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BACKGROUND: Primary aldosteronism (PA) is a common but underdiagnosed cause of hypertension. Many patients experience preventable end-organ injury due to delayed or missed diagnosis but data on the experience of patients are limited. METHODS: We evaluated the lived experience of PA and determines factors associated with diagnostic delay through an international anonymous online cross-sectional survey, codesigned by researchers and PA consumers. We distributed the survey through academic medical centers, Amazon Mechanical Turk, Twitter, PA patient advocacy groups, and hypertension support groups on Facebook between March 21 and June 5, 2022. RESULTS: Of 684 eligible respondents, 66.5% were women. Diagnostic delay (defined as ≥5 years between the diagnosis of hypertension and PA) was reported in 35.6%. Delay was more likely in women than in men (odds ratio, 1.55 [95% CI, 1.10-2.20]) and respondents with ≥3 comorbidities versus none (odds ratio, 1.77 [95% CI, 1.05-3.02]), ≥10 symptoms versus none (odds ratio, 2.73 [95% CI, 1.74-4.44]), and on ≥4 antihypertensive medications versus none (odds ratio, 18.23 [95% CI, 6.24-77.72]). Three-quarters of patients (74.4%) experienced reduced symptom burden following targeted PA treatment. Quality of life improved in 62.3% of patients, and greater improvement was associated with being a woman (odds ratio, 1.42, [95% CI, 1.02-1.97]), receiving adrenalectomy (odds ratio, 2.36 [95% CI, 1.67-3.35]), and taking fewer antihypertensive medications following diagnosis (odds ratio, 5.28 [95% CI, 3.55-7.90]). CONCLUSIONS: One-third of patients with PA experienced prolonged diagnostic delays. Targeted treatment led to reduced symptom burden and improved quality of life. Gender differences in diagnostic delay and symptom burden are prominent. These findings suggest that routine screening for PA at the onset of hypertension may reduce diagnostic delay and facilitate timely diagnosis. [ABSTRACT FROM AUTHOR]

BACKGROUND: About 10% of patients with arterial hypertension have a positive screening test for primary aldosteronism (PA) and 50% to 70% of them have a negative confirmatory test: the appropriate follow-up of these patients is currently unknown. We investigated the incidence of PA in patients with previous negative confirmatory testing, after at least a 2-year follow-up. METHODS: One hundred eighty-four patients with a previously elevated aldosterone-to-renin ratio followed by a negative confirmatory test were recruited in 2 hypertension centers (Torino and Munich). We repeated the screening test for PA and, if positive, the confirmatory test (seated saline infusion test or captopril challenge test). Primary end point of the study was the incidence of newly diagnosed overt PA, as defined by a positive confirmatory test. RESULTS: After a mean follow-up of 5 years, 20% of patients developed overt PA. When subtype diagnosis was offered systematically, one-third of patients displayed unilateral PA. Patients who developed PA showed worsening of blood pressure control and a higher rate of cardiac organ damage, despite similar implementation of antihypertensive therapy, compared with patients without PA. A mild progression of autonomous aldosterone secretion was evident even in patients without confirmed PA but with relatively stable control of blood pressure levels over time. CONCLUSIONS: About one-fifth of patients with a negative confirmatory test develop overt PA over time. A clinical follow-up of patients with a negative confirmatory test is advisable, along with the repetition of PA investigation, primarily in patients with worsening of blood pressure control. [ABSTRACT FROM AUTHOR]

BACKGROUND: Salt sensitivity of blood pressure (SSBP) is a substantial risk factor for cardiovascular morbidity and mortality. Striatin (STRN) is critical for estrogen and aldosterone nongenomic signaling. However, the role of biological sex on the SSBP phenotype associated with STRN gene variants remains unexplored. METHOD: Data from 1306 subjects participating in the Hypertensive Pathotype (HyperPATH) Consortium were used to identify STRN gene single-nucleotide variants associated with SSBP. Haploblock analysis revealed a novel diplotype in the upstream regulatory region of STRN (rs888083 and rs6744560), with 31% of subjects being homozygous for the risk diplotype. RESULTS: Individuals homozygous for the risk diplotype had significantly greater SSBP than nonrisk diplotypes (P<0.009). While a significant genotype/SSBP association was present in both sexes, their potential mechanisms differed. Women, but not men homozygous risk diplotypes, had significantly greater aldosterone levels than nonrisk diplotypes (5.8±0.4 versus 3.2±0.7 ng/dl; P=0.01; liberal Na+ diet, adjusted). Men, but not women, homozygous risk diplotypes, had significantly reduced renal plasma flow response to Angiotensin II than nonrisk diplotypes (delta 95.2±5.2 versus 122.9±10.2 mL/min per 1.73 m²; P=0.01; liberal Na+ diet, adjusted). The single-nucleotide variants composing the risk diplotype were associated with lower STRN mRNA expression in human tissues (in silico). CONCLUSION: In women, the primary driver of SSBP is increased aldosterone, while in men, it is reduced renal plasma flow responses. Thus, despite a common hypertensive phenotype (SSBP) in both sexes, the specific treatment approaches might differ to increase therapeutic gain and mitigate adverse effects. These genetic- and sex-based observational results require confirmation in a prospective clinical study. [ABSTRACT FROM AUTHOR]

When low blood pressure is detected, angiotensin II, a protein hormone, binds to two receptors, one of which is AT1-R (angiotensin II receptor type 1), resulting in three major signaling pathways leading to regulated blood pressure. Binding to its receptor, Angiotensin II (Ang II) activates PLC (phospholipase C) signaling pathway, which branches out and activates an instantaneous rapid production of 1,4,5-inositol triphosphate (IP3) and a sustainable release of diacylglycerol (DAG). IP3 will increase in cytosolic free Calcium concentration ([Ca2+]i) by increasing Ca2+ influx and mobilizing intracellular Ca2+. Increasing calcium concentration results in vascular smooth muscle cell contraction (VSMC), increasing vessel resistance and rapidly increasing blood pressure. Additionally, DAG production activates PKC (protein kinase C) mechanisms, which elicit an increase in intracellular pH [pHi]. Such alkalinization is only dependent on Na+/H+ exchangers. This increase in pH with the activation of Na+/H+ induces vasoconstriction in various vascular vessels, thus increasing blood pressure. Ang II binding to AT1-R also activates Src and PLC / DAG signaling pathways. This activation stimulates the expression of CYP11B2 in H295R cells. If regularly expressed, the CYP11B2 gene will, in turn, result in aldosterone secretion from the adrenal cortex in the zona glomerulosa. On the other hand, if the CYP11B2 gene is not expressed normally, it will result in several gene mutations causing several diseases, including aldosterone synthase deficiency, which exposes infants to electrolyte abnormalities and failure to thrive. Aldosterone secretion will result in the activation of the Na+/K+ pump. With Na+/H+ exchangers already induced, the result will be increased sodium concentrations, leading to an increased stroke volume and blood pressure increase, and understanding the mechanism of how angiotensin works yields several advantages. These include understanding hypertension treatment, explaining renal disorders linked to fluid retention, fostering drug innovation, and empowering patients with insights into the necessity of lifestyle adjustments, including the crucial role of salt intake in increasing blood pressure. [ABSTRACT FROM AUTHOR]

Purpose: Adrenal vein sampling (AVS) is used to lateralise and differentiate unilateral from bilateral aldosterone production in primary aldosteronism. The adrenal venous samples are standardised to a peripheral or low inferior vena cava (IVC) sample and compared. It is unknown whether the location of the non-adrenal sample affects the results. This study compares AVS results standardised to the low IVC and right external iliac vein (REIV). Methods: Patients who underwent AVS between March 2021 and May 2023 were included. All procedures were undertaken by a single operator (AA). Demographic data and AVS results were collected from patients' electronic records. Catheterisation success and lateralisation were assessed using both low IVC and REIV samples. Equivalence test was used to compare the cortisol and aldosterone levels. Results: Eighty-one patients, (M: F = 38:43), aged between 29 and 74 were included. Bilateral successful adrenal vein cannulation was achieved in 79/81 (97.5%) cases. The mean cortisol levels from the REIV were statistically equivalent although there was a small and not biologically significant difference from the low IVC (respective geometric means 183 nmol/l vs. 185 nmol/l, p = 0.015). This small difference in cortisol may be due to accessory adrenal venous drainage into the IVC. The aldosterone and aldosterone/cortisol ratios were statistically equivalent. There was no discordance in selectivity or lateralisation when the IVC or REIV measurements were used. Conclusion: The IVC and REIV samples may be used interchangeably during AVS. [ABSTRACT FROM AUTHOR]

