Mineralocorticoid Receptor Research Articles

7787 Primary Aldosteronism Medical Treatment Outcomes (PAMO): An International Consensus on Outcome Assessment Criteria and Multicentre Study

Abstract Disclosure: J. Yang: None. J. Burrello: None. J. Goi: None. T.A. Williams: None. W.F. Young: Consulting Fee; Self; Arena Pharmaceuticals, Inc.. Other; Self; Crinetics Pharmaceuticals. P.J. Fuller: None. P. Investigators: None. Primary aldosteronism (PA) is the most common endocrine cause of hypertension. Mineralocorticoid receptor antagonists, at adequate doses, lower blood pressure and cardiovascular risk in patients with PA. However, there is a lack of a standardized approach to medical therapy and subsequent outcomes assessment. We aimed to: 1) establish criteria for assessing outcomes of targeted medical treatment of PA, and 2) evaluate outcomes using these criteria across an international cohort. A panel of 31 PA experts from 31 centres across four continents used the Delphi method, including three rounds of online questionnaires, to reach consensus. Clinical data were then collected from consecutive patients with PA who started targeted medical treatment between 2016 and 2021 at the participating centres. Consensus was reached for six outcomes, including complete, partial, or absent biochemical response, and complete, partial, or absent clinical response. “Complete biochemical response” was defined as “correction of hypokalemia without potassium supplementation, and normalization of plasma renin activity or concentration”; while “absent biochemical response” was defined as “persistent hypokalemia and/or persistently suppressed or low plasma renin activity or concentration without change from baseline”. “Complete clinical response” was defined as “normal blood pressure without additional antihypertensive medications”; while “absent clinical response” was defined as “the same or increased blood pressure compared to before targeted treatment with same or more antihypertensive medications, not counting targeted therapy”. Of 1483 patients (mean age 52y, 48% female) from 28 centers, 232 (16%) had a complete clinical response, and 719 (49%) had a complete biochemical response at the most recent follow-up (median 29 months after treatment initiation). Compared to those with partial or absent clinical response, patients with complete clinical response had a significantly higher proportion of women and lower proportion with diabetes, stroke or left ventricular hypertrophy. They also had a significantly shorter duration of hypertension, lower BMI, higher eGFR and lower defined daily dose of antihypertensives at baseline. In contrast, these differences were not observed in those with a complete, partial or absent biochemical response. The defined daily dose of targeted therapy did not differ across the various response categories. In conclusion, we have established an international expert consensus for standardized criteria to evaluate the response to targeted medical treatment of PA, facilitate comparisons of outcome data and guide clinicians who manage PA. In a retrospective international cohort, less than half of medically-treated patients reached the established biochemical treatment targets. Further work is needed to increase the rate of complete response. Presentation: 6/3/2024

8647 Reversal Of Left Atrial Dilation In Heart Failure With Preserved Ejection Fraction (HFpEF) Treated With A GLP-1 Receptor Agonist And A Mineralocorticoid Receptor Antagonist

