Aldosterone Synthase Research Articles

Aldosterone Synthase Inhibitors and Mineralocorticoid Receptor Antagonists: Competitors or Collaborators?

Aldosterone Synthase Inhibitors and Mineralocorticoid Receptor Antagonists: Competitors or Collaborators?

Identification and functional characterization of compound heterozygous CYP11B1 gene mutations.

11β-Hydroxylase deficiency (11β-OHD) is the second leading cause of congenital adrenal hyperplasia (CAH), a rare autosomal recessive disease caused by mutations in the CYP11B1 gene. We previously reported the case of a male Chinese patient with typical 11β-OHD symptoms. Sanger sequencing revealed that the patient carried a splice-site mutation, c.595+1G>A in the CYP11B1 gene. His mother and sister harbored the heterozygous mutation, c.595+1G>A. Paradoxically, Sanger sequencing did not detect any abnormality in the CYP11B1 gene of his father and brother. Therefore, in this study, we aimed to further explore the exact genetic etiology of 11β-OHD in this pedigree and analyze the functional consequence of the c.595+1G>A mutation. Gemomic DNA was extracted from the peripheral blood leukocytes of the family members and normal control individuals, followed by quantitative real-time polymerase chain reaction (qPCR) to detect the copy number of the target CYP11B1 gene fragment. Mutation analysis was also performed via whole-exome sequencing (WES) followed by Sanger sequencing validation. In vitro minigene assay was also performed to investigate the impact of the c.595+1G>A mutation on pre-mRNA splicing. qPCR results suggested a heterozygous deletion encompassing position c.595+1 along with flanking exonic and intronic sequences in the CYP11B1 gene of the patient and his father. WES followed by Sanger sequencing verified that the patient carried compound heterozygous mutations in the CYP11B1 gene, including a novel 2840-bp deletion (c.395+661_c.1121+180del) and c.595+1G>A, while his father carried the heterozygous c.395+661_c.1121+180del mutation. No other novel CYP11B1 mutations were found in the rest of the family members. Furthermore, minigene assay revealed that the c.595+1G>A mutation resulted in a 70-bp deletion of exon 3 in the mRNA, and this altered the reading frame at amino acid 176 and created a premature stop codon at amino acid 197. We identified a novel 2840-bp-sized large deletion and confirmed that the c.595+1G>A mutation disrupts normal pre-mRNA splicing. Either mutation could significantly alter the reading frame and abolish CYP11B1 enzyme activity. Therefore, our findings widen the mutation spectrum of CYP11B1 and provide an accurate diagnosis of 11β-OHD at a molecular genetic level.

Neonatal salt wasting syndrome: Aldosterone synthase deficiency caused by a new splicing variant in CYP11B2

Aldosterone synthase deficiency (ASD) is a rare autosomal recessive disorder involving isolated aldosterone deficiency without any compromise of other adrenal hormones. This condition manifests mainly in the neonatal period and in infants as a salt wasting syndrome with vomiting and failure to thrive. Due to its potentially life-threatening effects, ASD requires a careful and early diagnosis based on appropriate hormonal investigations in order to initiate adequate management: rehydration as well as salt and fludrocortisone supplementation. Genetic analysis of the CYP11B2 gene will confirm ASD in most cases. We report the case of a newborn with a typical clinical presentation associated with some uncommon phenotypic features (hyperhidrosis, liver injury). Furthermore, our patient carries a new CYP11B2 splicing variant to be added to the approximately 60 pathogenic or likely pathogenic variants already reported.

New insights into the role of myostatin in fish fertility based on the findings in mstnb-deficient Nile tilapia (Oreochromis niloticus)