Background and aims: The important role of extracellular vesicles (EVs) in liver fibrosis has been confirmed. However, EVs derived from liver sinusoidal endothelial cells (LSECs) in the activation of hepatic stellate cells (HSCs) and liver fibrosis is still unclear. Our previous work demonstrated that Aldosterone (Aldo) may have the potential to regulate EVs from LSECs via autophagy pathway. Thus, we aim to investigate the role of Aldo in the regulation of EVs derived from LSECs. Approach and results: Using an Aldo-continuous pumping rat model, we observed that Aldo-induced liver fibrosis and capillarization of LSECs. In vitro, transmission electron microscopy (TEM) revealed that stimulation of Aldo led to the upregulation of autophagy and degradation of multivesicular bodies (MVBs) in LSECs. Mechanistically, Aldo upregulated ATP6V0A2, which promoted lysosomal acidification and subsequent autophagy in LSECs. Inhibiting autophagy with si-ATG5 adeno-associated virus (AAV) in LSECs effectively mitigated Aldo-induced liver fibrosis in rats. RNA sequencing and nanoparticle tracking (NTA) analyses of EVs derived from LSECs indicated that Aldo result in a decrease in both the quantity and quality of EVs. We also observed a reduction in the protective miRNA-342-5P in EVs derived from Aldo-treated LSECs, which may play a critical role in HSCs activation. Target knockdown of EV secretion with si-RAB27a AAV in LSECs led to the development of liver fibrosis and HSC activation in rats. Conclusion: Aldo-induced Autophagic degradation of MVBs in LSECs promotes a decrease in the quantity and quality of EVs derived from LSECs, resulting in the activation of HSCs and liver fibrosis under hyperaldosteronism. Modulating the autophagy level of LSECs and their EV secretion may represent a promising therapeutic approach for treating liver fibrosis. In a physiological state, LSECs transmit inhibitory signals to HSCs via the secretion of EVs that are rich in miR-342-5p. However, in pathological conditions, the elevated levels of serum aldosterone induce capillarization and excessive autophagy in LSECs. This autophagy leads to the degradation of MVBs in LSECs, resulting in a reduction of the number of EVs and miR-342-5p content within EVs. This reduction ultimately leads to a diminished inhibitory signal transmitted to HSCs, thereby activating HSCs and promoting the development of liver fibrosis. [ABSTRACT FROM AUTHOR]

Primary aldosteronism (PA) is an endocrinopathy characterized by dysregulated aldosterone production that occurs despite suppression of renin and angiotensin II, and that is non-suppressible by volume and sodium loading. The effectiveness of surgical adrenalectomy for patients with lateralizing PA is characterized by the attenuation of excess aldosterone production leading to blood pressure reduction, correction of hypokalemia, and increases in renin—biomarkers that collectively indicate a reversal of PA pathophysiology and restoration of normal physiology. Even though the vast majority of patients with PA will ultimately be treated medically rather than surgically, there is a lack of guidance on how to optimize medical therapy and on key metrics of success. Herein, we review the evidence justifying approaches to medical management of PA and biomarkers that reflect endocrine principles of restoring normal physiology. We review the current arsenal of medical therapies, including dietary sodium restriction, steroidal and nonsteroidal mineralocorticoid receptor antagonists, epithelial sodium channel inhibitors, and aldosterone synthase inhibitors. It is crucial that clinicians recognize that multimodal medical treatment for PA can be highly effective at reducing the risk for adverse cardiovascular and kidney outcomes when titrated with intention. The key biomarkers reflective of optimized medical therapy are unsurprisingly similar to the physiologic expectations following surgical adrenalectomy: control of blood pressure with the fewest number of antihypertensive agents, normalization of serum potassium without supplementation, and a rise in renin. Pragmatic approaches to achieve these objectives while mitigating adverse effects are reviewed. [ABSTRACT FROM AUTHOR]

Context Black women have a higher prevalence of hypertension as compared to White women. Differences in dietary sodium intake have been implicated as a contributing factor for the disparities in hypertension. Objective Our objective was to understand whether young Black women would have higher systolic blood pressure (SBP) than White women even on controlled sodium diets and to determine whether SBP differences were due to differences in dietary sodium intake and/or aldosterone regulation. Design The analyses included 525 hypertensive and normotensive women (ages 18-71) from the International Hypertensive Pathotype consortium, who were maintained on liberal sodium (LIB; >200 mEq sodium/day) and restricted sodium (RES; 10 mEq sodium/day) diets. Results Multivariate regression analyses (adjusted for age, race, study site, body mass index) found that Black women (ages 18-50) had significantly higher SBP than White women on both sodium diets: +8.7 ± 2.7 mmHg (P -value =.002) on a LIB diet and +8.5 ± 2.5 mmHg (P -value =.001) on a RES diet. Even among 18- to 35-year-olds—who were normotensive and nonobese—Black women had higher SBP: +7.9 ± 2.4 mmHg (P -value =.001) on a LIB diet and +7.6 ± 2.7 mmHg (P -value =.005) on a RES diet. Younger Black women also had higher plasma aldosterone concentration to plasma renin activity ratio (ARR) on both LIB and RES diets as well as a higher sodium-modulated aldosterone suppression-stimulation index—an indicator of aldosterone dysregulation. In younger Black women—but not in White women—there was a significant association between SBP and ARR on both LIB and RES diets. Conclusion Young Black women had increased SBP and ARR as compared to White women on LIB and RES diets, which offers insights into the possible mechanisms for the increased hypertension and cardiovascular disease risk in an at-risk and understudied population. [ABSTRACT FROM AUTHOR]

Diabetic Kidney Disease (DKD) is a significant complication of diabetes and primary cause of end-stage renal disease globally. The exact mechanisms underlying DKD remain poorly understood, but multiple factors, including the renin–angiotensin–aldosterone system (RAAS), play a key role in its progression. Aldosterone, a mineralocorticoid steroid hormone, is one of the key components of RAAS and a potential mediator of renal damage and inflammation in DKD. miRNAs, small noncoding RNA molecules, have attracted interest due to their regulatory roles in numerous biological processes. These processes include aldosterone signaling and mineralocorticoid receptor (MR) expression. Numerous miRNAs have been recognized as crucial regulators of aldosterone signaling and MR expression. These miRNAs affect different aspects of the RAAS pathway and subsequent molecular processes, which impact sodium balance, ion transport, and fibrosis regulation. This review investigates the regulatory roles of particular miRNAs in modulating aldosterone signaling and MR activation, focusing on their impact on kidney injury, inflammation, and fibrosis. Understanding the complex interaction between miRNAs and the RAAS could lead to a new strategy to target aldosterone signaling and MR activation using miRNAs. This highlights the potential of miRNA-based interventions for DKD, with the aim of enhancing kidney outcomes in individuals with diabetes. [ABSTRACT FROM AUTHOR]

Aldosterone (Aldo) exerts its action through binding with the mineralocorticoid receptor (MR). Clinically, a link between primary aldosteronism (PA) and thyroid diseases has been hypothesised. However, the presence and activity of MR on the thyroid have not yet been demonstrated. We investigated the gene/protein expression and activation of MR in primary thyroid cell cultures (normal rat thyroid [FRTL-5] and human papillary thyroid cancer [PTC] cell lines, BCPAP and K1) through qRT-PCR analysis, immunofluorescence, and confocal microscopy. We also studied the effects of Aldo on thyroid-specific and inflammation genes in vitro. Paired human normal and neoplastic thyroid tissues were also studied. We demonstrated both gene and protein expression and activation of MR in normal rat thyroid and human PTC lines. Incubation with Aldo induced an acute increase in IL-6 expression in both the FRTL-5 and BCPAP lines, which was antagonised by spironolactone, and an acute and late upregulation of thyroid-specific genes in FRTL-5. MR was also expressed at both gene and protein levels in normal human thyroid tissues and in PTC, with a progressive decline during neoplastic tumourigenesis, particularly in more aggressive histotypes. We present the first evidence of MR gene and protein expression in both normal and pathological thyroid cells and tissues. We have shown that MR is present and functionally activated in thyroid tissue. Binding of Aldo to MR induces the expression of inflammatory and thyroid-specific genes, and the thyroid may thus be considered a novel mineralocorticoid target tissue. [ABSTRACT FROM AUTHOR]

