Excessive Aldosterone Production Research Articles

Adverse Effects of Aldosterone: Beyond Blood Pressure.

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.

Recent progress in unraveling cardiovascular complications associated with primary aldosteronism: a succinct review.

This comprehensive review offers a thorough exploration of recent advancements in our understanding of the intricate cardiovascular complications associated with Primary Aldosteronism (PA). PA encompasses a spectrum of conditions characterized by hypertension and excessive production of aldosterone operating independently of the renin-angiotensin system. Given its association with an elevated risk of cardiovascular and cerebrovascular complications, as well as a higher incidence of metabolic syndrome in comparison to individuals with essential hypertension (EH), an accurate diagnosis of PA is of paramount importance. This review delves into the intricate interplay between PA and cardiovascular health and focuses on the key pathophysiological mechanisms contributing to adverse cardiac outcomes. The impact of different treatment modalities on cardiovascular health is also examined, offering insights into potential therapeutic approaches. By highlighting the significance of recognizing PA as a significant contributor to cardiovascular morbidity, this review emphasizes the need for improved screening, early diagnosis, and tailored management strategies to both enhance patient care and mitigate the burden of cardiovascular diseases. The findings presented herein underscore the growing importance of PA in the context of cardiovascular medicine and emphasize the potential for translating these insights into targeted interventions to improve patient outcomes.

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<0.01, 90% CI: -25.5 to -7.9 mmHg) and -12.3 mmHg (N=12, p<0.03, 90% CI: -21.6 to -3.1 mmHg) in subjects with body mass index (BMI) > 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<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.

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.

Expression of functional mineralocorticoid receptor (MR) and G-protein coupled estrogen receptor (GPER) in human T lymphocytes

Aldosterone plays a key role in controlling blood pressure (BP) values by maintaining body salt, water, and fluid homeostasis. Excess aldosterone production is associated with arterial hypertension, cardiovascular and metabolic diseases, partly via generation of an inflammatory state followed by fibrotic changes in the organs that are target of hypertension. Aldosterone exerts genomic effects that are known to involve activation of the mineralocorticoid receptor (MR). Other aldosterone effects, including those usually defined as ‘rapid’ or ‘non genomic’, involve additional receptors as the G-protein coupled estrogen receptor (GPER). To date, the receptor(s) implicated in the inflammatory action of aldosterone in cells of the innate and adaptive immunity are unknown. Considering the potential role of T-lymphocytes in adaptive immunity in arterial hypertension and related hypertension-mediated organ damage (HMOD), we herein investigated and quantified the expression of the MR and GPER in human CD4+ and CD8+ T-cells. Results provided compelling evidence for the presence at the mRNA and protein level and suggest a functional role of these receptors in the two T-lymphocyte subtypes, thus indicating that they can represent a potential target for modulation of steroid hormone-induced inflammation and ensuing HMOD.

Identification of a novel competing endogenous RNA network and candidate drugs associated with ferroptosis in aldosterone-producing adenomas.

Aldosterone-producing adenoma (APA), characterized by unilaterally excessive aldosterone production, is a common cause of primary aldosteronism. Ferroptosis, a recently raised iron-dependent mode of programmed cell death, has been involved in the development and therapy of various diseases. This study obtained datasets of the mRNA and lncRNA expression profiles for APA and adjacent adrenal gland (AAG) from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) and lncRNAs (DE lncRNAs) associated with ferroptosis were identified. Enrichment analyses indicated 89 ferroptosis-related DEGs were primarily enriched in ROS related processes and ferroptosis. Two physical cores, and one combined core were identified in the protein-protein interaction (PPI). DEGs and clinical traits were used in conjunction to screen eight hub genes from two hub modules and 89 DEGs. A competitive endogenous RNA (ceRNA) network was constructed via co-express analysis. Thereafter, molecular docking was used to identify potential targets. Two active compounds, QL-X-138 and MK-1775, bound to AURKA and DUOX1, respectively, with the lowest binding energies. Molecular dynamics simulation verified the stability of the two complexes. In summary, our studies identified eight hub genes and a novel ceRNA regulatory network associated with ferroptosis, wherein QL-X-138 and MK-1775 were considered to be potential drugs for treating APA.