Myostatin (Mstn) was reported to be involved in multiple biological processes including the regulation of skeletal muscle growth, lipid metabolism and reproduction in vertebrates, therefore, it might play an essential role in the fine balance between growth and reproduction. In order to clarify the roles of Mstn in fish reproduction, we systematically investigated the gonadal development and fertility of mstnb mutants in Nile tilapia (Orochromis niloticus). In the present study, mstnb was found to be expressed in the different cell types of gonads by fluorescence in situ hybridization (FISH). Mutation of mstnb resulted in excessive proliferation of phase II follicles in the ovaries while the numbers of phase III follicles were significantly reduced at 210 days after hatching (dah). Interestingly, significant decline of cyp19a1a gene expression, the serum 17β-estradiol (E2), vitellogenin (VTG) were detected at 210 dah. At 360 dah, the ovarian development of mstnb-/- XX tilapia was partially recovered and female fish spawn regularly, however, they were subfertile and produced the poor-quality eggs with significantly lower offspring survival rate. The dramatic up-regulation of cyp19a1a gene expression and serum E2 level at 360 dah might account for the recovery of ovarian development. In mstnb-/- males, excessive proliferation of spermatogonia and retardation of testicular differentiation were found throughout the whole development stages. In mstnb-/- males, evident declines of gonadosomatic index (GSI), cyp11b2 gene expression, and 11-Ketotestosterone (11-KT) were detected at 210 dah, while the mRNA level of cyp11b2 and serum 11-KT level were significantly upregulated at 360 dah. However, mstnb-/- males were infertile since mutation of mstnb gene led to excessive increase of apoptosis of testicular cells and spermiation obstacle. Taken together, these results indicated that Mstn might be an essential regulator for the maintenance of fish fertility.

Multifocal, Asymmetric Bilateral Primary Aldosteronism Cannot be Excluded by Strong Adrenal Vein Sampling Lateralization: An International Retrospective Cohort Study.

Primary aldosteronism (PA) has been broadly dichotomized into unilateral and bilateral forms. Adrenal vein sampling (AVS) lateralization indices (LI) ≥2 to 4 are the standard-of-care to recommend unilateral adrenalectomy for presumed unilateral PA. We aimed to assess the rates and characteristics of residual PA after AVS-guided adrenalectomy. We conducted an international, retrospective, cohort study of patients with PA from 7 referral centers who underwent unilateral adrenalectomy based on LI≥4 on baseline and/or cosyntropin-stimulated AVS. Aldosterone synthase (CYP11B2) immunohistochemistry and next generation sequencing were performed on available formalin-fixed paraffin-embedded adrenal tissue. The cohort included 283 patients who underwent AVS-guided adrenalectomy, followed for a median of 326 days postoperatively. Lack of PA cure was observed in 16% of consecutive patients, and in 22 patients with lateralized PA on both baseline and cosyntropin-stimulated AVS. Among patients with residual PA postoperatively, 73% had multiple CYP11B2 positive areas within the resected adrenal tissue (versus 23% in those cured), wherein CACNA1D mutations were most prevalent (63% versus 33% in those cured). In adjusted regression models, independent predictors of postoperative residual PA included Black versus White race (odds ratio, 5.10 [95% CI, 1.45-17.86]), AVS lateralization only at baseline (odds ratio, 8.93 [95% CI 3.00-26.32] versus both at baseline and after cosyntropin stimulation), and CT-AVS disagreement (odds ratio, 2.75 [95% CI, 1.20-6.31]). Multifocal, asymmetrical bilateral PA is relatively common, and it cannot be excluded by robust AVS lateralization. Long-term postoperative monitoring should be routinely pursued, to identify residual PA and afford timely initiation of targeted medical therapy.

No extra-adrenal aldosterone production in various human cell lines.

Extra-adrenal de novo aldosterone (Aldo) production has been described inconsistently. Systematic data based upon state-of-the-art technology including validated controls are sparse. We hypothesized that aldosterone synthase (CYP11B2) expression and de novo Aldo production are absent in nonadrenal human cell lines, either immortalized cell lines or commercially available primary cell lines, including peripheral blood mononuclear cells (PBMCs) of individuals without and with primary hyperaldosteronism (PA). CYP11B2-transfected COS-7 and endogenous CYP11B2 expressing adrenal H295R cells served as positive controls. Various well-characterized, purchased, immortalized (BeWo, HEK293, HTR-8/SVneo, JEG-3) and primary (HAEC, HLEC, HRGEC, HRMC, HUAEC, HUVEC, PBMC) cell lines as well as self-isolated PBMCs from PA patients (n = 5) were incubated with the steroid hormone substrates progesterone, deoxycorticosterone, corticosterone or 18-OH-corticosterone with and without Ang II for 24 h to assess CYP11B2 enzymatic activity. CYP11B2 expression was analyzed by real-time PCR and liquid chromatography-mass spectrometry was used to quantify Aldo production. Pronounced CYP11B2 mRNA expression and Aldo production were observed in both positive controls, which followed an incremental time course. Neither substrates alone nor coincubation with Ang II significantly stimulated CYP11B2 expression or Aldo production in various immortalized and primary cell lines and PBMCs of PA patients. These results strongly support the absence of relevant de novo extra-adrenal Aldo production in nonadrenal cells, including blood mononuclear cells, irrespective of the absence or presence of autonomous adrenal Aldo production.