BACKGROUND: Primary aldosteronism, characterized by overt renin-independent aldosterone production, is a common but underrecognized form of hypertension and cardiovascular disease. Growing evidence suggests that milder and subclinical forms of primary aldosteronism are highly prevalent, yet their contribution to cardiovascular disease is not well characterized. METHODS: This prospective study included 1284 participants between the ages of 40 and 69 years from the randomly sampled population-based CARTaGENE cohort (Québec, Canada). Regression models were used to analyze associations of aldosterone, renin, and the aldosterone-to-renin ratio with the following measures of cardiovascular health: arterial stiffness, assessed by central blood pressure (BP) and pulse wave velocity; adverse cardiac remodeling, captured by cardiac magnetic resonance imaging, including indexed maximum left atrial volume, left ventricular mass index, left ventricular remodeling index, and left ventricular hypertrophy; and incident hypertension. RESULTS: The mean (SD) age of participants was 54 (8) years and 51% were men. The mean (SD) systolic and diastolic BP were 123 (15) and 72 (10) mm Hg, respectively. At baseline, 736 participants (57%) had normal BP and 548 (43%) had hypertension. Higher aldosterone-to-renin ratio, indicative of renin-independent aldosteronism (ie, subclinical primary aldosteronism), was associated with increased arterial stiffness, including increased central BP and pulse wave velocity, along with adverse cardiac remodeling, including increased indexed maximum left atrial volume, left ventricular mass index, and left ventricular remodeling index (all P<0.05). Higher aldosterone-to-renin ratio was also associated with higher odds of left ventricular hypertrophy (odds ratio, 1.32 [95% CI, 1.002–1.73]) and higher odds of developing incident hypertension (odds ratio, 1.29 [95% CI, 1.03–1.62]). All the associations were consistent when assessing participants with normal BP in isolation and were independent of brachial BP. CONCLUSIONS: Independent of brachial BP, a biochemical phenotype of subclinical primary aldosteronism is negatively associated with cardiovascular health, including greater arterial stiffness, adverse cardiac remodeling, and incident hypertension. [ABSTRACT FROM AUTHOR]

In general, females present with stronger immune responses than males, but scarce data are available on sex-specific differences in immunometabolism. In this study, we characterized porcine peripheral blood mononuclear cell (PBMC) and granulocyte energy metabolism using a Bayesian 13C-metabolic flux analysis, which allowed precise determination of the glycolytic, pentose phosphate pathway (PPP), and tricarboxylic acid cycle (TCA) fluxes, together with an assessment of the superoxide anion radical (O2•−) production and mitochondrial O2 consumption. A principal component analysis allowed for identifying the cell type-specific patterns of metabolic plasticity. PBMCs displayed higher TCA cycle activity, especially glutamine-derived aspartate biosynthesis, which was directly related to mitochondrial respiratory activity and inversely related to O2•− production. In contrast, the granulocytes mainly utilized glucose via glycolysis, which was coupled to oxidative PPP utilization and O2•− production rates. The granulocytes of the males had higher oxidative PPP fluxes compared to the females, while the PBMCs of the females displayed higher non-oxidative PPP fluxes compared to the males associated with the T helper cell (CD3+CD4+) subpopulation of PBMCs. The observed sex-specific differences were not directly attributable to sex steroid plasma levels, but we detected an inverse correlation between testosterone and aldosterone plasma levels and showed that aldosterone levels were related with non-oxidative PPP fluxes of both cell types. [ABSTRACT FROM AUTHOR]

Introduction: Primary aldosteronism (PA) is associated with several cardiometabolic comorbidities. Specific treatment by mineralocorticoid receptor antagonists (MRA) or adrenalectomy has been reported to reduce the cardiometabolic risk. However, the cardiovascular benefit could depend on plasma renin levels in patients on MRA. Aim: To compare the development of cardiovascular, renal and metabolic complications between medically treated patients with PA and those who underwent adrenalectomy, taking the renin status during MRA treatment into account. Methods: A multicenter retrospective study (SPAIN-ALDO Register) of patients with PA treated at 35 Spanish tertiary hospitals. Patients on MRA were divided into two groups based on renin suppression (n = 90) or non-suppression (n = 70). Both groups were also compared to unilateral PA patients (n = 275) who achieved biochemical cure with adrenalectomy. Results: Adrenalectomized patients were younger, had higher plasma aldosterone concentration, and lower potassium levels than MRA group. Patients on MRA had similar baseline characteristics when stratified into treatment groups with suppressed and unsuppressed renin. 97 (55.1%) of 176 patients without comorbidities at diagnosis, developed at least one comorbidity during follow-up (median 12 months vs. 12.5 months' follow-up after starting MRA and surgery, respectively). Surgery group had a lower risk of developing new cardiovascular events (HR 0.40 [95% CI 0.18–0.90]) than MRA group. Surgical treatment improved glycemic and blood pressure control, increased serum potassium levels, and required fewer antihypertensive drugs than medical treatment. However, there were no differences in the cardiometabolic profile or the incidence of new comorbidities between the groups with suppressed and unsuppressed renin levels (HR 0.95 [95% CI 0.52–1.73]). Conclusion: Cardiovascular, renal, and metabolic events were comparable in MRA patients with unsuppressed and suppressed renin. Effective surgical treatment of PA was associated with a decreased incidence of new cardiovascular events when compared to MRA therapy. [ABSTRACT FROM AUTHOR]

Introduction: This study will test the hypothesis that primary aldosteronism (PA) involves alterations in Na+, K+, and water content in the skin that are corrected by adrenalectomy. Aim and Methods: In skin biopsies, we will measure the content of Na+, K+, water, by physical-chemical methods and the osmotic-stress-responsive transcription factor Tonicity-responsive Enhancer Binding Protein (TonEBP, NFAT5) mRNA copy number by droplet digital PCR, in sex-balanced cohorts of 18 -75-year-old consecutive consenting patients with unilateral and bilateral PA, primary (essential) hypertension, and normotension. Before surgery, the patients with unilateral PA will receive the mineralocorticoid receptor antagonist (MRA) canrenone at doses that correct hypokalemia and high blood pressure values. They will be reassessed in an identical way one month after surgical cure, while off MRA. PA patients not selected for adrenalectomy will similarly be assessed at diagnosis and follow-up while on stable MRA treatment. Since a pilot study showed a direct correlation of dry weight (DW) with skin electrolytes and water content and significant differences of biopsy DW between surgery and follow-up, meaningful comparison of the skin cations and water content and TonEBP mRNA copy number, between specimen obtained at different time points, will require DW- and total mRNA-adjustment, respectively. Conclusion: This study will provide novel information on the skin Na+, K+ and water content in PA, the paradigm of salt-dependent hypertension, and novel knowledge on the effect of surgical cure of hyperaldosteronism. The TonEBP-mediated regulation of Na+, K+ and water content in the skin will also be unveiled. Trail Registry: Trial Registration number: NCT06090617. Date of Registration: 2023-10-19. [ABSTRACT FROM AUTHOR]

Primary adrenal insufficiency (AI) is an endocrine disorder in which hormones of the adrenal cortex are produced to an insufficient extent. Since receptors for adrenal steroids have a wide distribution, initial symptoms may be nonspecific. In particular, the lack of glucocorticoids can quickly lead to a life-threatening adrenal crisis. Therefore, current guidelines suggest applying a low threshold for testing and to rule out AI not before serum cortisol concentrations are higher than 500 nmol/l (18 μg/dl). To ease the diagnostic, determination of morning cortisol concentrations is increasingly used for making a diagnosis whereby values of>350 nmol/l are considered to safely rule out Addison's disease. Also, elevated corticotropin concentrations (>300 pg/ml) are indicative of primary AI when cortisol levels are below 140 nmol/l (5 μg/dl). However, approximately 10 percent of our patients with the final diagnosis of primary adrenal insufficiency would clearly have been missed for they presented with normal cortisol concentrations. Here, we present five such cases to support the view that normal to high basal concentrations of cortisol in the presence of clearly elevated corticotropin are indicative of primary adrenal insufficiency when the case history is suggestive of Addison's disease. In all cases, treatment with hydrocortisone had been started, after which the symptoms improved. Moreover, autoantibodies to the adrenal cortex had been present and all patients underwent a structured national education program to ensure that self-monitored dose adjustments could be made as needed. [ABSTRACT FROM AUTHOR]