Aldosterone Synthase Inhibition With Lorundrostat for Uncontrolled Hypertension

Excess aldosterone production contributes to hypertension in both classical hyperaldosteronism and obesity-associated hypertension. Therapies that reduce aldosterone synthesis may lower blood pressure. To compare the safety and efficacy of lorundrostat, an aldosterone synthase inhibitor, with placebo, and characterize dose-dependent safety and efficacy to inform dose selection in future trials. Randomized, placebo-controlled, dose-ranging trial among adults with uncontrolled hypertension taking 2 or more antihypertensive medications. An initial cohort of 163 participants with suppressed plasma renin (plasma renin activity [PRA] ≤1.0 ng/mL/h) and elevated plasma aldosterone (≥1.0 ng/dL) were enrolled, with subsequent enrollment of 37 participants with PRA greater than 1.0 ng/mL/h. Participants were randomized to placebo or 1 of 5 dosages of lorundrostat in the initial cohort (12.5 mg, 50 mg, or 100 mg once daily or 12.5 mg or 25 mg twice daily). In the second cohort, participants were randomized in a 1:6 ratio to placebo or lorundrostat, 100 mg once daily. The primary end point was change in automated office systolic blood pressure from baseline to study week 8. Between July 2021 and June 2022, 200 participants were randomized, with final follow-up in September 2022. Following 8 weeks of treatment in participants with suppressed PRA, changes in office systolic blood pressure of -14.1, -13.2, -6.9, and -4.1 mm Hg were observed with 100 mg, 50 mg, and 12.5 mg once daily of lorundrostat and placebo, respectively. Observed reductions in systolic blood pressure in individuals receiving twice-daily doses of 25 mg and 12.5 mg of lorundrostat were -10.1 and -13.8 mm Hg, respectively. The least-squares mean difference between placebo and treatment in systolic blood pressure was -9.6 mm Hg (90% CI, -15.8 to -3.4 mm Hg; P = .01) for the 50-mg once-daily dose and -7.8 mm Hg (90% CI, -14.1 to -1.5 mm Hg; P = .04) for 100 mg daily. Among participants without suppressed PRA, 100 mg once daily of lorundrostat decreased systolic blood pressure by 11.4 mm Hg (SD, 2.5 mm Hg), which was similar to blood pressure reduction among participants with suppressed PRA receiving the same dose. Six participants had increases in serum potassium above 6.0 mmol/L that corrected with dose reduction or drug discontinuation. No instances of cortisol insufficiency occurred. Among individuals with uncontrolled hypertension, use of lorundrostat was effective at lowering blood pressure compared with placebo, which will require further confirmatory studies. ClinicalTrials.gov Identifier: NCT05001945.

Abstract 113: Aldosterone Synthase Inhibition With Lorundrostat For The Treatment Of Uncontrolled Hypertension: The Target-HTN Randomized Clinical Trial

Importance: Excess aldosterone production contributes to hypertension in both classical hyperaldosteronism and obesity-associated hypertension. Objective: To compare the safety and efficacy of lorundrostat, an aldosterone synthase inhibitor, with placebo, and characterize dose-dependent safety and efficacy. Design, Setting, and Participants: Randomized, placebo-controlled, dose-ranging, double-blind clinical trial among adults with uncontrolled hypertension taking 2 or more antihypertensive medications. A first cohort of participants with suppressed plasma renin (plasma renin activity (PRA) of less than 1.0 ng/mL/h) and elevated plasma aldosterone (greater than 1.0 ng/dL) were enrolled (n=163), with subsequent enrollment of participants with PRA greater than 1.0 ng/mL/h (n=37). Interventions: Participants were randomized to placebo or one of five doses of lorundrostat (12.5, 50, or 100 mg once daily, or 12.5 or 25 mg twice daily.) Results: Following 8 weeks of treatment in participants with suppressed PRA, dose-dependent changes in office systolic BP were observed (figure). The primary endpoint, placebo-subtracted change in modeled systolic BP was -9.6 mmHg (90% confidence interval [CI], -15.8 to -3.4, p=0.01) for the 50 mg once daily dose and -7.8 mmHg (90% CI, -14.1 to -1.5, p=0.04) for 100 mg daily. Six participants had increases in serum potassium above 6.0 mmol/L that were reversed with dose reduction or drug discontinuation. Conclusions and Relevance: Among individuals with uncontrolled hypertension, use of lorundrostat was effective at lowering blood pressure compared with placebo.