The RAAS system SNPs polymorphism is associated with essential hypertension risk in rural areas in northern China.

Objectives: Epidemiological evidence has shown that genetics and environment are associated with the risk of hypertension. However, the specific SNP effects of a cluster of crucial genes in the RAAS system on the risk of hypertension are unclear. Methods: A case-control study was performed on the baseline participants of Environment and Chronic Disease in Rural Areas of Heilongjiang China (ECDRAHC) study. According to the inclusion and exclusion criteria, 757 subjects (428 hypertensive patients) were enrolled. A total of 32 SNP sites and related haplotypes, involved in AGT (angiotensinogen), ACE (angiotensin-converting enzyme), AGTR1, CYP11B2 (aldosterone-synthase), LDLR (low-density lipoprotein receptor), LRP5 (low-density lipoprotein receptor associated protein 5), LRP6 (low-density lipoprotein receptor associated protein 6), PPARG (peroxisome proliferator-activated receptor gamma) and ACE2 (angiotensin-converting enzyme 2) genes which exert important roles in renin-angiotensin-aldosterone system (RAAS) system were analyzed. Furthermore, a polygenic scoring model was established to assess individual risk of developing hypertension based on the comprehensive SNPs effects in genes related the RAAS system. Results: After controlling the impact of confounding factors, multivariate logistic regression analysis revealed that the distribution of AGT/rs5046, LRP6/rs12823243 and ACE2/rs2285666 was associated with susceptibility to essential hypertension. In genetic score model, the score > -0.225 had a higher risk, the OR (95%CI) was 1.229 (1.110, 1.362). Conclusions: To the best of our knowledge, this is the first time a hypertension risk scoring model on RAAS associated gene cluster has been constructed, which will provide a novel approach for prevention and control of essential hypertension.

Aldosterone Synthase Inhibitors for Treatment of Hypertension and Chronic Kidney Disease

Aldosterone excess is known to worsen hypertension and kidney function. Three selective aldosterone synthase inhibitors (ASIs) were evaluated in 3 phase 2 trials. In the first study, the ASI baxdrostat 2 mg orally once daily decreased systolic blood pressure (SBP) by 11.0 mmHg compared with placebo after 12 weeks in patients with treatment-resistant hypertension. In the second study including patients with uncontrolled hypertension, placebo-corrected reduction in SBP with lorundrostat 50 mg once daily was 9.6 mmHg after 8 weeks. Patients receiving thiazides and those with body mass index (BMI) > 30 kg/m2 had the optimum blood pressure (BP) response to lorundrostat, whereas plasma renin activity (PRA) did not affect its antihypertensive potency. In the third trial including patients with chronic kidney disease (CKD), the ASI BI 690517 (10 mg once daily) decreased urinary albumin creatinine ratio (UACR) by 39% after 14 weeks compared with 3% reduction with placebo. Reduction in UACR was generally similar in presence or absence of concomitant treatment with empagliflozin. The 3 ASIs mildly decreased (by <15%) estimated glomerular filtration rate (eGFR) compared with placebo. The most common adverse effects of ASIs were hyperkalemia occurring in 2.9% and 7.9% among patients randomized to baxdrostat and lorundrostat, respectively versus none in the placebo groups. In patients with CKD, frequency of hyperkalemia was higher: 14.2% and 6.0% with BI 690517 and placebo, respectively. Adrenal insufficiency was reported in 1.3% of patients randomized to BI 690517 versus 1.0% with placebo. Preliminary data suggest that selective ASIs are effective in lowering BP in patients with resistant and uncontrolled hypertension and decreasing albuminuria in CKD. Phase 3 clinical trials should be conducted to assess long-term efficacy and safety of ASIs in a wide spectrum of patients with uncontrolled BP and CKD.

