 ng/0.1 μl) still induced a significant increase in NaCl intake (aldosterone: 1.3 ± 0.3 ml/30 min vs. control: 0.25 ± 0.02 ml/30 min) (p <.05). Conclusion: The results verified that the complete CeA may play an important role in aldosterone to regulate the nongenomic effect on rapid sodium intake. [ABSTRACT FROM AUTHOR]

Aim: By contrast with drugs inhibiting the renin‐angiotensin‐aldosterone system (RAAS), diuretics stimulate renin release by the kidneys. Although plasma aldosterone (PA) is thought to be mainly regulated by RAAS activity, serum potassium has been shown to be an important factor in animal models and humans. Here we perform a systematic review and meta‐analysis of randomised controlled trials (RCT) in hypertension investigating the effects of diuretic therapy on PA and the correlation of change in PA with that of potassium and blood pressure (BP). Methods: Three databases were searched: MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL). Titles were first screened by title and abstract for relevance before full‐text articles were assessed for eligibility according to a predefined inclusion/exclusion criteria. Results: A total of 1139 articles were retrieved, of which 42 met the prespecified inclusion/exclusion criteria. The average standardised difference in mean PA was similar for all classes of diuretic: thiazide/thiazide‐like 0.299 (95% confidence interval [CI] 0.150, 0.447), loop 0.927 (0.37, 1.49), MRA/potassium‐sparing 0.265 (0.173, 0.357) and combination 0.466 (0.137, 0.796), Q = 6.33, P =.097. In subjects untreated with another antihypertensive, there was a significant relationship between change in PA and change in systolic BP but no relationship with the change in potassium. Conclusion: In RCTs of diuretic therapy in hypertension, there is an increase in PA with all classes of diuretic and no significant between‐class heterogeneity. Change in PA is not related with potassium but correlates with the change in BP in subjects untreated with another antihypertensive medication. [ABSTRACT FROM AUTHOR]