Mineralocorticoid Receptor Research Articles

Therapeutic Effects of Heart Failure Medical Therapies on Standardized Kidney Outcomes: Comprehensive Individual Participant-Level Analysis of 6 Randomized Clinical Trials.

Background: Kidney outcomes have been variably defined using non-standardized composite endpoints in key heart failure (HF) trials, thus introducing complexity in their interpretation and cross-trial comparability. We examined the effects of steroidal mineralocorticoid receptor antagonists (MRAs), the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan, and sodium-glucose cotransporter-2 (SGLT2) inhibitors on composite kidney endpoints using uniform definitions in 6 contemporary HF trials. Methods: Individual participant-level data from trials of steroidal MRAs (EMPHASIS-HF, TOPCAT Americas), ARNI (PARADIGM-HF, PARAGON-HF), and SGLT2 inhibitors (DAPA-HF, DELIVER) were included. The standardized composite kidney endpoint was defined as a sustained decline (a reduction in estimated glomerular filtration rate (eGFR) confirmed by a subsequent measurement at least 30 days later) in eGFR by 40%, 50%, or 57%, end-stage kidney disease, or renal death. eGFR was recalculated in a standardized manner using the 2009 Chronic Kidney Disease Epidemiology Collaboration creatinine equation. Results: Among 28,690 participants across the 6 trials (median age 69 years [IQR, 62-76]; 9,656 [33.7% ] women), the proportion experiencing the composite kidney endpoint with a more stringent definition of a sustained decline in kidney function (eGFR threshold of 57%) ranged from 0.3% to 3.3%. The proportion of patients experiencing this endpoint with a less stringent definition (eGFR threshold of 40%) ranged from 1.0% and 10.0%. The steroidal MRAs doubled the risk of the composite kidney endpoint when applying the least stringent definition compared with placebo, but these effects were less apparent and no longer significant with application of more stringent definitions. ARNI appeared to consistently reduce the occurrence of the composite kidney endpoints irrespective of specific eGFR threshold applied. The potential benefits of SGLT2-inhibitors on the composite kidney endpoints appeared more apparent when defined by more stringent eGFR thresholds, although none of these effects individually were statistically significant. Conclusions: When applying standardized stringent kidney endpoint definitions, steroidal MRAs, ARNI, and SGLT2-inhibitors have either neutral or beneficial effects on kidney outcomes in HF. Applying less stringent definitions increased event rates but included acute declines in eGFR that might not ultimately reflect long-term effects on kidney disease progression.

Finerenone in heart failure and chronic kidney disease with type 2 diabetes: FINE-HEART pooled analysis of cardiovascular, kidney and mortality outcomes.

Cardiovascular-kidney-metabolic syndrome is an emerging entity that connects cardiovascular diseases, chronic kidney disease and diabetes. The non-steroidal mineralocorticoid receptor antagonist finerenone has been studied in three prospective randomized clinical trials of patients with cardiovascular-kidney-metabolic syndrome: FIDELIO-DKD, FIGARO-DKD and FINEARTS-HF. In light of the strong epidemiological overlap and shared mechanistic drivers of clinical outcomes across cardiovascular-kidney-metabolic syndrome, we summarize the efficacy and safety of finerenone on cardiovascular, kidney and mortality outcomes in this pre-specified participant-level pooled analysis. The three trials included 18,991 participants (mean age 67 ± 10 years; 35% women). During 2.9 years of median follow-up, the primary outcome of cardiovascular death occurred in 421 (4.4%) participants assigned to finerenone and 471 (5.0%) participants assigned to placebo (hazard ratio (HR): 0.89; 95% confidence interval (CI): 0.78-1.01; P = 0.076). Death from any cause occurred in 1,042 (11.0%) participants in the finerenone arm and in 1,136 (12.0%) participants in the placebo arm (HR: 0.91; 95% CI: 0.84-0.99; P = 0.027). Finerenone further reduced the risk of hospitalization from heart failure (HR: 0.83; 95% CI: 0.75-0.92; P < 0.001) and the composite kidney outcome (HR: 0.80; 95% CI: 0.72-0.90; P < 0.001). While in this pooled analysis the reduction in cardiovascular death was not statistically significant, finerenone reduced the risks for deaths of any cause, cardiovascular events and kidney outcomes. PROSPERO identifier: CRD42024570467 .