Genetic polymorphism of the CYP11B2 gene in an Iraqi patient with essential hypertension.

Aim: To demonstrate the genetic variant of CYP11B2 Gen rs1799998 and rs4539 and their ef f ect on systolic and diastolic blood pressure in Iraqi patient with essential hypertension in Aldiwania province. Materials and Methods: This is an observational cross sectional descriptive single centre study for hypertensive patients at Al-Diwaniyah province, Iraq which is diagnosed according to 2020 ISH. All candidate patients were diagnosed and recruited by specialist caregiving physician/ cardiologist. There was a total of 90 participants, 37 males and 53 women. Aldosterone and renine levels in the plasma were determined from blood samples given voluntarily by patients undergoing genetic testing. Results: Regarding rs4539 the most frequent allele was T (112, 62%) while the most frequent genotype was TC (54, 60%). Regarding rs1799998 the most frequent allele was G (97, 54%) while the most frequent genotype was AG (49, 54%). Conclusions: There was no signif i cant relationship between rs1799998 (A344>G) and rs4539 (T2718C) with systolic and diastolic blood pressure in Iraqi patient with essential hypertension.

Анализ частоты встречаемости полиморфизмов генов CYP2C9, AGTR1, AGT, ACE, CYP11B2 у пациентов с впервые выявленной артериальной гипертензией 1–2 степеней

Анализ частоты встречаемости полиморфизмов генов CYP2C9, AGTR1, AGT, ACE, CYP11B2 у пациентов с впервые выявленной артериальной гипертензией 1–2 степеней

Assessment of methomyl-induced adrenal gland disruption in rat fetuses and pups: Potential protective effects of propolis supplementation.

The present study aimed to unravel the possible adverse effects of methomyl on the developing adrenal gland of rat fetuses and pups. Additionally, this study explored the potential improving effects of propolis against these possible hazards induced by methomyl exposure. To achieve that, pregnant rats were divided into four groups: control group, received 1 mL distilled water, propolis group, received 1 mL propolis at a dose of 300 mg/kg, methomyl group, received 1 mL methomyl at a dose of 2 mg/kg, and combined group, received 1 mL methomyl followed by 1 mL propolis, an hour later at the same previous doses. The results revealed that methomyl exposure, during pregnancy and lactation, induced many histological and ultrastructural changes, caused DNA damage and downregulated the expression of steroidogenic acute regulatory (StAR) and CYP11B2 genes in the adrenal glands of both rat fetuses and pups. Interestingly, propolis supplementation demonstrated a remarkable ability to mitigate these deleterious effects and restored the histology and ultrastructure architecture of the adrenal glands of both fetuses and pups, as well as decreased DNA damage and upregulated the expression of StAR and CYP11B2 genes in the adrenal gland of rat fetuses and pups. In conclusion, our study highlights the potential hazardous impact of methomyl exposure during pregnancy and lactation on the development of the adrenal gland in rat fetuses and pups, moreover, the study presents a new approach to alleviate these effects through propolis administration which could be used as a dietary supplement to mitigate the adverse effects of methomyl exposure.

Aldosterone and aldosterone synthase inhibitors in cardiorenal disease.