Primary aldosteronism is an endocrine disorder caused by excessive production of aldosterone by the adrenal glands, and is recognized as the most important cause of endocrine hypertension. With specific therapy, this type of hypertension is potentially curable. In the general population, high salt intake increases the risk for cardiovascular diseases like stroke. In populations with aldosterone excess, observational and experimental data suggest that aldosterone-induced organ damage requires a combination of high dietary salt intake and high plasma aldosterone, i.e., plasma aldosterone levels inappropriately high for salt status. Therefore, understanding the relationship between plasma aldosterone levels and dietary salt intake and the nature of their combined effects is crucial for developing effective prevention and treatment strategies. In this review, we present an update on findings about primary aldosteronism and salt intake and the underlying mechanisms governing their interaction. [ABSTRACT FROM AUTHOR]

A key regulator of blood pressure homeostasis is the steroid hormone aldosterone, which is released as the final signaling hormone of the renin-angiotensin-aldosterone-signaling (RAAS) system. Aldosterone increases sodium (Naþ) reabsorption in the kidney distal nephron to regulate blood volume. Unregulated RAAS signaling can lead to hypertension and cardiovascular disease. The serum and glucocorticoid kinase (SGK1) coordinates much of the Na+ reabsorption in the cortical collecting duct (CCD) tubular epithelial cells. We previously demonstrated that aldosterone alters the expression of microRNAs (miRs) in CCD principal cells. The aldosterone-regulated miRs can modulate Na+ transport and the cellular response to aldosterone signaling. However, the sex-specific regulation of miRs by aldosterone in the kidney distal nephron has not been explored. In this study, we report that miR-19, part of the miR-17-92 cluster, is upregulated in female mouse CCD cells in response to aldosterone activation. Mir-19 binding to the 30-untranslated region of SGK1 was confirmed using a dual-luciferase reporter assay. Increasing miR-19 expression in CCD cells decreased SGK1 message and protein expression. Removal of this cluster using a nephron-specific, inducible knockout mouse model increased SGK1 expression in female mouse CCD cells. The miR-19-induced decrease in SGK1 protein expression reduced the response to aldosterone stimulation and may account for sex-specific differences in aldosterone signaling. By examining evolution of the miR-17-92 cluster, phylogenetic sequence analysis indicated that this cluster arose at the same time that other Na+-sparing and salt regulatory proteins, specifically SGK1, first emerged, indicating a conserved role for these miRs in kidney function of salt and water homeostasis. NEW & NOTEWORTHY: Expression of the microRNA-17-92 cluster is upregulated by aldosterone in mouse cortical collecting duct principal cells, exclusively in female mice. MiR-19 in this cluster targets the serum and glucocorticoid kinase (SGK1) to downregulate both mRNA and protein expression, resulting in a decrease in sodium transport across epithelial cells of the collecting duct. The miR-17-92 cluster is evolutionarily conserved and may act as a novel feedback regulator for aldosterone signaling in females. [ABSTRACT FROM AUTHOR]

The present study describes the case of a 71-yearold male patient with hypocalcemia, hypomagnesemia and hypokalemia. Following infusion therapy, the serum calcium and serum magnesium levels were normalized. Conversely, serum potassium did not respond to the infusion therapy, with the progressive reduction of the serum concentration, in spite of the high dose of potassium infusion. Although unusual, the present study analyzed how infusion treatment affects kalemia. The present study used, over time, the measurements of variables on a single patient as 'cases' and the set of measurements of the patient himself (single patient) as a 'cohort'. One patient can be considered as one single cluster; thus, the independence assumption is not violated. The present study quantitatively analyzed the effect of one or more treatments and in finding unknown causes that may influence the therapeutic response, particularly in situations with a paradoxical response. Thus, it was found that only potassium canreonate was related to an increase in kalemia (β=0.03, P<0.01). Based on this finding, together with the low aldosterone concentration in hypokalemia, an apparent excess of mineral corticoids was assumed. [ABSTRACT FROM AUTHOR]

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Our objective was to overview the novel aspects in the field of adrenal gland neoplasms, namely, the management of bone status with respect to primary aldosteronism (PA). In the current narrative review, a PubMed study was conducted from inception until June 2023. The inclusion criteria were: human (clinically relevant) studies of any study design (at least 10 patients per study); English papers; and the following combination of key words within the title and/or abstract: "aldosterone" AND "bone", "skeleton", "osteoporosis", "fracture", "calcium", "parathyroid", "DXA", "osteocalcin", "P1NP", "alkaline phosphatase", "bone marker", "trabecular bone score", or "FRAX". The exclusion criteria were in vitro or animal studies, reviews, and case reports/series. We screened 1027 articles and finally included 23 studies (13 of case-control type, 3 cross-sectional, 5 prospective, 1 observational cohort, and 1 retrospective study). The assessments provided in these studies were as follows: nine studies addressed Dual-Energy X-ray Absorptiometry (DXA), another study pointed out a bone microarchitecture evaluation underlying trabecular bone score (TBS), and seven studies investigated the bone turnover markers (BTMs) profile. Moreover, 14 studies followed the subjects after adrenalectomy versus medical treatment, and 21 studies addressed secondary hyperparathyroidism in PA patients. According to our study on published data during a period of almost 40 years (n = 23, N = 3965 subjects aged between 38 and 64, with a mean age 56.75, and a female-to-male ratio of 1.05), a higher PTH in PA versus controls (healthy persons or subjects with essential hypertension) is expected, secondary hyperparathyroidism being associated in almost half of the adults diagnosed with PA. Additionally, mineral metabolism anomalies in PA may include lower serum calcium and higher urinary calcium output, all these three parameters being reversible under specific therapy for PA, regardless medical or surgical. The PA subgroup with high PTH seems at higher cardiovascular risk, while unilateral rather than bilateral disease was prone to this PTH anomaly. Moreover, bone mineral density (BMD) according to central DXA might show a higher fracture risk only in certain adults, TBS being a promising alternative (with a still unknown perspective of diabetes' influence on DXA-TBS results in PA). However, an overall increased fracture prevalence in PA is described in most studies, especially with respect to the vertebral site, the fracture risk that seems correctable upon aldosterone excess remission. These data recommend PA as a cause of secondary osteoporosis, a treatable one via PA intervention. There is still an area of debate the way to address BMTs profile in PA, the case's selection toward specific bone evaluation in every day practice, and further on, the understanding of the potential genetic influence at the level of bone and mineral complications in PA patients. [ABSTRACT FROM AUTHOR]

Hyporeninemic hypoaldosteronism has been reported in only a few cases with methylmalonic acidemia (MMA) and has been attributed to the renal involvement. This study aims to investigate renin-aldosterone levels along with the renal functions of the patients with organic acidemia. This is a cross-sectional study conducted in patients with MMA, propionic acidemia (PA), and isovaleric acidemia (IVA). Serum renin, aldosterone, sodium, and potassium levels were measured, and glomerular filtration rates (GFR) were calculated. Comparisons were made between the MMA and non-MMA (PA+IVA) groups. Thirty-two patients (MMA:PA:IVA = 14:13:5) were included. The median GFR was significantly lower in the MMA group than in the non-MMA group (p < 0.001). MMA patients had the highest incidence of kidney damage (71.4%), followed by PA patients (23%), while none of the IVA patients had reduced GFR. GFR positively correlated with renin levels (p = 0.015, r = 0.433). Although renin levels were significantly lower in the MMA group than the non-MMA group (p = 0.026), no significant difference in aldosterone levels was found between the two groups. Hyporeninemic hypoaldosteronism was found in 3 patients with MMA who had different stages of kidney damage, and fludrocortisone was initiated, which normalized serum sodium and potassium levels. Conclusions: This study, which has the largest number of patients among the studies investigating the renin-angiotensin system in organic acidemias to date, has demonstrated that hyporeninemic hypoaldosteronism is not a rare entity in the etiology of hyperkalemia in patients with MMA, and the use of fludrocortisone is an effective treatment of choice in selected cases. What is Known: • Hyperkalemia may be observed in cases of methylmalonic acidemia due to renal involvement and can be particularly prominent during metabolic decompensation. • Hyporeninemic hypoaldosteronism has been reported to be associated with hyperkalemia in only a few cases of methylmalonic acidemia. What is New: • Hyporeninemic hypoaldosteronism was found in one-fifth of cases with methylmalonic acidemia. • Fludrocortisone therapy leads to the normalization of serum sodium and potassium levels. [ABSTRACT FROM AUTHOR]