Finerenone in Heart Failure with Mildly Reduced or Preserved Ejection Fraction

BackgroundSteroidal mineralocorticoid receptor antagonists reduce morbidity and mortality among patients with heart failure and reduced ejection fraction, but their efficacy in those with heart failure and mildly reduced or preserved ejection fraction has not been established. Data regarding the efficacy and safety of the nonsteroidal mineralocorticoid receptor antagonist finerenone in patients with heart failure and mildly reduced or preserved ejection fraction are needed.MethodsIn this international, double-blind trial, we randomly assigned patients with heart failure and a left ventricular ejection fraction of 40% or greater, in a 1:1 ratio, to receive finerenone (at a maximum dose of 20 mg or 40 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of total worsening heart failure events (with an event defined as a first or recurrent unplanned hospitalization or urgent visit for heart failure) and death from cardiovascular causes. The components of the primary outcome and safety were also assessed.ResultsOver a median follow-up of 32 months, 1083 primary-outcome events occurred in 624 of 3003 patients in the finerenone group, and 1283 primary-outcome events occurred in 719 of 2998 patients in the placebo group (rate ratio, 0.84; 95% confidence interval [CI], 0.74 to 0.95; P=0.007). The total number of worsening heart failure events was 842 in the finerenone group and 1024 in the placebo group (rate ratio, 0.82; 95% CI, 0.71 to 0.94; P=0.006). The percentage of patients who died from cardiovascular causes was 8.1% and 8.7%, respectively (hazard ratio, 0.93; 95% CI, 0.78 to 1.11). Finerenone was associated with an increased risk of hyperkalemia and a reduced risk of hypokalemia.ConclusionsIn patients with heart failure and mildly reduced or preserved ejection fraction, finerenone resulted in a significantly lower rate of a composite of total worsening heart failure events and death from cardiovascular causes than placebo. (Funded by Bayer; FINEARTS-HF ClinicalTrials.gov number, NCT04435626.)

Mineralocorticoid receptor antagonists for every patient with heart failure

Mineralocorticoid receptor antagonists for every patient with heart failure

Abstract MP11: Evaluation of a Remote Patient Monitoring Hypertension Program with Telehealth Pharmacist Management in Nephrology Clinic Patients

Introduction: Remote patient monitoring (RPM) and physician-pharmacist collaborative models have potential in improving hypertension control. Herein, we report the effectiveness of a community based, self-measured blood pressure (SMBP) RPM program on BP control and healthcare utilization in a largely rural health system. Methods: A multidisciplinary team developed a self-measured blood pressure (SMBP) RPM program in central and northeast PA using a virtual platform with bluetooth-connected BP devices targeting patients with BP ≥140/90 mmHg seen in nephrology clinics. From 3/2022 to 9/2022, high BP notifications were transmitted to nephrologists. After 9/2022, BP notifications were transmitted first to pharmacists, who co-managed BP through collaborative practice agreements via telehealth. We captured pharmacist interventions by reviewing electronic health record documentation. Changes in SMBP over time and the effect of pharmacist interventions were analyzed using mixed effects models. All-cause hospitalizations and emergency room (ER) visits were compared in 6-month pre/post-enrollment periods. Results: A total of 205 patients (mean age 62.3y, clinic BP 146/84, 3.1 BP classes, 48% female, 53% CKD) were enrolled into the program and had ≥ 6 months follow-up data. SMBP control &lt;140/90 improved from 30% during week 1 to 67% at 6 months and 74% at 12 months. Overall, systolic SMBP improved over the first 6 months with stronger effect on patients with higher baseline BP (baseline BP ≥150/100 mmHg: -3.3 mmHg/month (95% CI: -3.5, -3.1); baseline 140-149/90-99: -2.4 (95% CI: -2.6, -2.1) mmHg/month; baseline &lt;140/90: -0.6 (-0.9, -0.4) mmHg/month). Pharmacist telehealth encounters were documented in 65% of patients; 46% had a BP medication adjustment; 37% had new BP medication classes, including 9% mineralocorticoid receptor antagonist. Pharmacist medication intervention was associated with greater decline in systolic BP over time (-1.3 mmHg/month; 95% CI: -1.6, -1.1). Comparing the 6 months pre vs. post-enrollment, patients experienced a reduction in hospitalizations (6.0% vs. 0%; Exact Mcnemar p=0.0005) and no difference in ER visits (14.9% vs. 12.9%; p=0.6). Conclusion: Participation in a nephrologist-pharmacist SMBP RPM program was associated with improvement in BP control and reduced hospitalizations. Future efforts are underway to refine delivery of this program for the largest impact on improving BP control.