Modulation of the renin-angiotensin-aldosterone system is a foundation of therapy for cardiovascular and kidney diseases. Excess aldosterone plays an important role in cardiovascular disease, contributing to inflammation, fibrosis, and dysfunction in the heart, kidneys, and vasculature through both genomic and mineralocorticoid receptor (MR)-mediated as well as nongenomic mechanisms. MR antagonists have been a key therapy for attenuating the pathologic effects of aldosterone but are associated with some side effects and may not always adequately attenuate the nongenomic effects of aldosterone. Aldosterone is primarily synthesized by the CYP11B2 aldosterone synthase enzyme, which is very similar in structure to other enzymes involved in steroid biosynthesis including CYP11B1, a key enzyme involved in glucocorticoid production. Lack of specificity for CYP11B2, off-target effects on the hypothalamic-pituitary-adrenal axis, and counterproductive increased levels of bioactive steroid intermediates such as 11-deoxycorticosterone have posed challenges in the development of early aldosterone synthase inhibitors such as osilodrostat. In early-phase clinical trials, newer aldosterone synthase inhibitors demonstrated promise in lowering blood pressure in patients with treatment-resistant and uncontrolled hypertension. It is therefore plausible that these agents offer protection in other disease states including heart failure or chronic kidney disease. Further clinical evaluation will be needed to clarify the role of aldosterone synthase inhibitors, a promising class of agents that represent a potentially major therapeutic advance.

Efficacy and safety of aldosterone synthase inhibition with and without empagliflozin for chronic kidney disease: a randomised, controlled, phase 2 trial

Excess aldosterone accelerates chronic kidney disease progression. This phase 2 clinical trial assessed BI 690517, an aldosterone synthase inhibitor, for efficacy, safety, and dose selection. This was a multinational, randomised, controlled, phase 2 trial. People aged 18 years or older with an estimated glomerular filtration rate (eGFR) of 30 to less than 90 mL/min/1·73 m2, a urine albumin to creatinine ratio (UACR) of 200 to less than 5000 mg/g, and serum potassium of 4·8 mmol/L or less, taking an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, were enrolled. Participants were randomly assigned (1:1) to 8 weeks of empagliflozin or placebo run-in, followed by a second randomisation (1:1:1:1) to 14 weeks of treatment with once per day BI 690517 at doses of 3 mg, 10 mg, or 20 mg, or placebo. Study participants, research coordinators, investigators, and the data coordinating centre were masked to treatment assignment. The primary endpoint was the change in UACR measured in first morning void urine from baseline (second randomisation) to the end of treatment. This study is registered with ClinicalTrials.gov (NCT05182840) and is completed. Between Feb 18 and Dec 30, 2022, of the 714 run-in participants, 586 were randomly assigned to receive BI 690517 or placebo. At baseline, 33% (n=196) were women, 67% (n=390) were men, 42% (n=244) had a racial identity other than White, and mean participant age was 63·8 years (SD 11·3). Mean baseline eGFR was 51·9 mL/min/1·73 m2 (17·7) and median UACR was 426 mg/g (IQR 205 to 889). Percentage change in first morning void UACR from baseline to the end of treatment at week 14 was -3% (95% CI -19 to 17) with placebo, -22% (-36 to -7) with BI 690517 3 mg, -39% (-50 to -26) with BI 690517 10 mg, and -37% (-49 to -22) with BI 690517 20 mg monotherapy. BI 690517 produced similar UACR reductions when added to empagliflozin. Investigator-reported hyperkalaemia occurred in 10% (14/146) of those in the BI 690517 3 mg group, 15% (22/144) in the BI 690517 10 mg group, and 18% (26/146) in the BI 690517 20 mg group, and in 6% (nine of 147) of those receiving placebo, with or without empagliflozin. Most participants with hyperkalaemia did not require intervention (86% [72/84]). Adrenal insufficiency was an adverse event of special interest reported in seven of 436 study participants (2%) receiving BI 690517 and one of 147 participants (1%) receiving matched placebo. No treatment-related deaths occurred during the study. BI 690517 dose-dependently reduced albuminuria with concurrent renin-angiotensin system inhibition and empagliflozin, suggesting an additive efficacy for chronic kidney disease treatment without unexpected safety signals. Boehringer Ingelheim.