Abstract Disclosure: M. Marino: None. L.S. Phillips: Advisory Board Member; Self; Diasyst, Inc.. Research Investigator; Self; Abbvie, Research Support, Jansen Pharmaceuticals, Research Support, Novo Nordisk, Research Support, Abbott Laboratories, Research Support, GlaxoSmithKline, Research Support, Sanofi-Aventis, Research Support, Pfizer, Inc.. Background: HFpEF is a major public health problem, since contributors include age, hypertension, hyperglycemia, and inactivity - and the US population is aging, hypertension and hyperglycemia are often inadequately treated, and inactivity is common. Moreover, management is difficult, since few medications have improved outcomes, and there is little long-term experience with sodium-glucose co-transporter-2 (SGLT-2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and mineralocorticoid receptor antagonists. Clinical Case: In October 2010, a 69-year-old male with a history of lung adenocarcinoma with left lower lobe segmentectomy, prostate cancer post prostatectomy, and well-managed hypertension and hyperglycemia experienced severe shortness of breath while running on a track as part of his routine exercise. A left heart catheterization was performed to determine if the symptoms reflected inadequate perfusion, revealing only 30% stenosis in the left anterior descending coronary artery, ruling out coronary disease as the primary etiology. However, the left ventricular end diastolic pressure (LVEDP) was elevated (25 mmHg vs. normal <12), indicating heart failure. A transthoracic echocardiogram (TTE) in December 2010 revealed a normal left ventricular ejection fraction (EF 65%), a severely dilated left atrium [left atrial volume index (LAVI) 57 mL/m2 vs. normal <34], and diastolic dysfunction [flow velocity across the mitral valve (E/A ratio 1.61 and E/e’ 7.26). The patient was given pioglitazone 30mg daily before and nebivolol 2.5mg BID after the TTE, but in March 2011, a TTE showed an EF of 57% with persistent left atrial dilation (LAVI 50 mL/m2). A dipeptidyl peptidase-4 (DPP-4) inhibitor (sitagliptin 100mg daily) was begun August 2011, changed to liraglutide 1.8mg daily in December 2011, and eplerenone 75mg daily was begun February 2012. In June 2012, the LAVI was markedly improved (39 mL/m2). The nebivolol was switched to irbesartan 225mg daily in August 2012, and canagliflozin 300mg daily was added September 2013. A repeat TTE in March 2014 found an EF of 60%, and showed that the LAVI had returned to normal (34 mL/m2). During this period, mean blood pressure was 111/67 mmHg, LDL cholesterol 57 mg/dL, and HbA1c 5.4%, indicating that inadequate risk factor management was unlikely to be contributing to the diastolic dysfunction. Presently, the patient takes semaglutide, pioglitazone, telmisartan, empagliflozin, and eplerenone, continues to exercise vigorously, and a recent TTE showed an EF of 62% with mild left atrial dilation (LAVI 36.6). Conclusion: Left atrial dilation was improved after addition of a GLP-1 receptor agonist and a mineralocorticoid receptor antagonist, prior to use of an SGLT-2 inhibitor. Future investigations are needed to further understand the cardiovascular utility of these medications - beyond glycemic control and electrolyte balance. Presentation: 6/3/2024

7469 A Case of Severe Transient Hypercortisolism In a Patient With Bacterial Meningitis

Abstract Disclosure: R. Harxhi: None. D.V. Mihailescu: None. Background: Increased cortisol levels are known to occur in states of significant stress caused by acute illness. This may be attributed to stress leading to a rise in the corticotrophin releasing hormone thereby increasing adrenocorticotrophic hormone levels. This may consequently result in severe transient hypercortisolism and bilateral adrenal structural changes.Clinical case:A 55-year-old female with a past medical history of HTN and pre-diabetes presented to the hospital with a headache and altered mental status starting the day prior to admission. On arrival, she was found to be hypertensive, confused and was diagnosed with acute bacterial meningitis caused by streptococcus pneumoniae. Initial labs were notable for a potassium level of 2.5 mEq/L (normal 3.5-5 mEq/L). Work-up of persistent hypokalemia revealed a cortisol of 54.83 ug/dL (normal 6.7-22.6 ug/dL), ACTH 166 pg/mL (normal 9-50 pg/mL), aldosterone < 1 ng/dL (normal 3-16 ng/dL), and renin 0.57 (normal 0.25-5.82). CT of the abdomen showed bilateral periadrenal fat stranding, larger on the left with no adrenal nodules. On physical exam, patient did not exhibit any cushingoid features. Significantly elevated AM cortisol levels persisted despite treatment with high dose dexamethasone as part of the meningitis regimen (20 mg) resulting in unsuppressed AM cortisol of 9.22 ug/dL. An MRI of the brain showed a partially empty sella rendering a pituitary adenoma unlikely. Patient’s clinical status improved rapidly, and hypokalemia resolved. A low dose dexamethasone suppression test performed 9 days post admission produced an appropriately suppressed cortisol (1.0 ug/dL) and ACTH (14 pg/mL) levels, thus confirming a functional response to acute illness. Conclusion: This is a rare case of severe transient hypercortisolism with periadrenal congestion (“fat stranding”) resulting in hypokalemia (likely due inappropriate activation of mineralocorticoid receptors) in the setting of acute illness. There have been a very limited number of similar cases reported in literature, particularly with respect to CNS infections. It is important to recognize the response to acute stress could produce significant elevation of cortisol levels leading to the activation of mineralocorticoid receptors, therefore mimicking primary hyperaldosteronism. Presentation: 6/1/2024