O99 RELATIONSHIP BETWEEN RENIN, ALDOSTERONE, ALDOSTERONE-TO-RENIN RATIO AND LEFT VENTRICULAR MASS INDEX IN YOUNG ADULTS

Background and Objective: Primary aldosteronism (PA), characterised by excessive aldosterone production and mineralocorticoid receptor activation, is associated with adverse cardiovascular outcomes including left ventricular hypertrophy and failure. Elevated cardiovascular risk is observed even in milder and subclinical forms of PA, based on studies primarily conducted in middle-aged and elderly populations. It is unclear if the biomarkers of PA, including renin, aldosterone, and aldosterone-to-renin ratio (ARR), are associated with left ventricular mass index (LVMI), which is a strong predictor of cardiovascular diseases, in young adults. Methods: The Raine Study is a longitudinal, population-based cohort study in Western Australia that enrolled women during pregnancy. We analysed the data from the offspring of these women at age 27 years. Participants with elevated high-sensitivity C-reactive protein (&gt;10 mg/L) and females who were on oral contraception were excluded. LVMI was measured by cardiac magnetic resonance imaging. We examined the relationship between LVMI and plasma renin, aldosterone, and ARR using multivariate-adjusted linear regression and used mediation analysis to test whether these relationships were dependent on systolic blood pressure (SBP). Results: Of 758 participants, 252 (33.2%) were females. Females had lower median plasma renin concentration (12.0 vs 15.4mU/L; p&lt;0.001) and higher median ARR (21.0 vs 15.6; p&lt;0.001) than males. There was no sex-difference in median plasma aldosterone concentration (257 vs 237pmol/L in males; p=0.143). Females had lower LVMI (52.2 vs 70.2 g/m2; p&lt;0.001) than males. A significant association between LVMI and aldosterone was detected in males (β-coefficient 0.009; 95% CI 0.001 to 0.017; p=0.027), and between LVMI and ARR in females (β-coefficient 0.098; 95% CI 0.001 to 0.196; p=0.050) after adjusting for confounders. This relationship was not mediated by brachial SBP. Conclusions: An elevated aldosterone concentration or ARR was associated with higher LVMI in young adults, independent of brachial SBP. Long-term follow-up is required to determine if the relationship persists over time and leads to reduced cardiac function.

Cardiovascular and Renal Treatment in Heart Failure Patients With Hyperkalemia or High Risk of Hyperkalemia: Rationale and Design of the CARE-HK in HF Registry

Despite guideline recommendations, many patients with heart failure (HF) do not receive target dosages of renin-angiotensin-aldosterone system inhibitors (RAASis) in clinical practice due, in part, to concerns about hyperkalemia (HK). This noninterventional, multinational, multicenter registry (NCT04864795; 111 sites in Europe and the USA) enrolled 2558 eligible adults with chronic HF (mostly with reduced ejection fraction [HFrEF]). Eligibility criteria included use of angiotensin-converting-enzyme inhibitor/angiotensin-II receptor blocker/angiotensin-receptor-neprilysin inhibitor, being a candidate for or treatment with a mineralocorticoid receptor antagonist, and increased risk of HK (eg, current serum potassium > 5.0 mmol/L), history of HK in the previous 24 months, or estimated glomerular filtration rate < 45 mL/min/1.73 m2). Information on RAASi and other guideline-recommended therapies was collected retrospectively and prospectively (≥ 6 months). Patients were followed according to local clinical practice, without study-specific visits or interventions. The main objectives were to characterize RAASi treatment patterns compared with guideline recommendations, describe RAASi modifications following episodes of HK, and describe RAASi treatment in patients treated with patiromer. Baseline characteristics for the first 1000 patients are presented. CARE-HK is a multinational prospective HF registry designed to report on the management and outcomes of patients with HF at high risk for HK in routine clinical practice.