Effect of The Critical Period and Gene Silencing on Blood Cellular Traits in Local Chicken and Level of Welfare

The study aimed to tame the ferocious local chickens and calm them down by changing the behavioral or genetic factors and improving the blood traits that are reflected in the level of welfare. 144 one-day-old chicks were used from local chickens White and (36) broiler chicks. The chicks were divided into six treatments with four replicates for each treatment (24 chicks for treatment, 6 chicks for replicates) as follows: T1 was a control treatment consisting of 24 local chicks, T2 welfare treatment consisting of 24 local chicks,T3 consisted of 25% broilers + 75% local chicks, T4 consisted of 50% broilers + 50% local chicks, and T5 consisted of From 75% broiler chickens + 25% local chicks, and T6 siRNA consisting of 24 local chicks White, was using silencing of the corticosterone hormone pathway to the (CYP11B2 and CYP11B1 genes) by injected in the jugular vein at the age of 16 and 18 weeks. The results showed a significant improvement in Hemoglobin (Hb), Hematocrit (PCV), Red Blood Cells (RBC), and White Blood Cells (BWC).and significant improvement (P≤0.05) in Platelets for T6 compared with other treatments, a significant improvement (P≤0.05) in the level of heterophil /lymphocytes for T6 compared to other treatments. That there is an effect of the critical period and gene silencing on blood traits that have a final effect on the level of welfare chickens.

Discovery of a Potent Dual Inhibitor of Aromatase and Aldosterone Synthase

Discovery of a Potent Dual Inhibitor of Aromatase and Aldosterone Synthase

Effects of CYP11B2 gene polymorphisms on adrenocorticotropic hormone and angiotensin II in type 2 diabetes patients with hypertension

The aim of this study is to investigate the effects of CYP11B2 gene polymorphisms with the adrenocorticotropic hormone (ACTH) and angiotensin II (Ang II) in Chinese patients with type 2 diabetes (T2DM) and hypertension (T2MH). A total of 457 T2DM patients were genotyped for the polymorphism of rs3802228 and rs1799998 using SNP-scan high-throughput technology. The levels of adrenocorticotropic hormone in peripheral blood and related biochemical indices including aldosterone, renin, and Angiotensin II were measured and analyzed in relation to CYP11B2 polymorphisms in T2DM patients. As we found that Compared with T2DM patients, ACTH levels were higher in the rs3802228 AA/AG and rs1799998 AA/AG genotype T2MH subgroups (P < 0.001, P = 0.001). However, the difference in ACTH levels between two identical genotypes of T2MH was not statistically significant compared with T2DM patients (P > 0.05), whereas both AA and AG genotype subgroups had different AngII levels (P < 0.001, P = 0.004), which were higher than those of T2DM patients, but with a decrease in ACTH levels compared with patients with a single AA or AG genotype. Logistic regression analyses indicated that there was no significant relationship between genotype and allele polymorphisms with T2MH progression after adjustment for confounders. As a conclusion, CYP11B2 gene polymorphism was not associated with susceptibility to hypertension in Chinese T2DM patients, but its association with ACTH and Ang II levels may be a risk factor for susceptibility to hypertension in Chinese T2DM patients.

Pseudohypoadrenalism, a subclinical cortisol metabolism disorder in hyperuricemia.

Hyperuricemia is a known risk factor of lipid metabolism disorder. However, the mechanisms have not been fully understood. The serum samples from hyperuricemia subjects were used to analyze the correlation between serum uric acid and clinical characteristics. Hyperuricemia mice induced by potassium oxonate (PO) and adenine were used to explore glucocorticoid metabolism. In hyperuricemia patients, the levels of serum uric acid were positively correlated with the levels of γ-glutamyltransferase, associated with a cortisol metabolism disorder. In hyperuricemia state, the adrenal glands failed to respond to adrenocorticotropic hormone properly, leading to low cortisol, but not corticosterone production, and decreased mRNA levels of aldosterone synthase, 11β-hydroxylase, and 3β-hydroxysteroid dehydrogenase 1, three key enzymes for cortisol synthesis. The expression of both hepatic 5α-reductase and renal 11β-hydroxysteroid dehydrogenase 2 was significantly reduced, which led to low cortisol clearance. We denominated this cortisol metabolism disorder in hyperuricemia as pseudohypoadrenalism (PHAL). PHAL increased exposure to the bioavailable cortisol in the liver, leading to local amplification of the biological action of corticosteroids. Unregulated biosynthesis pathway of bile acid expanded bile acid pool, and further aggravated cholestatic liver injury.