7533 Mifepristone For Primary Hypercortisolism Contributing To Profound Hypokalemia

Abstract Disclosure: J. Watkins: None. J.G. Melendez-Rivera: None. E. Florin: None. K.B. Rivera: None. Background: Primary hypercortisolism is typically treated surgically, but when adrenalectomy is not pursued, medical therapy can be effective. Adrenal enzyme inhibitors or glucocorticoid antagonists can be used. Mifepristone is the only available glucocorticoid antagonist at this time. Mifepristone is approved specifically for glucose control in Cushing’s syndrome. Because mifepristone blocks cortisol action rather than production, hormone levels may increase and are unhelpful in titrating the mifepristone dose. Rather, titration is based on clinical manifestations of Cushing’s syndrome. Further, the increased hormone levels can lead to increased activation of mineralocorticoid receptor, in addition to the increased activation caused by hypercortisolism, which can cause hypokalemia. Clinical Case: An 82-year-old woman had been following with endocrinology for hypercortisolism found to be secondary to bilateral adrenal adenomas. She preferred medical therapy rather than surgery given her age, and she was started on mifepristone 300 mg/day. Within a few weeks, she developed leg swelling and was started on a low dose of chlorthalidone by her primary care doctor. She then presented to the emergency department after five days of nausea, abdominal pain, palpitations, and reduced oral intake. She was found to have severe hypokalemia (potassium 1.8 mEq/L, normal 3.5 - 5.0 mEq/L), and her creatinine was 0.97 µmol/L (baseline 0.6-0.75 µmol/L). Physical exam was unremarkable. CT abdomen/pelvis revealed three adrenal lesions, similar to a study from one year prior. Her mifepristone was stopped, and she was given potassium supplementation and started on spironolactone with eventual stabilization of her potassium level. She was also started on ketoconazole for management of her hypercortisolism. It was discussed that she might now consider adrenal vein sampling to pursue adrenalectomy. Severe hypokalemia and borderline metabolic alkalosis were most likely multifactorial in etiology. Hypercortisolism predisposed the patient to hypokalemia. She was then started on mifepristone, which inhibits the glucocorticoid receptor thereby increasing activation of the mineralocorticoid receptor, which likely further contributed to hypokalemia. The leg swelling that she developed and saw her primary doctor for may have been a sign of over-activation of the mineralocorticoid receptor due to the mifepristone, and prescription of chlorthalidone at that time would have worsened the hypokalemia that was likely present at that time. Conclusion: It is important to be aware of the possible severity of side effects of medical therapy for hypercortisolism, such as severe hypokalemia. There is a role for increased awareness of routine monitoring of potassium levels, as well as considering spironolactone in many patients even prior to onset of hypokalemia. Presentation: 6/3/2024

8437 Improved Quality Of Life&Blood Pressure Following Diagnosis And Medical Management Of Primary Aldosteronism (PA) / Georgian Experience

Abstract Disclosure: Q. Gvazava: None. N. Zavrashvili: None. N. Shonia: None. Improved Quality of Life and Blood Pressure Following Diagnosis and Medical Management of Primary Aldosteronism (PA) - Georgian Experience Introduction: PA is the most common cause of secondary hypertension which still remains as an underdiagnosed condition in many countries, including Georgia. The choice of pharmacological or surgical therapy depends on the results of computed tomography scans of the adrenal glands and adrenal venous sampling. In patients with bilateral aldosterone hypersecretion, the optimal is a low-sodium diet and lifelong treatment with a mineralocorticoid receptor antagonist administered at a dosage to reach a high-normal serum potassium concentration. Discussion: 60 y/o male with a 17-year history of hypertension. He was treated with 3 drug-program: valsartan, amlodipine, bisoprolol. BP was not adequately managed with systolic BP >140 mm/Hg. Patient had a history of hypokalaemia and required regular potassium supplements. Patient had never been evaluated for possible PA. We planned case detection test, which came up positive, with increased aldosterone, suppressed renin concentration and increased aldosterone-renin ratio. Abdominal CT performed 1 year ago for another reason revealed “normal” adrenals.After discussing treatment options patient preferred medical management and Eplerenone was started, dose titrated accordingly, K supplements were discontinued which over time resulted in decrease in requirement of his other antihypertensive medications, with BP adequately managed. Patient’s quality of life improved significantly, he has shared his test results and progress on his follow up visits; He is very grateful and feels content with the treatment. We present another case of 49 y/o male patient with a 19 year history of hypertension. Patient was treated with 4 drug-regimen: Valsartan, Hydrochlorothiazide, Amlodipine, nebivolol with average BP findings – 140/90 mm/Hg.Case detection test was positive with increased aldosterone, suppressed renin and increased aldosterone-renin ratio. Patient required confirmatory testing. Salt loading was done which confirmed the diagnosis of PA. On unenhanced CT of the abdomen, bilateral adrenal hyperplasia was found. Patient was started on Eplerenone, on follow up, his BP findings are significantly improved, number of BP meds are also decreased. Conclusion: Diagnosis of PA provides clinicians with unique opportunity to cure or effectively improve hypertension and hypokalaemia, as well as to prevent potential target organ damage and complications. That’s why the importance of increased awareness and having high clinical suspicion cannot be understated. Presentation: 6/3/2024