Mineralocorticoid receptor antagonists in heart failure: an individual patient level meta-analysis

Mineralocorticoid receptor antagonists (MRAs) reduce hospitalisations and death in patients with heart failure and reduced ejection fraction (HFrEF), but the benefit in patients with heart failure and mildly reduced ejection fraction (HFmrEF) or heart failure and preserved ejection fraction (HFpEF) is unclear. We evaluated the effect of MRAs in four trials that enrolled patients with heart failure across the range of ejection fraction. This is a prespecified, individual patient level meta-analysis of the RALES (spironolactone) and EMPHASIS-HF (eplerenone) trials, which enrolled patients with HFrEF, and of the TOPCAT (spironolactone) and FINEARTS-HF (finerenone) trials, which enrolled patients with HFmrEF or HFpEF. The primary outcome of this meta-analysis was a composite of time to first hospitalisation for heart failure or cardiovascular death. We also estimated the effect of MRAs on components of this composite, total (first or repeat) heart failure hospitalisations (with and without cardiovascular deaths), and all-cause death. Safety outcomes were also assessed, including serum creatinine, estimated glomerular filtration rate, serum potassium, and systolic blood pressure. An interaction between trials and treatment was tested to examine the heterogeneity of effect in these populations. This study is registered with PROSPERO, CRD42024541487. 13 846 patients were included in the four trials. MRAs reduced the risk of cardiovascular death or heart failure hospitalisation (hazard ratio 0·77 [95% CI 0·72-0·83]). There was a statistically significant interaction by trials and treatment (p for interaction=0·0012) due to the greater efficacy in HFrEF (0·66 [0·59-0·73]) compared with HFmrEF or HFpEF (0·87 [0·79-0·95]). We observed significant reductions in heart failure hospitalisation in the HFrEF trials (0·63 [0·55-0·72]) and the HFmrEF or HFpEF trials (0·82 [0·74-0·91]). The same pattern was observed for total heart failure hospitalisations with or without cardiovascular death. Cardiovascular death was reduced in the HFrEF trials (0·72 [0·63-0·82]) but not in the HFmrEF or HFpEF trials (0·92 [0·80-1·05]). All-cause death was also reduced in the HFrEF trials (0·73 [0·65-0·83]) but not in the HFmrEF or HFpEF trials (0·94 [0·85-1·03]). With an MRA, the risk of hyperkalaemia was doubled compared with placebo (odds ratio 2·27 [95% CI 2·02-2·56]), but the incidence of serious hyperkalaemia (serum potassium >6·0 mmol/L) was low (2·9% vs 1·4%); the risk of hypokalaemia (potassium <3·5 mmol/L) was halved (0·51 [0·45-0·57]; 7% vs 14%). Steroidal MRAs reduce the risk of cardiovascular death or heart failure hospitalisation in patients with HFrEF and non-steroidal MRAs reduce this risk in patients with HFmrEF or HFpEF. None.

Abstract P147: Inappropriate Activation of the Leptin-Aldosterone-Endothelial Mineralocorticoid Receptor Axis Promotes Salt Sensitivity of Blood Pressure in Young Female Mice

While compelling clinical evidence indicates that women are more salt-sensitive than men, the mechanisms of the onset of women’s salt-sensitive blood pressure (SSBP) remain largely elusive. Herein, we employed salt-sensitive (SS)-Balb/C and salt-resistant (SR)-C57Bl/6 mice to investigate the etiopathology of SSBP in females. We hypothesized that a high-salt diet alters the leptin-aldosterone-endothelial mineralocorticoid receptor axis (ECMR), leading to SSBP and vascular dysfunction in young SS-female mice. Eleven-week-old female mice were fed a normal (0.4%, NSD) or a high salt diet (4%, HSD) for 7-days. We implanted radiotelemeters for BP monitoring at baseline, HSD, and in response to the leptin receptor (LepR) blockade combined with HSD. Following euthanasia, mesenteric arteries are isolated to measure vascular function via wire myography. HSD elevated mean arterial pressure in Balb/C (NSD: 98.4±2.3 vs. HSD: 105.1±0.9 mmHg) but not in C57 mice (NSD: 99.3±0.9 vs. HSD: 101.3±0.5 mmHg). However, SS-Balb/C mice showed superior natriuretic function in response to salt loading experiments (NSD: 13.3% vs. HSD: 42.3%) as opposed to C57 mice (NSD: 25.8% vs. HSD: 35.1%) (N=3). HSD feeding notably blunted endothelial relaxation to acetylcholine in Balb/c (NSD: 96.5% vs. HSD: 75.4%, N=7), an effect not seen in C57. SS-Balb/C mice failed to suppress aldosterone and adrenal aldosterone synthase (CYP11B2) levels (protein and transcript) compared to C57 mice. This concomitated a 1.8-fold increase in adrenal steroidogenic acute regulatory (StAR) mRNA in SS-Balb/C mice. HSD raised CYP11B2 protein levels in the visceral adipose tissue (VAT) of Balb/C mice. Leptin regulating CYP11B2 expression; we measured fat mass, leptin, and LepR expression. HSD enhanced fat accumulation (C57: +0.7% vs. Balb/c: +26.5%, N=12), leptin levels, and LepR transcript in the adrenal and VAT only in Balb/C mice. LepR blockade reduced BP in Balb/C mice fed a HSD (HSD: 105.1±0.9 vs. HSD+Allo-aca: 100.3±1.9 mmHg). HSD elevated ECMR expression only in Balb/C mice (N=6). To test the potential role of aldosterone-mediated ECMR activation in SSBP, we employed mice with selective overexpression of MR in endothelial cells (ECMR-OE). ECMR-OE young female mice exhibited impaired endothelial function (N=7), reproducing the effects of HSD. In conclusion, SSBP involves an over-activation of the leptin-aldosterone axis in both adrenal and adipose tissue, along with an escalated ECMR expression in females.