Objective: Primary aldosteronism (PA) is the most common surgically curable cause of hypertension. Unilateral aldosterone-producing adenoma can be treated with adrenalectomy. Clinical and biochemical outcomes are assessed 6-12 months after adrenalectomy according to primary aldosteronism surgical outcome (PASO) consensus criteria. Earlier prediction of biochemical remission would be desirable as it could reduce cumbersome follow-up visits. We hypothesized that postoperative adrenocorticotropic hormone (ACTH) stimulated plasma aldosterone concentrations (PAC) measured shortly after adrenalectomy can predict PASO outcomes. Design: Retrospective cohort study. Methods: We analyzed 100 patients of the German Conn's registry who underwent adrenalectomy and postoperative ACTH stimulation tests within the first week after adrenalectomy. Six to twelve months after adrenalectomy we assessed clinical and biochemical outcomes according to PASO criteria. Serum cortisol and PAC were measured by immunoassay at baseline and 30 min after the intravenous ACTH infusion. We used receiver operating characteristics (ROC) curve analysis and matched the parameters to PASO outcomes. Results: Eighty-one percent of patients had complete, 13% partial, and 6% absent biochemical remission. Complete clinical remission was observed in 28%. For a cut-off of 58.5 pg/mL, stimulated PAC could predict partial/absent biochemical remission with a high sensitivity (95%) and reasonable specificity (74%). Stimulated PAC's area under the curve (AUC) (0.89; confidence interval (CI) 0.82-0.96) was significantly higher than other investigated parameters. Conclusions: Low postoperative ACTH stimulated PAC was predictive of biochemical remission. If confirmed, this approach could reduce follow-up visits to assess biochemical outcome. [ABSTRACT FROM AUTHOR]

The purpose of the review is to summarize the current pharmacological management of chronic kidney disease (CKD) in pediatric patients and critically present emerging evidence for the use of mineralocorticoid receptor antagonists and sodium-glucose cotransporter-2 (SGLT2) inhibitors. Globally, CKD is the 19th leading cause of years of life lost and the current total number of children and adolescents affected with CKD Stages II-V is predicted to exceed 2 million in a global population of 2 billion children. The severity of kidney disease is strongly correlated with the extent of proteinuria. Agents that target the renin-angiotensin-aldosterone-system reduce proteinuria in mild to moderate CKD, slowing disease progression. Recent clinical trials evaluating mineralocorticoid receptor antagonists, such as finerenone and SGLT2 inhibitors, demonstrate similar results. However, additional pediatric clinical trials are necessary to determine their complete therapeutic potential. [ABSTRACT FROM AUTHOR]

Objective: To investigate the role of Nox2 on AngII-stimulated aldosterone biosynthesis. Methods: H295R cells were cultured and randomly divided into control group, Angll group, AngII+gp91ds-tat group, AngII+PEG-Cat group, AngII+Nox2 siRNA group. Q-PCR and western blot were performed to determine CYP1IB2 and Nox2 expression in H295R cells. Aldosterone level in cells culture supernatant was determined by radioimmunoassay. Nox2-derived ROS and H2O2 production in H295R cells were determined by flow cytometric analysis and fluorescence microplate reader. Results: 10 nmol/L Angll increased cellular ROS and H2O2 generation, increased the Nox2 and CYP11B2 expression and accelerated aldosterone biosynthesis in a time-dependent manner (P<0.05). And AngII-induced cellular ROS and H₂O, production in both AngII+gp91ds-tat and AngII+PEG-Cat groups were lower than those in AngII group (P<0.05). However, there were no difference in inhibition of cellular ROS and H2O2 between treatment with gp91ds-tat and PEG-Cat (P>0.05). The expression of CYP11B2 in H295R cells was up-regulated after treated with 10 nmol/L Angll for 24 h (P<0.05), while gp91ds-tat, PEG-Cat and Nox2 siRNA significantly abrogated the CYP11B2 expression in H295R cells (P<0.05). Conclusion: Nox2 dependent ROS play an important role in aldosterone synthesis. [ABSTRACT FROM AUTHOR]

Primary aldosteronism (PA) is considered the number one aetiology for secondary hypertension. Apart from confirmatory tests and localisation of PA determined by computed tomography (CT), adrenal venous sampling (AVS) is used to define whether aldosterone hypersecretion occurs inside one or both adrenal glands. However, even correctly-performed AVS may lead to undiagnostic results such as apparent bilateral adrenal suppression (apparent bilateral aldosterone suppression), in which the adrenal aldosterone-to-cortisol ratios (AC ratios) are decreased bilaterally compared to the peripheral blood sample, with several causes contributing to it. Here, we describe the case of a 48-year-old man who was referred to our department for further investigation with a history of refractory hypertension, hypokalaemia, and aortic dissection. His hypertension and hypokalaemia were initially attributed to ectopic aldosteronoma due to his adrenal CT scan and AVS results. However, the correct diagnosis of an adenoma with duplicated right adrenal veins (duplicated adrenal veins) due to apparent bilateral aldosterone suppression was confirmed during surgery. AVS is the gold standard accepted for PA subtyping, but sometimes when apparent bilateral aldosterone suppression is present, it can give ambiguous results. Duplicated right adrenal veins, may impact results, thus, AVS may not accurately provide evidence of unilateral hypersecretion for all PA patients. Repeat AVS or adrenal surgery can provide worthwhile diagnostic conclusions. The recognition and diagnosis of primary aldosteronism (PA) have increased in recent years and clinicians usually require adrenal venous sampling (AVS) to identify the affected side, and it's crucial for further treatments of PA patients (surgery or medicine). We presented an example of unilateral aldosteronoma with duplicated adrenal veins whose AVS results suggested apparent bilateral aldosterone suppression (the adrenal venous aldosterone/cortisol ratios are bilaterally lower than the peripheral ratios). He was misdiagnosed with ectopic aldosteronoma due to computed tomography (CT) features, but surgery findings revealed duplicated adrenal veins. Unclear AVS results such as apparent bilateral aldosterone suppression can lead to a missed diagnosis of unilateral PA, preventing patients from receiving potentially curative adrenal resection. Our case can serve as an example for clinicians that encounter the same condition to provide further investigational clues to ensure the correct aetiological diagnosis for patients with PA. [ABSTRACT FROM AUTHOR]

BACKGROUND: Disease-causing mutations in CACNA1D gene occur in aldosterone-producing adenomas and familial hyperaldosteronism. We determined whether single nucleotide polymorphisms in CACNA1D gene associate with higher aldosterone resulting in salt sensitivity of blood pressure (BP) and increased BP in men and women. METHODS: Data were obtained from the HyperPATH (International Hypertension Pathotypes) cohort, where participants completed a cross-over intervention of liberal and restricted sodium diets. Multi-Ethnic Genotyping Array identified 104 CACNA1D single nucleotide polymorphisms that met quality control. Single nucleotide polymorphism is rs7612148 strongly associated with systolic BP and was selected for study in 521 White participants in 3 scenarios ([1] hypertensives; [2] normotensives; [3] total population=hypertensives+normotensives) using multivariate regression analysis. RESULTS: In the total population and hypertensives, but not normotensives, risk allele carriers (CC, GC), as compared with nonrisk allele homozygotes (GG), exhibited higher salt sensitivity of BP and, on liberal sodium diet, higher systolic BP, lower baseline and angiotensin II-stimulated aldosterone, and lower plasma renin activity. On restricted sodium diet, BP was similar across genotypes, suggesting sodium restriction corrected/neutralized the genotype effect on BP. Because increased aldosterone did not seem to drive the increased salt sensitivity of BP and increased BP on liberal sodium diet, we assessed renal plasma flow. Renal plasma flow increase from restricted to liberal sodium diets was blunted in risk allele homozygotes in the total population and in hypertensives. A replication study in another cohort HyperPATH B (International Hypertension Pathotypes Cohort B) confirmed BP-genotype associations. CONCLUSIONS: CACNA1D rs7612148 risk allele associated with increased BP and salt sensitivity of BP, likely due to an impaired ability to increase renal plasma flow in response to a liberal sodium diet and not to excess aldosterone. [ABSTRACT FROM AUTHOR]