Prescription of quadruple therapy in heart failure with reduced ejection fraction during hospitalization

BackgroundHospitalization of patients with heart failure makes it possible to optimize drug therapy, considerably improving the prognosis of this serious condition.MethodsWe conducted a retrospective descriptive study of patients with reduced left ventricular ejection fraction (≤ 40%) in the Cardiology Department of a community hospital center in France to measure the prescription rate of heart failure medications in hospitalized patients with reduced ejection fraction heart failure and identify their limiting factors. The primary endpoint was the prescription on the discharge prescription of the following four drug classes: beta-blockers, renin–angiotensin–aldosterone system blockers, mineralocorticoid receptor antagonists, and sodium-glucose co-transporter inhibitors.ResultsFrom September 1, 2022, to March 31, 2023, 73 patients were included in the study. About one-third of patients were discharged with the recommended four drug classes. Those discharged with all 4 drug classes were younger and had preserved renal function.ConclusionsThe low rate of prescription of heart failure medications after hospitalization is a reminder of the need to develop a specialized follow-up structure to optimize the drug treatment of reduced ejection fraction heart failure, even in the most fragile patients.

The Increasing Problem of Resistant Hypertension: We'll Manage till Help Comes!

Arterial hypertension remains the major cardiovascular risk worldwide. It is estimated that under 50 years of age one in every three adults is hypertensive while beyond the age of 50 the prevalence is almost 50% globally. The latest World Health Organization (WHO) Global Report on Hypertension indicated that the global number of hypertensive patients almost doubled in the last three decades, with related increasing deaths, disability, and costs annually. Because of this global increase, early diagnosis and timely treatment is of great importance. However, based on the WHO Global Report, it is estimated that up to 46% of individuals were never diagnosed. Of those diagnosed, less than 50% were on treatment, with nearly half among these at target according to the current guidelines. It is also important to note that an increasing number of hypertensive patients, despite the use of three or more drugs, still do not achieve a blood pressure normalization, thus defining the clinical scenario of resistant hypertension (RH). This condition is associated to a higher risk of hypertension-mediated organ damage and hospitalization due to acute cardiovascular events. Current guidelines recommend a triple combination therapy (renin angiotensin system blocking agent + a thiazide or thiazide-like diuretic + a dihydropyridinic calcium-channel blocker) to all patients with RH. Beta-blockers and mineralocorticoid receptor antagonists, alone or in combination, should be also considered based on concomitant conditions and potential contraindications. Finally, the renal denervation is also proposed in patients with preserved kidney function that remain hypertensive despite the use of maximum tolerated medical treatment. However, the failure of this procedure in the long term and the contraindication in patients with kidney failure is a strong call for a new therapeutic approach. In the present review, we will discuss the pharmacological novelties to come for the management of hypertension and RH in the next future.

Water and Electrolyte Content in Hypertension in the Skin (WHYSKI) in Primary Aldosteronism.

Primary aldosteronism (PA), the most common curable salt-dependent form of arterial hypertension, features renal K+ loss and enhanced Na+ reabsorption. We investigated whether the electrolyte, water, and TonEBP (tonicity-responsive enhancer binding protein)/NFAT5 (nuclear factor of activated T cells 5) content is altered in the skin of patients with PA and corrected by surgical cure. We obtained skin biopsies from 80 subjects: 49 consecutive patients with PA, optimally treated with a mineralocorticoid receptor antagonist; 6 essential hypertensives; and 25 normotensive controls. We measured Na+, K+, water content with atomic absorption spectroscopy after ashing, and NFAT5 mRNA with digital droplet polymerase chain reaction. The patients with PA were retested after adrenalectomy. We discovered a higher dry weight of the skin biopsy specimen at surgery than at follow-up (P<0.001) and a direct correlation with electrolyte and water content (all P<0.01), indicating the need for dry weight adjustment of electrolyte and water data. Surgical cure of PA markedly increased skin dry weight-adjusted K+ (from 1.14±0.1 to 2.81±0.27 µg/mg; P<0.001) and water content (from 2.92±1.4 to 3.85±0.23 mg/mg; P<0.001), but left dry weight-adjusted skin Na+ content unaffected. In patients with PA, NFAT5 mRNA was higher (P=0.031) than in normotensive controls and decreased after surgery (P=0.035). Despite mineralocorticoid receptor antagonist treatment ensuring normokalemia, the patients with PA had a skin cell K+ depletion that was corrected by adrenalectomy. The activated NFAT5/TonEBP pathway during mineralocorticoid receptor antagonist administration suggests enhanced skin Na+ lymphatic drainage and can explain the lack of overt skin Na+ accumulation in patients with PA. Its deactivation after surgical cure can account for the lack of skin Na+ decrease postadrenalectomy. URL: https://www.clinicaltrials.gov; Unique identifier: NCT06090617.