HYPERTENSION AND HYPERALDOSTERONISM

Objective: describe the importance of investigating secondary hypertension in cases of hypertension that is difficult to control through clinical signs Design and method: Case Report: Patient R.A., female, 47 years old, hypertensive for seventeen years appears in the emergency department with a report of a hypertensive peak in a periodic consultation. At the time she was asymptomatic with a blood pressure of 260 x 120 mmHg. The electrocardiogram showed sinus rhythm with reduced T wave amplitude, increased U wave amplitude, and increased QT interval. The laboratory test showed hypokalemia associated with metabolic alkalosis, and slight elevation of renal slag. Results: The investigation of arterial hypertension secondary to primary hyperaldosteronism was initiated with plasma aldosterone dosage and plasma renin activity, showing an AP/ARP ratio > 100 ng/mL/h. Computed tomography of the abdomen and pelvis showed adenoma in the right adrenal, which was resected laparoscopically. One month after hospital discharge, the patient returns to the emergency room with nausea, vomiting and general malaise. Laboratory with hyperkalemia and worsening of renal function. At this moment, the patient was using a potassium-sparing diuretic, considered as a possible cause of the disorder, since other tests performed did not show any alteration. The diuretic was discontinued, with clinical and laboratory evolutionary improvement. The patient is discharged from hospital, with adequate blood pressure control and stable renal function. Conclusions: Primary hyperaldosteronism is a clinical condition determined by excessive production of aldosterone, caused by bilateral adrenal hyperplasia or unilateral adenoma. Hyperaldosteronism is suspected when we observe hypertension associated with difficult control, hypokalemia, adrenal incidentaloma. The investigation continues through serum levels of aldosterone and renin activity, as well as imaging tests, such as computed tomography. Laparoscopic surgery is indicated, with a success rate between 30-60%. It is important to emphasize that regular follow-up after the surgical procedure is essential to control blood pressure, with the aim of preventing the progression of renal hypertensive disease.

An Abbreviated History of Aldosterone Metabolism, Current and Future Challenges.

The initial isolation of adrenal steroids from large quantities of animal adrenals resulted in an amorphous fraction resistant to crystallization and identification and had potent effects on electrolyte transport. Aldosterone was eventually isolated and identified in the fraction and was soon shown to cause hypertension when in excess. The autonomous and excessive production of aldosterone, primary aldosteronism, is the most common cause of secondary hypertension. Aldosterone is metabolized in the liver and kidney, and its metabolites are conjugated with glucuronic acid for excretion. The most common liver metabolite is 3α,5β-tetrahydroaldosterone-3-glucuronide, while that of the kidney is aldosterone-18-oxo-glucuronide. In terms of their value, especially the aldosterone-18-oxo-glucuronide, is commonly used for the diagnosis of primary aldosteronism because they provide an integrated value of the total daily production of aldosterone. Conversion of aldosterone to 18-oxo-glucuronide is impeded by drugs, like some common non-steroidal anti-inflammatory drugs that compete for UDP-glucuronosyltransferase-2B7, the most important glucuronosyltransferase for aldosterone metabolism. Tetrahydroaldosterone is the most abundant metabolite and the most reliable for the diagnosis of primary aldosteronism, but it is not commonly measured.