Indian Consensus on the Role and Position of Angiotensin Receptor-neprilysin Inhibitors in the Management of Heart Failure.

The incidence of heart failure (HF) in India is estimated to be 0.5-1.7 cases per 1,000 people per year, and approximately 4,92,000-1.8 million new cases are detected every year. Despite the high rate of mortality associated with HF, most patients do not receive maximal guideline-directed medical therapy (GDMT). Current guidelines advocate early multidrug combination therapy with four classes of drugs, namely, beta-blockers (BBs), mineralocorticoid receptor antagonists (MRAs), angiotensin receptor-neprilysin inhibitors (ARNIs), and sodium-glucose transport protein 2 inhibitors (SGLT-2is), particularly in patients with heart failure with reduced ejection fraction (HFrEF). ARNIs reduce cardiac morbidity and mortality in patients with HFrEF. However, recent data indicated that only 4.8% of patients with HFrEF receive ARNI in India. Hence, at a national consensus on HF meeting, cardiology experts from India formulated a national consensus on the use of ARNI in HF based on current evidence and guidelines. The consensus states that ARNI should be used early in HF, particularly in de novo patients with HFrEF, and those with acute decompensated heart failure (ADHF), irrespective of the presence of low systolic blood pressure (SBP) or diabetes. Moreover, those with HFrEF on renin-angiotensin-aldosterone system (RAAS) inhibitors should be switched to ARNI to reduce the risk of repeated hospitalization for HF, worsening HF, and cardiac death, and to improve the quality of life (QoL). Starting ARNI during the first hospitalization is preferable, and it is safe and effective across all doses. ARNIs can also be used for secondary benefits in patients with preserved ejection fraction [heart failure with preserved ejection fraction (HFpEF)] and HF with mildly reduced EF [heart failure with mildly reduced ejection fraction (HFmrEF)].

Fixed-dose Combination of Torsemide and Mineralocorticoid Receptor Antagonists.

The combination of torsemide and spironolactone presents a promising approach to managing conditions such as edema and hypertension. Torsemide, a loop diuretic, enhances diuresis by inhibiting sodium reabsorption in the kidneys, while spironolactone, a potassium-sparing diuretic and mineralocorticoid receptor antagonist (MRA), complements this effect by preventing potassium loss and offering additional cardiovascular benefits. This review examines clinical evidence supporting their combined effectiveness in treating fluid retention and improving outcomes in conditions like heart failure (HF). Given the limited research available, it is essential to carefully evaluate patient-specific factors. However, several side effects necessitate careful patient selection and monitoring. Moreover, optimizing dosing regimens is crucial to ensure the safety and efficacy of torsemide and MRAs in clinical settings.

Abstract P101: Surgical and not medical treatment of Primary Aldosteronism increase skin K + levels: pathophysiological and clinical implications