Differential Effect of Aldosterone or Mineralocorticoid Receptor Overexpression on Retinal Inflammation.

Overactivation of the mineralocorticoid receptor (MR) pathway is proinflammatory and contributes to the pathogenesis of diabetic retinopathy and of age-related macular degeneration. Excess of aldosterone, the specific MR ligand, is known to stimulate the production of proinflammatory cytokines and chemokines in extrarenal tissues and cells. In the RPE/choroid complex, aldosterone upregulated genes encoding proteins of the inflammatory response and downregulated genes encoding proteins involved in synaptic activity and neurotransmitters. Yet, cortisol, which is the main MR ligand in the eye, is a potent anti-inflammatory endogenous glucocorticoid. The aim of the present work was to better understand the role of MR activation in retinal inflammation either by acute injection of aldosterone or overexpression of the receptor. We first analyzed the retinal transcriptomic regulation induced by acute intraocular injection of aldosterone in the rat. Then, we used a transgenic rat overexpressing human MR (hMR) to also conduct retinal transcriptomic analysis as well as histological evaluation of the retina, retinal pigment epithelium and choroid. Our results show that acute intravitreal injection of aldosterone is highly proinflammatory, upregulating pathways related to microglial activation, oxidative stress, cell death, and downregulating pathways related to glial/neuronal cells activity and proper neurotransmission. On the other hand, hMR overexpression mediates a low-grade inflammation in the retina, associated with notable choroidal inflammation and choroidal neuropathy. Consequences of hMR overexpression or aldosterone-injection on retinal transcriptome reveal very distinct pathological mechanisms, with only a few common genes regulated, most of them not being regulated in the same way. Although aldosterone is highly proinflammatory in the retina, MR overactivation in its physiologic milieu mediates a low-grade inflammation in the neural retina.

Rho-associated, coiled-coil-containing protein kinase 2 regulates expression of mineralocorticoid receptor to mediate sodium reabsorption in mice

The mineralocorticoid receptor (MR) is a member of the nuclear receptor family that was initially identified to regulate blood pressure through its ability to modulate kidney sodium handling in response to aldosterone. MR can be regulated by signals other than aldosterone; however, the detailed mechanisms remain to be elucidated. We found that MR is controlled in a Rho-associated coiled-coil-containing protein kinase 2 (ROCK2)-dependent manner. Mice with a specific deletion of ROCK2 in the kidney tubules showed decreased MR expression levels and increased urinary excretion of sodium. Mechanistically, signal transducer and activator of transcription 3 (STAT3) is a key molecule that mediates MR expression in these mice. This study highlights an important role of tubular ROCK2 in electrolyte homeostasis.

Aldosterone, mitochondria and regulation of cardiovascular metabolic disease.

Aldosterone is a mineralocorticoid hormone involved in controlling electrolyte balance, blood pressure, and cellular signaling. It plays a pivotal role in cardiovascular and metabolic physiology. Excess aldosterone activates mineralocorticoid receptors, leading to subsequent inflammatory responses, increased oxidative stress, and tissue remodeling. Various mechanisms have been reported to link aldosterone with cardiovascular and metabolic diseases. However, mitochondria, responsible for energy generation through oxidative phosphorylation, have received less attention regarding their potential role in aldosterone-related pathogenesis. Excess aldosterone leads to mitochondrial dysfunction, and this may play a role in the development of cardiovascular and metabolic diseases. Aldosterone has the potential to affect mitochondrial structure, function, and dynamic processes, such as mitochondrial fusion and fission. In addition, aldosterone has been associated with the suppression of mitochondrial DNA, mitochondria-specific proteins, and ATP production in the myocardium through mineralocorticoid receptor, nicotinamide adenine dinucleotide phosphate oxidase, and reactive oxygen species pathways. In this review, we explore the mechanisms underlying aldosterone-induced cardiovascular and metabolic mitochondrial dysfunction, including mineralocorticoid receptor activation and subsequent inflammatory responses, as well as increased oxidative stress. Furthermore, we review potential therapeutic targets aimed at restoring mitochondrial function in the context of aldosterone-associated pathologies. Understanding these mechanisms is vital, as it offers insights into novel therapeutic strategies to mitigate the impact of aldosterone-induced mitochondrial dysfunction, thereby potentially improving the outcomes of individuals affected by cardiovascular and metabolic disorders.