Abstract 17143: Lorundrostat for Treatment of Obesity-Related, Aldosterone-Dependent Hypertension - An Endotype-Specific, Targeted Approach to the Treatment of Uncontrolled Hypertension

Hyperaldosteronism manifests as low renin hypertension (HTN) with endothelial dysfunction and vascular fibrosis. In the aging vasculature, these pathological changes may be exacerbated by non-genomic aldosterone signaling via GPER (GPR30), which is not inhibited by mineralocorticoid receptor antagonists (MRA). In trials with healthy subjects and patients with uncontrolled HTN, the novel, highly selective aldosterone synthase inhibitor, lorundrostat, reduced median morning plasma aldosterone concentration (PAC) by approximately 70%. PAC reduction was dose-dependent and associated with a mean placebo-adjusted reduction in systolic blood pressure (BP) of -16.7 mmHg (N=15, p&lt;0.01, 90% CI: -25.5 to -7.9 mmHg) and -12.3 mmHg (N=12, p&lt;0.03, 90% CI: -21.6 to -3.1 mmHg) in subjects with body mass index (BMI) &gt; 30 kg/m 2 receiving 50mg or 100mg QD of lorundrostat, respectively. In contrast, in non-obese individuals, BP reductions were modest and not statistically significant. Salutary BP effects of 100mg QD lorundrostat at week 8 were observed in individuals with normal to high renin (N=30, -11.4 ± 2.5 mmHg) and low renin (N=25, -11.9 ± 2.8 mmHg). Linkage between obesity, HTN and increased aldosterone has been suggested by studies in a mouse model of obesity, hyperleptinemia and HTN. In this model, both leptin receptor blockade and lorundrostat restored normal BP. As anticipated, in the Phase 2 trial, mean serum leptin was elevated at baseline in obese (N=103, 37.8 ± 2.4 ng/mL) v. non-obese (N=88, 21.6 ± 1.9 ng/mL, p&lt;0.001) individuals with uncontrolled HTN and could be a useful biomarker to identify lorundrostat-responsive HTN. MRAs are recommended as fourth-line therapy for resistant HTN. However, MRAs can be associated with hormonal side-effects and stimulate excess aldosterone production that may increase non-genomic signaling, endothelial dysfunction and vessel wall remodeling. Lorundrostat has neither of these liabilities and may be an important new antihypertensive. Renin-independent, leptin- and aldosterone-dependent HTN defines a unique endotype in obese hypertensive individuals. Endotype-targeted therapy may allow early identification, intervention and improved BP control in obese individuals.

Aldosterone synthase inhibitor "Baxdrostat" for resistant hypertension: A clinical approach or futuristic idea?

Aldosterone synthase inhibitor "Baxdrostat" for resistant hypertension: A clinical approach or futuristic idea?

Bilateral Cortical-sparing Adrenalectomy for the Treatment of Bilateral Aldosterone-producing Adenomas

Abstract Aldosterone-producing adenoma (APA) is 1 of the major subtypes of primary aldosteronism (PA). Although most APA occurs unilaterally, bilateral APAs have rarely been documented. Because of its rarity, optimal management of patients with bilateral APAs has not been established. Here, we report a case of bilateral APAs that was successfully treated with simultaneous bilateral cortical-sparing surgery. A 44-year-old Japanese woman was referred to us for the evaluation of PA. She had typical clinical characteristics of PA, including hypertension, hypokalemia, and high plasma aldosterone concentration with suppressed renin. She was diagnosed as having PA based on the results of confirmatory testing. Computed tomography revealed bilateral adrenal nodules with diameters of 17 and 10 mm on the right and left adrenal gland, respectively. Adrenal venous sampling indicated excess aldosterone production from bilateral adrenal lesions. She underwent simultaneous bilateral laparoscopic partial adrenalectomy that normalized her blood pressure and serum potassium levels. Aldosterone synthase immunohistochemistry on the resected adrenal tumor tissue confirmed the diagnosis of bilateral APAs. Long-term postsurgical follow-up data suggest cure of the disease without the need for glucocorticoid replacement therapy. Bilateral cortical-sparing adrenalectomy appears to be a viable treatment option at least for selected patients with bilateral APAs.