BACKGROUND: Primary aldosteronism (PA) is associated with increased mortality. The extent to which this phenomenon is affected by sex, age, comorbidities at diagnosis, and different treatment modalities is largely unknown. The objective was to determine all-cause and cause-specific mortality in a population-based cohort of patients with PA and the impact of age at diagnosis, sex, comorbidities, and treatment modalities. METHODS: We used national registers to identify patients diagnosed with PA between 1997 and 2019 (n=2419) and controls (n=24 187) from the general population, matched for sex, age, and county of residence. We obtained mortality data from the Cause-of-Death Register. We used Cox regression models, adjusted for socioeconomic factors and diabetes, to estimate adjusted hazard ratios (HRs [95% CI]). RESULTS: Overall, 346 (14.3%) patients with PA and 2736 (11.3%) controls died during a median follow-up time of 8.1 years. PA was associated with increased risk from all-cause mortality (HR, 1.23 [95% CI, 1.10-1.38]), death from cardiovascular disease (HR, 1.57 [95% CI, 1.30-1.89]), and stroke (HR, 1.85 [95% CI, 1.16-2.93]). Patients with cardiovascular disease at diagnosis (HR, 1.53 [1.26-1.85]), age >56 years (HR, 1.28 [95% CI, 1.13-1.45]), patients treated with a low dose of a mineralocorticoid receptor antagonist (HR, 1.30 [95% CI, 1.02-1.66]), and untreated patients (HR, 2.51 [95% CI, 1.72-3.67]) had excess mortality. CONCLUSIONS: Mortality, mainly due to cardiovascular disease, is increased in patients with PA compared with controls from the general population, particularly in patients aged >56 years, patients with preexisting cardiovascular comorbidities, and patients receiving low dose of a mineralocorticoid receptor antagonist. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is a global growing health threat. This case-control clinical trial aimed to detect the predictive value and difference in aldosterone level between right side heart failure, heart failure with decreased ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) and compare the efficacy and safety of adding mineralocorticoid receptor antagonist (MRA) for treatment. We recruited 151 participants, 135 HF patients divided equally into 45 patients in each group:(1) right side HF (2) HFrEF and (3) HFpEF and 16 healthy controls. Serum aldosterone, troponin and echocardiography were evaluated at the beginning of the study, three and six months after administration of MRA. Aldosterone level was significantly greater in HF patients relative to controls. Aldosterone level can detect HF with excellent accuracy. There were significantly lower levels of aldosterone in right side HF compared to left side HF. There was a significant decrease in right ventricle dimensions, pulmonary artery systolic pressure and pulmonary artery size and significant increase in tricuspid annular plane systolic excursion after treatment in patients with right side HF. In the HFrEF group, there was a significant decrease in left ventricular end diastolic dimension and a significant increase in left ventricular EF after treatment. In the HFpEF group, there was a significant decrease in E/A and E/e′ after treatment. Aldosterone may have pathogenic role in HF. Measuring and follow-up of aldosterone levels should be considered in HF patients. MRA treatment gives a significant improvement in right side HF group. [ABSTRACT FROM AUTHOR]

Summary: Background: Primary aldosteronism (PA) is caused by autonomous aldosterone overproduction and characterised by uncontrolled hypertension. There are currently no treatments that target aldosterone synthesis. We evaluated the safety and efficacy of a novel aldosterone synthase inhibitor, dexfadrostat phosphate, in patients with PA. Methods: This multi-centre, randomised, phase 2 trial was conducted between November 2019 and May 2022 (NCT04007406; EudraCT code 2019-000919-85). Adults with PA and an office systolic blood pressure of 145–190 mmHg were included. After a 2-week single-blind placebo run-in period, participants were randomised 1:1:1 to receive oral dexfadrostat phosphate 4, 8, or 12 mg once daily for an 8-week double-blind treatment period, followed by a 2-week single-blind placebo withdrawal period. Randomisation was conducted centrally and stratified by centre and sex. At the beginning and end of the treatment period, 24 h ambulatory systolic blood pressure (aSBP) was recorded. Blood samples were taken every 2 weeks. Primary endpoints were the change in aldosterone-to-renin ratio (ARR) and mean 24 h aSBP from baseline to the end of the treatment period in the combined dose group of all participants receiving any dose of dexfadrostat phosphate. Safety endpoints were the occurrence of treatment-emergent adverse events (TEAEs) and serious adverse events over the entire study in all randomised participants who received at least one dose of dexfadrostat phosphate. Findings: In total, 35 participants received dexfadrostat phosphate and all participants completed the study. Twenty-six participants (74.3%) were male, the mean age was 51.9 years (SD 8.7), and most were White (n = 32, 91.4%). The median ARR and the mean 24 h aSBP significantly decreased from the beginning to the end of the treatment period in the combined dose group (ARR: 15.3 vs 0.6, least-squares mean [LSM] change in log-normal values −2.5, p

Abstract 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.

Hypertension is associated with increased risk of cardiovascular disease and death. Evidence suggests that Mg2+ depletion contributes to hypertension. It is estimated that 25% or more of the United States population experiences chronic, latent Mg2+ depletion. This review explores mechanisms by which Mg2+ influences blood pressure, modifying risk of hypertension and complicating its treatment. Mechanisms addressed include effects upon i) sympathetic tone, via the modulation of N-methyl-D-aspartate (NMDA) receptor and N-type Ca2+ channel activity, influencing catecholamine release from sympathetic nerve endings; ii) vascular tone, via alteration of L-type Ca2+ and endothelial nitric oxide synthase (eNOS) activity and prostacyclin release; iii) renal K+ handling, influencing systemic K+ balance and potentially indirectly influencing blood pressure; iv) aldosterone secretion from the adrenal cortex; and v) modulation of pro-hypertensive inflammatory processes in dendritic cells and macrophages, including activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome and stimulation of isolevuglandin (IsoLG) production. Discovery of these mechanisms has furthered our understanding of the pathogenesis of hypertension, with implications for treatment and has highlighted the role of Mg2+ balance in hypertension and cardiovascular disease.

Aldosterone is a steroid hormone that primarily acts through activation of the mineralocorticoid receptor (MR), a nuclear receptor responsible for downstream genomic regulation. Classically, activation of the MR in the renal tubular epithelium is responsible for sodium retention and volume expansion, raising systemic blood pressure. However, activation of the MR across a wide distribution of tissue types has been implicated in multiple adverse consequences for cardiovascular, cerebrovascular, renal, and metabolic disease, independent of blood pressure alone. Primary aldosteronism, heart failure, and chronic kidney disease are states of excessive aldosterone production and MR activity where targeting MR activation has had clinical benefits out of proportion to blood pressure lowering. The growing list of established and emerging therapies that target aldosterone and MR activation may provide new opportunities to improve clinical outcomes and enhance cardiovascular and renal health.

Background: Acinetobacter species are environmental microorganisms that inhabit the skin and can become opportunistic pathogens in immunocompromised hosts. This study investigated the pathogenicity of proteins released extracellularly by Acinetobacter radioresistens (A. radioresistens), isolated from the small intestine of two patients with severe Kawasaki disease, in a mouse model. Methods: The sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of culture supernatants derived from Acinetobacter species showed large variations in protein compositions among species and strains. The biological effects of soluble proteins secreted by A. radioresistens were evaluated in mice by intraperitoneal injection of culture supernatants. Results: The administration of culture supernatant derived from A. radioresistens caused weight loss, electrolyte imbalance, and decreased aldosterone levels. The sustained infiltration of the inflammatory mononuclear cells was observed in the liver of mice 6 weeks after the last administration. Conclusions: A. radioresistens expressed virulence through its extracellular proteins, leading to acute adrenal gland insufficiency and chronic inflammation of the livers.