PS-BPR01-7: CONCURRENT SOMATIC MUTATIONS IN CTNNB1 AND GNA11 IN AN ALDOSTERONE-PRODUCING ADENOMA

Background: Aldosterone-producing adenoma (APA) is a major subtype of primary aldosteronism (PA), a common form of secondary hypertension. In the past decade, there has been significant progress in the determination of genetic causes of APA. The use of next-generation sequencing (NGS) has led to the identification of somatic mutations in APA that cause excess aldosterone production. Most of the affected genes encode ion channels or transporters. Somatic activating mutations in CTNNB1 (β;-catenin) have also been detected in 2–5% of APA. As a possible pathogenesis, an association of CTNNB1-mutated APA with pregnancy and menopause has been proposed. A recent study reported double somatic mutations in CTNNB1 and GNA11/Q in APA. However, due to its rare incidence, characteristics of APA with these mutations are not well determined. Herein, we report a case of APA harboring somatic CTNNB1 and GNA11 mutations. Case presentation: A 46-year-old Japanese woman presented with hypertension and spontaneous hypokalemia. She had no history of pregnancy-induced hypertension. She had regular menstrual cycle at presentation. Endocrine testing showed elevated plasma aldosterone concentration (677.5 pg/mL) under suppressed renin (plasma renin activity, 0.3 ng/mL/h). Computed tomography revealed a 2 cm right adrenal mass. Adrenal venous sampling indicated excess aldosterone production from the right adrenal gland. NP-59 scintigraphy further demonstrated increased tracer uptake in the right adrenal lesion. She underwent right laparoscopic adrenalectomy. Histologic diagnosis of the resected tumor was adrenocortical adenoma based on the Weiss criteria. Notably, Ki-67 labeling index was high (6% at hotspots). After surgery, her blood pressure and serum potassium both normalized. Based on the PASO (the primary aldosteronism surgical outcome) study criteria, PA remained clinically and biochemically cured at follow-up 18 months after surgery. Methods: Formalin-fixed, paraffin-embedded adrenal tumor tissue was used for immunohistochemical and genetic analysis. Results: Immunohistochemistry (IHC) showed high and diffuse expression of CYP11B2 (aldosterone synthase) within the tumor, whereas 11β;-hydroxylase (CYP11B1, a steroidogenic enzyme for cortisol biosynthesis) was mostly negative. VSNL1, a marker for the zona glomerulosa where physiologic aldosterone biosynthesis occurs, was highly expressed within the tumor. CYP11B2 IHC-guided targeted NGS identified concurrent somatic CTNNB1 (p.D32Y) and GNA11 (p.Q209H) mutations with similar variant allele frequencies (29.5% and 29.7%, respectively). Conclusions: To best of our knowledge, this is the first Asian case of APA with CTNNB1 and GNA11 mutations. Detailed clinical and histologic examination would provide useful information for better characterization of patients with PA due to these rare mutations.

PS-C37-5: NEW THERAPEUTIC PERSPECTIVES FOR BLOOD PRESSURE CONTROL: DEXFADROSTAT PHOSPHATE, A NOVEL ALDOSTERONE SYNTHASE INHIBITOR, IN PATIENTS WITH PRIMARY ALDOSTERONISM

Objective: Aldosterone, the primary mineralocorticoid produced by the adrenal gland, regulates fluid homeostasis by stimulating sodium reabsorption in exchange for potassium in the distal tubules and collecting duct of the kidney. Aldosterone synthase (CYP11B2) is the rate-limiting enzyme for aldosterone biosynthesis. Patients with primary aldosteronism (PA) are characterized by an uncontrolled, excess production of aldosterone and are at higher risk of stroke, atrial fibrillation, and heart failure compared to patients with essential hypertension. Furthermore, PA increases the risk of death even after initiation of medical treatment to control blood pressure. Therefore, PA is the compelling indication to demonstrate the value for an aldosterone synthase inhibitor (ASI) as targeted treatment. Previous attempts to eliminate the excessive spontaneous aldosterone synthesis defining PA have been unsuccessful, particularly due to the unintended inhibition of other steroid hormones. Dexfadrostat phosphate is a novel ASI that acts directly on CYP11B2, targeting the root cause of primary aldosteronism. Design and method: Dexfadrostat phosphate was first investigated in patients with PA diagnosed within 1 year of study entry according to medical guidelines including a suppression test to demonstrate autonomous aldosterone production. Eligibility was verified and approved by a Central Review panel. Following a 2-week placebo-controlled run-in period, enrolled patients were randomized to one of three doses of dexfadrostat taken orally, once daily. After 8 weeks of treatment, patients were switched to placebo and followed for an additional 2 weeks. Blood samples were taken at 2-week intervals and evaluated in a central laboratory for steroid and peptide hormone as well as electrolyte levels. Blood pressure was measured in the office during each clinic visit. Ambulatory systolic blood pressure (aSBP) was monitored over 24-hours at baseline and after 8 weeks of dexfadrostat treatment. Results: All endpoints of the study were met with high significance. Dexfadrostat phosphate treatment was safe and well tolerated. We present the effects on the aldosterone-to-renin ratio (ARR) and subsequent blood pressure reduction, the correction of hypokalemia, and the persistence and reversal of therapeutic effects upon drug withdrawal. Conclusions: The phase 2 study in patients evaluated the ability of dexfadrostat phosphate to deliver both biochemical (ARR, potassium) and subsequent clinical (aSBP) correction of the consequences of uncontrolled aldosterone production. By demonstrating its clinical utility in a rarely diagnosed indication of extreme aldosterone dysregulation, the potential of dexfadrostat phosphate may well expand to address essential hypertension, chronic kidney disease, hypokalemia, volume expansion and organ remodeling.