Mineralocorticoid receptor expression and the effects of the mineralocorticoid receptor antagonist spironolactone in a murine model of graft-versus-host disease

PurposeThe topical administration of spironolactone, a mineralocorticoid receptor antagonist (MRA) improves dry eye symptoms in patients with ocular graft-versus-host disease (GVHD); however, the detailed mechanism remains unclear. This study aimed to investigate the effects of spironolactone eyedrops on the ocular surface using a chronic GVHD (cGVHD) mouse model and to determine the expression of the mineralocorticoid receptor (MR). MethodsA cGVHD mouse model was established by allogeneic bone marrow transplantation (BMT) from B10.D2 mice to BALB/c mice. Subsequently, cGVHD mice were treated with either 0.005 % spironolactone or vehicle eyedrops. The eyelids, cornea and conjunctiva of the recipients were analyzed at 4-week intervals post-BMT in both groups. ResultsSigns of ocular GVHD, such as corneal epithelial damage, depletion of meibomian glands, and inflammatory cell infiltration onto the ocular surface, were significantly decreased in cGVHD mice treated with spironolactone eyedrops. The expression of the MR NR3C2 in the corneal and conjunctival epithelia was significantly increased in cGVHD mice. HSP47+NR3C2+ MR-expressing fibroblasts, CD45+NR3C2+ MR-expressing leukocytes, and CD4+NR3C2+ MR-expressing T cells infiltrated the ocular surface tissue of cGVHD mice significantly more than that of syngeneic controls. ConclusionsMR expression is increased in epithelial cells, fibroblasts, and T cells in a murine cGVHD model, whereas MRA and spironolactone eyedrops could attenuate the severity of ocular GVHD. These findings suggest that MR signaling partially contributes to the development of ocular GVHD in this mouse model.

The Association of Genetic Polymorphisms and Atypical Depression in Adults: A Systematic Review.

Atypical depression (AD) is a clinical subtype of depression characterised by mood reactivity and at least two of the following features: significant weight gain/increased appetite, hypersomnia, leaden paralysis, and/or interpersonal rejection sensitivity. The role of genetics in the development of depression remains a considerable level of interest among individuals. Due to the large number of breakthrough studies in genetics, there is currently a wealth of heterogeneous data on the existence of genetic markers for depression, including AD. However, it appears that there is a gap in the literature, as we were unable to identify any systematic reviews or meta-analyses that comprehensively describe these data. Therefore, our research aims to provide high-quality, solid evidence for further studies in this area. Electronic bibliographic databases (Scopus, MEDLINE) were systematically searched from inception to September 2023. We searched for any specific genetic markers that could be retrieved associated with AD. The quality of studies has been assessed by means of the Q-genie tool. Nine studies meeting the inclusion criteria were selected, which appeared to link genetic polymorphisms to atypical depression. Four studies examined genetic polymorphisms associated with the serotonin transporter gene (5-HTT), three studies examined genetic polymorphisms associated with endocrine regulation, two studies considered genetic polymorphisms associated with immune and/or cellular regulation, specifically the melanin-concentrating hormone receptor 2 (MCHR2), mineralocorticoid receptor (MR), and fat mass and obesity-associated protein (FTO) genes involved in the regulation of energy balance. The extracted data confirm that the atypical type of major depressive disorder is heritable to a certain extent. Individual risk markers for developing this type of depression may be identified in the future.

Patterns of corticosterone exposure affect the subcellular localisation of mineralocorticoid and glucocorticoid receptor complexes and gene expression

Mineralocorticoid (MR) and glucocorticoid receptors (GR) act as transcription factors and major mediators of glucocorticoid signalling, with pivotal roles in regulating the stress response and hormonal signalling, mood, cognition and memory. The MR and GR and share many target genes, have a high degree of homology in their DNA binding (DBD) and ligand binding domain (LBD) but differ considerably in the N-terminal domain (NTD). Using Proximity Ligation Assay (PLA) we quantitatively assessed MR-GR complex subcellular localisation and transcriptional regulation in murine neuroblastoma (N2A) cells stimulated by constant or pulsatile corticosterone (CORT) patterns. We observe that continuous receptor activation by CORT caused localisation at the periphery of the cell nucleus. Truncation of the receptor Ligand Binding Domain (LBD) led to a stronger localisation of MR-GR complexes at the periphery of the cell nuclei. This was also observed for GR immunofluorescence (IF), while in cells expressing only MR or GR the mRNA response to pulsatile hormone treatment was substantially attenuated. However, there was no clearcut correlation between the spatial distribution of MR-GR complexes and the mRNA levels of target genes. Overall, our findings suggest that longer presence in the cell nucleus favors more peripheral nuclear localisation.