Adrenal venous sampling (AVS) is a crucial method for the lateralization of primary aldosteronism (PA). It is advised to halt the use of the patient's antihypertensive medications and correct hypokalemia prior to undergoing AVS. Hospitals equipped to conduct AVS should establish their own diagnostic criteria based on current guidelines. If the patient's antihypertensive medications cannot be discontinued, AVS can be performed as long as the serum renin level is suppressed. The Task Force of Taiwan PA recommends using a combination of adrenocorticotropic hormone stimulation, quick cortisol assay, and C-arm cone-beam computed tomography to maximize the success of AVS and minimize errors by using the simultaneous sampling technique. If AVS is not successful, an NP-59 (131 I-6-β-iodomethyl-19-norcholesterol) scan can be used as an alternative method to lateralize PA. We depicted the details of the lateralization procedures (mainly AVS, and alternatively NP-59) and their tips and tricks for confirmed PA patients who would consider to undergo surgical treatment (unilateral adrenalectomy) if the subtyping shows unilateral disease.

The aldosterone-to-renin ratio (ARR) is the standard screening test for primary aldosteronism (PA). Because of the poor reproducibility of the ARR, repeat testing is recommended if the result is not compatible with the clinical condition. Various methods to measure renin are used in different hospitals in Taiwan, and the ARR cutoff values also differ among laboratories. The Task Force of Taiwan PA recommend using plasma renin activity (PRA) to calculate ARR instead of direct renin concentration (DRC) unless PRA is unavailable, because PRA is widely used in international guidelines and most studies.

Background Myosin phosphatase targeting subunit 2 (MYPT2) is an important subunit of cardiac MLC (myosin light chain) phosphatase, which plays a crucial role in regulating the phosphorylation of MLC to phospho‐MLC (p‐MLC). A recent study demonstrated mineralocorticoid receptor‐related hypertension is associated with RhoA/Rho‐associated kinase/MYPT1 signaling upregulation in smooth muscle cells. Our purpose is to investigate the effect of MYPT2 on cardiac function and fibrosis in mineralocorticoid receptor‐related hypertension. Methods and Results HL‐1 murine cardiomyocytes were incubated with different concentrations or durations of aldosterone. After 24‐hour stimulation, aldosterone increased CTGF (connective tissue growth factor) and MYPT2 and decreased p‐MLC in a dose‐dependent manner. MYPT2 knockdown decreased CTGF. Cardiac‐specific MYPT2‐knockout (c‐MYPT2−/−) mice exhibited decreased type 1 phosphatase catalytic subunit β and increased p‐MLC. A disease model of mouse was induced by subcutaneous aldosterone and 8% NaCl food for 4 weeks after uninephrectomy. Blood pressure elevation and left ventricular hypertrophy were observed in both c‐MYPT2−/− and MYPT2+/+ mice, with no difference in heart weights or nuclear localization of mineralocorticoid receptor in cardiomyocytes. However, c‐MYPT2−/− mice had higher ejection fraction and fractional shortening on echocardiography after aldosterone treatment. Histopathology revealed less fibrosis, reduced CTGF, and increased p‐MLC in c‐MYPT2−/− mice. Basal global radial strain and global longitudinal strain were higher in c‐MYPT2−/− than in MYPT2+/+ mice. After aldosterone treatment, both global radial strain and global longitudinal strain remained higher in c‐MYPT2−/− mice compared with MYPT2+/+ mice. Conclusions Cardiac‐specific MYPT2 knockout leads to decreased myosin light chain phosphatase and increased p‐MLC. MYPT2 deletion prevented cardiac fibrosis and dysfunction in a model of mineralocorticoid receptor‐associated hypertension.

Abstract Background Aortic diseases remain a highly perilous macrovascular condition. The relationship between circulating aldosterone and aortic diseases is rarely explored, thus we investigated the difference in plasma aldosterone concentration (PAC) between patients with and without aortic disease in hypertensive people. Methods We analyzed 926 patients with hypertension, ranging in age from 18 to 89 years, who had their PAC measured from the hospital's electronic database. The case group and control group were defined based on inclusion and exclusion criteria. The analysis included general information, clinical data, biochemical data, and medical imaging examination results as covariates. To further evaluate the difference in PAC between primary hypertension patients with aortic disease and those without, we used multivariate logistic regression analysis and also employed propensity score matching to minimize the influence of confounding factors. Results In total, 394 participants were included in the analysis, with 66 individuals diagnosed with aortic diseases and 328 in the control group. The participants were predominantly male (64.5%) and over the age of 50 (68.5%), with an average PAC of 19.95 ng/dL. After controlling for confounding factors, the results showed hypertension patients with aortic disease were more likely to have high PAC levels than those without aortic disease (OR = 1.138, 95% CI [1.062 to 1.238]). Subgroup analysis revealed consistent relationship between PAC and primary hypertensive patients with aortic disease across the different stratification variables. Additionally, hypertensive patients with aortic disease still have a risk of higher PAC levels than those without aortic disease, even after propensity score matching. Conclusions The results of this study suggest that primary hypertensive patients with aortic diseases have elevated levels of PAC, but the causal relationship between PAC and aortic disease requires further study.

The latest anti-diabetic medication sodium-glucose co-transporter inhibitor along with the lowering of blood glucose has a cardioprotective and reno-protective effect, it has the ability to reduce the development of heart failure and decrease hospitalization in heart failure subjects with and without diabetes. This study was conducted to evaluate the effect of sodium-glucose co-transporter inhibitor dapagliflozin alone and in combination with eplerenone on the aldosterone hormone in the treatment of rats with experimentally induced heart failure

The human adrenal cortex secretes aldosterone and cortisol as major corticosteroids. For their production, CYP11B2 and CYP11B1 catalyze the last steps in the syntheses of aldosterone and cortisol, respectively. In our previous study, CYP11B2 was the first successfully purified from rat adrenals and human clinical samples and then was proved to be aldosterone synthase. We demonstrated the immunohistochemistry for CYP11B2 of both rats and humans and applied it clinically to visualize the functional histology of aldosterone-producing adenoma (APA) causing primary aldosteronism (PA). We discovered aldosterone-producing cell clusters (APCCs) and possible APCC-to-APA transitional lesions (pAATLs) and further visualized aldosterone-producing lesions for rare forms of PA including familial hyperaldosteronism type 3 and novel non-familial juvenile PA. Here we review the history of our research on aldosterone-producing lesions.

Primary Aldosteronism (PA) should be suspected in patients with resistant hypertension, early-onset hypertension, hypertension with hypokalaemia, and metabolic alkalosis. The diagnosis is often missed due to a lack of awareness and cumbersome investigations. Eleven cases of PA who attended the Endocrinology Outpatient Department (OPD) and were also admitted to the hospital over the last three years (January 2020 to January 2023) were studied, and data were collected and analysed. All 11 patients had hypertension, and five out of 11 had resistant hypertension and 36.36% (four patients) had a family history of hypertension. In this cohort, nine out of 11 patients presented with hypokalaemia (81.81%), and five of them had hypokalaemic paralysis at presentation. In 54.54% of patients, plasma aldosterone was in the range of 20-40 ng/dL, with a mean plasma Aldosterone conc. of 31.7 ng/dL. Plasma Renin Activity (PRA) was suppressed in all eight patients. In nine out of 11 patients, PAC/PRA was >20. A left-sided adrenal adenoma was observed in 54.54% of cases. Six patients (54.54%) received surgical management (laparoscopic adrenalectomy), and the remaining five patients were doing well with medical management (antihypertensives and spironolactone). This case series illustrates the need for screening of PA in patients with resistant hypertension, specifically those with hypokalaemia. Elevated PAC is diagnostic, especially in the context of suppressed PRA. Computed Tomography (CT) is the modality of choice for localising the adenoma in most cases. Clinicians can make decisions regarding the choice of treatment based on these two investigations.