CaV3.2 (CACNA1H) in Primary Aldosteronism.

Aldosterone is a steroid hormone produced in the zona glomerulosa (ZG) of the adrenal cortex. The most prominent function of aldosterone is the control of electrolyte homeostasis and blood pressure via the kidneys. The primary factors regulating aldosterone synthesis are the serum concentrations of angiotensin II and potassium. The T-type voltage-gated calcium channel CaV3.2 (encoded by CACNA1H) is an important component of electrical as well as intracellular calcium oscillations, which govern aldosterone production in the ZG. Excessive aldosterone production that is (partially) uncoupled from physiological stimuli leads to primary aldosteronism, the most common cause of secondary hypertension. Germline gain-of-function mutations in CACNA1H were identified in familial hyperaldosteronism, whereas somatic mutations are a rare cause of aldosterone-producing adenomas. In this review, we summarize these findings, put them in perspective, and highlight missing knowledge.

Vascular and hormonal interactions in the adrenal gland.

Primary aldosteronism is the most common form of secondary arterial hypertension, due to excessive aldosterone production from the adrenal gland. Although somatic mutations have been identified in aldosterone producing adenoma, the exact mechanisms leading to increased cell proliferation and nodule formation remain to be established. One hypothesis is that changes in vascular supply to the adrenal cortex, due to phenomena of atherosclerosis or high blood pressure, may influence the morphology of the adrenal cortex, resulting in a compensatory growth and nodule formation in response to local hypoxia. In this review, we will summarize our knowledge on the mechanisms regulating adrenal cortex development and function, describe adrenal vascularization in normal and pathological conditions and address the mechanisms allowing the cross-talk between the hormonal and vascular components to allow the extreme tissue plasticity of the adrenal cortex in response to endogenous and exogenous stimuli. We will then address recent evidence suggesting a role for alterations in the vascular compartment that could eventually be involved in nodule formation and the development of primary aldosteronism.

Potassium Homeostasis and WNK Kinases in the Regulation of the Sodium-Chloride Cotransporter: Hyperaldosteronism and Its Metabolic Consequences

Potassium Homeostasis and WNK Kinases in the Regulation of the Sodium-Chloride Cotransporter: Hyperaldosteronism and Its Metabolic Consequences

PMON285 Hypokalemic Periodic Paralysis: A Rare Presentation of Primary Hyperaldosteronism