7722 Temporal mineralocorticoid receptor activation regulates the molecular clock and transcription of cardiovascular disease modulators in myeloid cells

7722 Temporal mineralocorticoid receptor activation regulates the molecular clock and transcription of cardiovascular disease modulators in myeloid cells

Impact of primary aldosteronism on kidney function: results from the SPAIN-ALDO registry.

To evaluate the impact of aldosterone excess on renal function in individuals with primary aldosteronism and to compare its evolution after surgery or mineralocorticoid receptor antagonist (MRA) treatment. A multicentre, retrospective cohort study of primary aldosteronism patients in follow-up in 36 Spanish tertiary hospitals, who underwent specific treatment for primary aldosteronism (MRA or adrenalectomy). A total of 789 patients with primary aldosteronism were included, with a median age of 57.5 years and 41.8% being women. At primary aldosteronism diagnosis, the prevalence of chronic kidney disease (CKD) was 10.7% ( n = 84), with 75% of cases classified as state 3a ( n = 63). Primary aldosteronism patients with CKD had a longer duration of hypertension, a higher prevalence of type 2 diabetes, dyslipidaemia, cardiovascular events, hypokalaemia, and albuminuria. Unilateral adrenalectomy was performed in 41.8% of cases ( n = 330), and 459 patients were treated with MRA. After a median follow-up of 30.7 months (range 13.3-68.4), there was a significant decline in the estimated glomerular filtration rate (eGFR) in operated patients and those receiving MRA. During follow-up, 24.4% of patients with CKD at the time of primary aldosteronism diagnosis had normalized renal function, and 39% of those with albuminuria had albuminuria remission. There were no differences in renal function or albuminuria regression between the two therapy groups. However, development of albuminuria was less common in operated than in medically treated patients (0 vs. 6.0%, P = 0.009). CKD affects around 10% of the patients with primary aldosteronism, with a higher risk in individuals with long-term hypertension, type 2 diabetes, dyslipidaemia, cardiovascular events, hypokalaemia, and albuminuria. At short-term, both MRA and surgical treatment lead to a reduction of renal function, but adrenalectomy led to higher renal protection.

Digoxin Discontinuation in Patients with HFrEF on Beta-Blockers: Implication for Future “Knock-Out Trials” in Heart Failure

Background: National heart failure guidelines recommend quadruple therapy with renin-angiotensin system inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter 2 inhibitors for patients with heart failure with reduced ejection fraction (HFrEF), most of whom also receive loop diuretics. However, the guidelines are less clear about the safe approaches to discontinuing older drugs whose decreasing or residual benefit is less well understood. The objective of this study was to examine whether digoxin can be safely discontinued in patients with HFrEF receiving beta-blockers. Methods: In OPTIMIZE-HF, of 2,477 patients with HFrEF (EF ≤45%) receiving beta-blockers and digoxin, digoxin was discontinued in 450 patients. We assembled a propensity score-matched cohort of 433 pairs of patients in which digoxin continuation vs. discontinuation groups were balanced on 51 baseline characteristics. Using the same approach, from 992 patients not on beta-blockers, we assembled a matched cohort of 198 pairs of patients also balanced on 51 baseline characteristics. Hazard ratios (HRs) and 95% CIs for one-year outcomes were estimated. Results: Among patients receiving beta-blockers, digoxin discontinuation had no association with the combined endpoint of heart failure readmission or death (HR, 1.01; 95% CI, 0.85–1.19), heart failure readmission (HR, 1.03; 95% CI, 0.85–1.25) or death (HR, 0.91; 95% CI, 0.72–1.14). Respective HRs (95% CIs) among patients not receiving beta-blockers were 1.60 (1.25–2.04), 1.62 (1.18–2.22) and 1.43 (1.08–1.89). Conclusions: Digoxin can be discontinued without increasing the risk of adverse outcomes in patients with HFrEF receiving beta-blockers. Future studies need to examine the residual benefit of older heart failure drugs to ensure their safe discontinuation in patients with HFrEF receiving newer guideline-directed medical therapy.