Abstract Background Aldosterone represents an important target of heart failure therapy and may be a valuable indicator of the renin-angiotensin-aldosterone system activity. However, its assessment might be challenging because of the effect of individual factors. In a recent study, intact female dogs showed the highest value of urinary aldosterone-to-creatinine ratio (UAldo:C) compared to other sex categories. In humans and rodents, an influence of progesterone has been reported by several studies. To our knowledge, the relationship between aldosterone and progesterone has not yet been investigated in dogs. The aim of this prospective study was to investigate this relationship in sexually intact Chihuahua females, measuring both hormones twice in the same bitch, that is in anoestrus when progesterone concentrations are baseline and in dioestrus when they are high. Results The study population consisted of 14 sexually intact Chihuahua bitches. Serum progesterone (34.06 (21.17–44.90) vs. 0.19 [0.13–0.38] ng/ml; P

The article discusses the potential benefits of combining a mineralocorticoid receptor antagonist (MRA) with a thiazide diuretic in the treatment of hypertension. The combination of spironolactone and hydrochlorothiazide was approved by the FDA in 1982 but is currently underutilized due to lack of marketing and concerns about side effects. The article argues that the combination of an MRA and a thiazide diuretic can effectively lower blood pressure, mitigate the risk of hyperkalemia, and reduce the risk of cardiovascular and kidney diseases. The authors suggest that further research is needed to evaluate the efficacy, safety, and cost-effectiveness of these combinations. [Extracted from the article]

Multiple sclerosis (MS) is associated with alterations in neuroendocrine function, primarily the hypothalamic–pituitary–adrenal axis, including lower expression of the glucocorticoid receptor (GR) and its target genes in peripheral blood mononuclear cells (PBMC) or full blood. We previously found reduced mineralocorticoid receptor (MR) expression in MS patients’ peripheral blood. MS is being treated with a widening variety of disease-modifying treatments (DMT), some of which have similar efficacy but different mechanisms of action; body-fluid biomarkers to support the choice of the optimal initial DMT and/or to indicate an unsatisfactory response before clinical activity are unavailable. Using cell culture of volunteers’ PBMCs and subsequent gene expression analysis (microarray and qPCR validation), we identified the mRNA expression of OTUD1 to represent MR signaling. The MR and MR target gene expression levels were then measured in full blood samples. In 119 MS (or CIS) patients, the expression of both MR and OTUD1 was lower than in 42 controls. The expression pattern was related to treatment, with the MR expression being particularly low in patients treated with fingolimod. While MR signaling may be involved in the therapeutic effects of some disease-modifying treatments, MR and OTUD1 expression can complement the neuroendocrine assessment of MS disease course. If confirmed, such assessment may support clinical decision-making.

Primary aldosteronism (PA) is the most common cause of endocrine arterial hypertension, and the suggested screening test for case detection is the aldosterone-to-renin ratio (ARR) or aldosterone-to-direct renin ratio (ADRR) based on radio-immunoassay (RIA) and chemiluminescence assay (CLIA), respectively. The objective of our study was to evaluate the reliability of CLIA for aldosterone and renin measurement and the diagnostic performance of ADRR. A prospective cohort of 1110 patients referred to a single laboratory medicine center underwent measurement of aldosterone and direct renin concentration (DRC) by CLIA and measurement of aldosterone and plasma renin activity (PRA) by RIA. Of 1110 patients, 640 obtained a final diagnosis of hypertension, and 90 of these patients were diagnosed with PA. Overall, between-method correlation was highly significant for aldosterone concentrations (R = 0.945, p < 0.001) and less strong but significant for DRC/PRA (R = 0.422, p < 0.001). Among hypertensive patients, in PA cases, the areas under the receiver operator characteristics (ROC) curves were 0.928 (95% confidence interval 0.904–0.954) for ADRR and 0.943 (95% confidence interval 0.920–0.966) for ARR and were comparable and not significantly different. The highest accuracy was obtained with an ADRR cut-off of 25 (ng/L)/(mIU/L), displaying a sensitivity of 91% and a specificity of 85%. The chemiluminescence assay for aldosterone and DRC is a reliable method for PA diagnosis compared to the classical RIA method.

Introduction: Long-term sodium balance studies show that sodium can be temporarily stored and released in tissues, mediated by circaseptan rhythms of aldosterone and cortisol. This complicates the reliability of a single 24-h urine collection to estimate individual sodium intake. We investigated whether repeated timed urine collection with and without correction for plasma aldosterone is a more accurate alternative for estimating daily sodium intake. Methods: We conducted a post hoc analysis of a metabolic ward study in which 16 healthy male adults consumed a diet with a fixed sodium content (50 or 200 mmol/day) for 7 days. Each day, urine was collected in 4 intervals (7:00–13:00 h, 13:00–19:00 h, 19:00–23:00 h, and 23:00–07:00 h). Plasma aldosterone was measured at 6:30 h, 12:30 h, and 18:30 h. Sodium intakes were estimated by various formulas using 3 timed urines of day 5–7. Results: During a 200-mmol daily sodium intake, sodium intake estimates based on three repeated timed urine samples and the Toft equation differed 10 [IQR: 3–14], 8 [6–19], 36 [16–49], and 20 [10–43] mmol from the actual intake for intervals 7:00–13:00 h, 13:00–19:00 h, 19:00–23:00 h, 23:00–7:00 h, respectively. These measurements did not significantly differ from a single 24-h urine (20 [12–55] mmol). During a 50-mmol daily sodium intake, repeated timed urine collection performed worse than a single 24-h urine collection. On both diets, correction for plasma aldosterone increased accuracy and sodium intake estimates were significantly more accurate than a single 24-h urine. Conclusion: In a controlled environment, repeated timed urine collection corrected for plasma aldosterone is more accurate than a single 24-h urine collection.

Background: Vascular smooth muscle cell (VSMC) injury caused by the inflammatory response plays a key role in cardiovascular disease (CVD), and the vasoprotective effects of mineralocorticoid receptor blockers (MRBs) support the role of mineralocorticoid receptor (MR) activation. Methods: C57BL/6 mice and VSMCs isolated from rats were treated with aldosterone and esaxerenone. Caspase-1, GSDMD-N, IL-1β, and NR3C2 expression and DNA damage in aortic VSMCs were detected using immunohistochemistry, Western blotting, and TUNEL staining. Mitochondrial changes were detected by transmission electron microscopy (TEM). Reactive oxygen species (ROS), MitoTracker, JC-I, mitochondrial respiratory chain complexes I–V, and NR3C2 were detected using immunofluorescence and flow cytometry. Pyroptosis was detected with scanning electron microscopy (SEM). Results: After aldosterone treatment, the number of TUNEL-positive cells increased significantly, and the expression of caspase-1, GSDMD-N, and IL-1β increased. TEM revealed mitochondrial damage, and SEM revealed specific pyroptotic changes, such as cell membrane pore changes and cytoplasmic extravasation. Increased ROS levels and nuclear translocation of NR3C2 were also observed. These pyroptosis-related changes were reversed by esaxerenone. Conclusions: Aldosterone activates the MR and mediates mitochondrial damage, thereby inducing pyroptosis in VSMCs via the NLRP3/caspase-1 pathway. Esaxerenone inhibits MR activation and reduces mitochondrial damage and oxidative stress, thereby inhibiting pyroptosis.

Activation of the renin–angiotensin–aldosterone system (RAAS) plays an important pathophysiological role in hypertension. Increased mRNA levels of the angiotensinogen angiotensin-converting enzyme, angiotensin type 1 receptor gene, Agtr1a, and the aldosterone synthase gene, CYP11B2, have been reported in the heart, blood vessels, and kidneys in salt-sensitive hypertension. However, the mechanism of gene regulation in each component of the RAAS in cardiovascular and renal tissues is unclear. Epigenetic mechanisms, which are important for regulating gene expression, include DNA methylation, histone post-translational modifications, and microRNA (miRNA) regulation. A close association exists between low DNA methylation at CEBP-binding sites and increased AGT expression in visceral adipose tissue and the heart of salt-sensitive hypertensive rats. Several miRNAs influence AGT expression and are associated with cardiovascular diseases. Expression of both ACE and ACE2 genes is regulated by DNA methylation, histone modifications, and miRNAs. Expression of both angiotensinogen and CYP11B2 is reversibly regulated by epigenetic modifications and is related to salt-sensitive hypertension. The mineralocorticoid receptor (MR) exists in cardiovascular and renal tissues, in which many miRNAs influence expression and contribute to the pathogenesis of hypertension. Expression of the 11beta-hydroxysteroid dehydrogenase type 2 (HSD11B2) gene is also regulated by methylation and miRNAs. Epigenetic regulation of renal and vascular HSD11B2 is an important pathogenetic mechanism for salt-sensitive hypertension.