Abstract Background Primary hyperaldosteronism (PHA) is caused by excessive production of aldosterone from the adrenal glands. Aldosterone levels are usually independent of renin, angiotensin II or sodium status, and often result in hypertension (HTN), hypokalemia and metabolic alkalosis. The most common presentation of this condition is with asymptomatic mild to severe or refractory HTN. This case highlights a patient presenting with hypokalemic periodic paralysis as the first sign of PHA. Clinical Case A 35 year old previously healthy Chinese male, presented with sudden onset bilateral lower extremity weakness for 1 day. This was associated with mild transient lower back pain and fatigue. He had no history of trauma, recent travel, exposure to animal or tick bites. He reported no recent illness or vaccination. His family history was negative for hypertension and various endocrinopathies. The patient was not on any medications and did not consume licorice. His exam was significant for a blood pressure (BP) of 217/136 mmHg, with lower limb evaluation revealing power of 3/5, normal reflexes and a positive heel to shin test. He demonstrated an unsteady gait but Romberg's sign was negative. Upper limb exam was normal. Laboratory findings were remarkable for potassium 1.9 mmol/L, bicarbonate (CO2) 37 mmol/L, normal magnesium (Mg), normal TSH and blood gas showing metabolic alkalosis. Subsequent testing showed renin 0.35 ng/ml/hr, aldosterone 23 ng/dl and aldosterone/pra ratio 66. Saline infusion test confirmed the diagnosis of PHA. Other endocrinologic tests were normal. Electrocardiogram showed prolonged QT interval and U waves. Renal ultrasound was negative for renal artery stenosis and CT abdomen/pelvis showed a 2.4 cm left adrenal adenoma. The patient was admitted to the intensive care unit for 24 hours, where he received intravenous potassium replacement and was started on spironolactone and other antihypertensive medications, which he was discharged on, along with oral potassium. His symptoms resolved after potassium levels normalized and he subsequently had a left adrenalectomy. Conclusion With PHA being the most common endocrinological cause of HTN, clinicians should recognize indicators of underlying PHA even in rare presentations such as this. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

ODP065 Impact of Comorbid Adrenal Insufficiency on Outcomes During Hospitalization For Cardiogenic Shock

Abstract Background The catabolic stress associated with cardiogenic shock requires a robust metabolic, neuroendocrine, and immunologic response to mitigate, and adrenocortical hormones play a huge role in this process. On the other hand, excessive aldosterone production is known to play a key part in the long-term progression of myocardial insufficiency through myocyte remodeling. It is thus intriguing to understand how adrenocortical insufficiency impacts the outcomes of patients admitted for cardiogenic shock. Method: A retrospective cohort study was designed using data obtained from the 2016 to 2018 combined National Inpatient Sample (NIS) database. Adult patients (age >18) with principal admission diagnosis of cardiogenic shock were identified using the international diseases classification code, tenth revision (ICD 10), and separated into two cohorts based on the presence of a secondary diagnosis of adrenal insufficiency. Primary outcomes assessed were, mortality, length of stay (LOS) and total hospital charge. Secondary outcomes evaluated included rate of mechanical ventilation, mechanical circulatory support device use and cardiac arrest. Multivariate linear and logistic regressions were used to adjust for confounders. Results There was a total of 477,695 adult hospitalizations for cardiogenic shock, out of which 1.28% had associated secondary diagnosis of adrenal insufficiency. There was a statistically insignificant increased odds of mortality among patients with adrenal insufficiency (33.42% vs 33.35%, AOR: 1. 05, 95% CI: 0.93 to 1.19, p: 0.462). There was also an increased length of stay (18.91 days vs 11.35 days, adjusted mean difference: 6.5 days, 95%CI: 5.22 days to 7.78 days, p < 0. 001) and an increased total charge (364,864.5 vs 238,591.9 USD, adjusted mean difference: 105,491.9 USD, 95%CI: 78,252.2USD to 132,731.3 USD, p < 0. 001) among patients with adrenal insufficiency compared with the counterpart cohort group and these were statistically significant. Patients with adrenal insufficiency also had 42% increased odds of being mechanically ventilated during cardiogenic shock admission compared to patients without (55.67% vs 46.61%, AOR: 1.42, 95%CI: 1.26 to 1.60, p < 0. 001). Other secondary clinical outcomes assessed, including mechanical circulatory support devices use and cardiac arrest were not statistically different between the two groups. Conclusion Adrenal insufficiency as a comorbid diagnosis among patients admitted with cardiogenic shock was associated with increased odds of requiring mechanical ventilation, prolonged length of stay and higher total hospital charges. There was a trend towards increased mortality, but this was not statistically significant. There was no difference in other clinical outcomes including mechanical circulatory support devices and cardiac arrest rate. Presentation: No date and time listed

Neutrophil gelatinase-associated lipocalin as an immunomodulator in endocrine hypertension.