7836 Targeting of Mineralocorticoid Receptor Expression by miR-124-3p-Loaded Extracellular Vesicles as Potential Therapy for Vascular Cognitive Impairment

7836 Targeting of Mineralocorticoid Receptor Expression by miR-124-3p-Loaded Extracellular Vesicles as Potential Therapy for Vascular Cognitive Impairment

Efficacy, Safety and Mechanistic Impact of a Heart Failure Guideline-Directed Medical Therapy Clinic

BackgroundAlthough clinical evidence supports rapid institution of guideline-directed medical therapy (GDMT) for heart failure (HF), in actual practice, there remain large gaps in adherence to guideline recommendations. Recent data support safety and efficacy of rapid GDMT implementation; however, rapid GDMT deployment within a general cardiology environment remains unexplored. ObjectivesThe purpose of this study was to evaluate the efficacy and safety of a GDMT clinic within a general cardiology practice relative to usual care, the impact on prescription of GDMT, HF symptoms, N-terminal pro–B-type natriuretic peptide concentrations and echocardiographic parameters of remodeling. MethodsIndividuals with HF with an abnormal ejection fraction (<50%) referred to the GDMT clinic underwent rapid GDMT titration with close monitoring of clinical data. Rates of GDMT prescription were compared with a matched reference group. Patients underwent echocardiography at baseline and after GDMT clinic completion. ResultsA total of 114 persons were treated in GDMT clinic. The mean age was 67.6 ± 14.6 years, and 32 (28%) were women. Among those referred, 100 (87.7%) had no contraindications for 4-drug GDMT. From baseline to clinic completion (median 15.8 weeks [Q1-Q3: 10.7-23.0 weeks]), patients without medication contraindications experienced significant increases in 4-drug GDMT use (from 21% to 88%; P < 0.001); of 4-drug GDMT recipients, 92% received angiotensin receptor neprilysin inhibitor. GDMT clinic participants achieved higher medication doses than those in usual care, with greater achievement of ≥50% target dose of angiotensin receptor neprilysin inhibitor (52% vs 8%), beta-blocker (78% vs 6.2%), mineralocorticoid receptor antagonist (98% vs 15.6%), and sodium-glucose cotransporter 2 inhibitors (92% vs 6.2%). Target doses of all 4 drugs were reached in nearly 1 in 4 participants. HF symptoms improved (94% to 75% NYHA functional class II/III; P < 0.001) and N-terminal pro–B-type natriuretic peptide concentration decreased (median 587 to 534 ng/L; P = 0.03) despite loop diuretic reduction. Additionally, we observed an absolute 6% LVEF increase (from 37% [Q1-Q3: 31%-41%] to 43% [Q1-Q3: 38%-53%]; P < 0.001) and substantial decrease in moderate or severe mitral regurgitation. GDMT titration was well-tolerated. ConclusionsRapid GDMT implementation via an outpatient GDMT clinic was effective, safe, and associated with improvement in key clinical parameters. The more widespread role of GDMT clinics to improve HF care warrants further study.

Design and cohort characteristics of TRACK, a prospective study of hyperkalaemia management decision-making.

Guideline-recommended hyperkalaemia management includes dietary potassium (K+) restriction, bicarbonate correction, diuretics and K+ binders with dose reduction of renin-angiotensin-aldosterone system inhibitors as a last resort. The extent to which these recommendations are implemented is uncertain, as real-world data on hyperkalaemia management are limited. The Tracking Treatment Pathways in Adult Patients with Hyperkalemia (TRACK) study is a multinational, prospective, longitudinal study that is being conducted to address this knowledge gap. We report the design and baseline cohort characteristics of this real-world study of hyperkalaemia management decision-making. This study enrolled participants within 21days of an episode of hyperkalaemia in four European countries (UK, Spain, Germany, Italy) and the USA. During the 12-month follow up, data collected will include participant and healthcare provider characteristics (specialty and practice setting), hyperkalaemia treatment objectives and strategies, rationale for management decisions and indicators of response and patient-reported perceptions of their hyperkalaemia treatment. The enrolled cohort includes 1330 participants, mean age 68years, of whom 31% were women. At baseline, 6% reported heart failure, 55% chronic kidney disease, 29% both and 9% neither. Most participants (57%) were taking an angiotensin-converting enzyme inhibitor, angiotensin receptor blocker or angiotensin receptor/neprilysin inhibitor at baseline. Mineralocorticoid receptor antagonist use was lower (14%). The prospective TRACK study will shed light on practitioners' hyperkalaemia management decision-making and assess the impact of their decisions on hyperkalaemia recurrence. Understanding practitioners' underlying thought processes will facilitate efforts to improve hyperkalaemia management.ClinicalTrials.gov: NCT05408039.