In recent studies, primary aldosteronism (PA) has been reported as the most common etiology for secondary hypertension of endocrine origin, accounting for approximately 10% of cases. In PA, excess aldosterone production can lead to deleterious effects at the cardiovascular (CV) and renal levels by activating mineralocorticoid receptors, which involves an increase in pro-inflammatory and pro-fibrotic mediators. Among these mediators, neutrophil gelatinase-associated lipocalin (NGAL), a secretion glycoprotein belonging to the lipocalin superfamily, has been closely linked to CV and renal damage in several pathological conditions. Because NGAL can be detected in biofluids such as plasma and urine, it has been proposed as a damage biomarker for target tissues and has also been studied for its role in hypertension and associated with PA. NGAL is produced by many different cell types, can be carried on extracellular vesicles, and is modulated by microRNAs, which would support its use as a biomarker for endocrine hypertension due to PA. Over the last decade, studies have shown that NGAL is necessary for the development of aldosterone-induced hypertension and that is associated with end-organ damage. In addition, it has been proposed that some mechanisms are dependent on the activation of immune cells, such as dendritic cells and macrophages, where the release of specific cytokines (i.e., interleukin [IL]-23) or chemokines (i.e., CCL-5) induced by aldosterone would depend on NGAL. Subsequently, this activates the T helper (Th) lymphocytes, such as Th17 and Th2, resulting in CV and renal fibrosis due to the high aldosterone levels. Although the immune system has been closely associated with essential hypertension, its participation in endocrine hypertension has not been fully elucidated. This review discusses the link between NGAL and endocrine hypertension, particularly in the context of PA, and their possible regulators and mechanisms, with a focus on its role as an immunomodulator.

Genetic Dissection of Primary Aldosteronism in a Patient With MEN1 and Ipsilateral Adrenocortical Carcinoma and Adenoma.

Adrenal tumors are found in up to 40% of patients with multiple endocrine neoplasia type 1 (MEN1). However, adrenocortical carcinomas (ACC) and primary aldosteronism (PA) are rare in MEN1. A 48-year-old woman known to have primary hyperparathyroidism and hypertension with hypokalemia was referred for a right complex 8-cm adrenal mass with a 38.1 SUVmax uptake on 18F-FDG PET/CT. PA was confirmed by saline suppression test (aldosterone 1948 pmol/L-1675 pmol/L; normal range [N]: <165 post saline infusion) and suppressed renin levels (<5 ng/L; N: 5-20). Catecholamines, androgens, 24-hour urinary cortisol, and pituitary panel were normal. A right open adrenalectomy revealed a concomitant 4-cm oncocytic ACC and a 2.3-cm adrenocortical adenoma. Immunohistochemistry showed high expression of aldosterone synthase protein in the adenoma but not in the ACC, supporting excess aldosterone production by the adenoma. After genetic counseling, the patient underwent genetic analysis of leucocyte and tumoral DNA. Sequencing of MEN1 revealed a heterozygous germline pathogenic variant in MEN1 (c.1556delC, p.Pro519Leufs*40). The wild-type MEN1 allele was lost in the tumoral DNA of both the resected adenoma and carcinoma. Sequencing analysis of driver genes in PA revealed a somatic pathogenic variant in exon 2 of the KCNJ5 gene (c.451G>A, p.Gly151Arg) only in the aldosteronoma. To our knowledge, we describe the first case of adrenal collision tumors in a patient carrying a germline pathogenic variant of the MEN1 gene associated with MEN1 loss of heterozygosity in both oncocytic ACC and adenoma and a somatic KCNJ5 pathogenic variant leading to aldosterone-producing adenoma. This case gives new insights on adrenal tumorigenesis in MEN1 patients.

Primary aldosteronism: Pathophysiological mechanisms of cell death and proliferation.

Primary aldosteronism is the most common surgically curable form of hypertension. The sporadic forms of the disorder are usually caused by aldosterone overproduction from a unilateral adrenocortical aldosterone-producing adenoma or from bilateral adrenocortical hyperplasia. The main knowledge-advances in disease pathophysiology focus on pathogenic germline and somatic variants that drive the excess aldosterone production. Less clear are the molecular and cellular mechanisms that lead to an increased mass of the adrenal cortex. However, the combined application of transcriptomics, metabolomics, and epigenetics has achieved substantial insight into these processes and uncovered the evolving complexity of disrupted cell growth mechanisms in primary aldosteronism. In this review, we summarize and discuss recent progress in our understanding of mechanisms of cell death, and proliferation in the pathophysiology of primary aldosteronism.