Introduction: Primary aldosteronism (PA), the most common curable salt-dependent form of arterial hypertension, features renal K + loss and enhanced Na + reabsorption. Hypothesis: We assessed the hypothesis that alterations of electrolyte, water, and Tonicity-responsive Enhancer Binding Protein/NFAT5 mRNA content occur in the skin of PA patients and are corrected by surgical cure. Methods: We obtained skin biopsies in 80 subjects: 49 consecutive consenting PA patients, optimally treated with a mineralocorticoid receptor antagonist (MRA) before adrenalectomy; 6 patients with essential hypertension, and 25 normotensive controls. We measured Na + , K + and water content with atomic absorption spectrometry after ashing and NFAT5 mRNA with digital droplet PCR. The PA patients were retested after adrenalectomy. Results: We discovered that the skin biopsy specimen dry weight (DW) was higher at surgery than follow-up (p&lt;0.001) and correlated directly with electrolyte and water content (all p&lt;0.01), indicating the need for adjusting electrolyte and water data for DW. Surgical cure of PA markedly increased skin DW-adjusted K + (from 1.14±0.1 µg/mg to 2.81±0.27 µg/mg, p&lt;0.001) and water content (from 2.92±1.4 mg/mg to 3.85±0.23 mg/mg, p&lt;0.001), but left DW-adjusted skin Na + content unaffected. In the PA patients NFAT5 mRNA copy number was higher (p=0.03) than in the normotensive controls and decreased after surgery (p=0.03). Conclusions: In conclusion, surgical cure, but not optimal MRA treatment corrected the prominent skin cell K + depletion that occurred despite normal serum K + levels. The lack of overt skin Na + accumulation in PA patients during MRA treatment could be explained by enhanced skin Na + lymphatic drainage due to the documented activation of the skin NFAT5/TonEBP pathway.

Prescription Patterns in Management of Heart Failure and Its Association With Readmissions: A Retrospective Analysis

BackgroundThe American Heart Association/American College of Cardiology/Heart Failure Society of America recently added sodium-glucose cotransporter-2 inhibitors in addition to renin–angiotensin–aldosterone system inhibitors, beta-blockers, and mineralocorticoid receptor antagonists to form the 4 pillars of guideline-directed medical therapy (GDMT) for the management of heart failure with reduced ejection fraction (HFrEF). Despite strong evidence suggesting improved outcomes with inpatient initiation of GDMT at target doses, significant lag has been noted in prescription practices. We sought to study GDMT prescription rates in patients with HFrEF at the time of hospital discharge and evaluate its association with various patient characteristics and all-cause readmission rates. Methods and ResultsWe used a modified version of Heart Failure Collaboratory (HFC) score to characterize patients into 2 groups (those with an HFC score of <3 and an HFC score of ≥3) and to examine various socioeconomic and biomedical factors affecting GDMT prescription practices. Out of the eligible patients, the prescription rates for beta-blockers was 77.9%, renin–angiotensin–aldosterone system inhibitor was 70.3%, and mineralocorticoid receptor antagonists was 41%. Furthermore, prescription rates for sacubitril/valsartan was 27.7% and sodium-glucose cotransporter-2 inhibitors was 17%. Only 1% of patients had an HFC score of 9 (drugs from all 4 classes at target doses). Patients of black ethnicity, those admitted on teaching service and those with HFrEF as the primary cause of admission were more likely to have an HFC of ≥3 at discharge. An HFC of ≥3 was associated with lower rates of 1-month all-cause readmissions. ConclusionsConsistent with the prior research, our data show significant gaps in prescription of GDMT in HFrEF. Further implementation research should be done to improve GDMT prescription during inpatient stay.

Abstract P307: A Review Of The Burden, Management And Outcomes Of Patients With Aldosterone Dysregulation

Introduction: Aldosterone dysregulation (excess aldosterone production) is a complex physiological driver of uncontrolled hypertension as well as cardiovascular (CV) and kidney outcomes. Understanding the clinical and economic burden of excess aldosterone in routine practice is critical to optimizing treatment and improving long-term outcomes. This review examines the burden of excess aldosterone production as a driver of disease and its impact on clinical and economic outcomes. Hypothesis: Excess aldosterone production has a broad impact on long-term outcomes, and left untreated, contributes to worsened patient outcomes. Methods: A targeted literature review was conducted to identify articles on the burden, management and outcomes of patients with excess aldosterone production (2013 – 2024) with 27 manuscripts included. Results: More studies document the impact of excess aldosterone on organ function in the cardiovascular system and kidney (10, 8 manuscripts) compared to liver (1 manuscript). Excess aldosterone levels and aldosterone-induced oxidative stress and inflammation are associated with increased risk of CV events including myocardial infarction, heart failure, stroke, and increased morbidity and mortality. For example, Framingham Offspring Study showed increased CV disease risk with each rise in serum aldosterone levels (HR, 1.11; 95% CI, 1.02–1.21). Kidney, hepatic and metabolic manifestations are also well-documented, with implications for progression to chronic kidney disease, liver disease and metabolic syndrome. Another study reported an 11% increased risk of CKD progression associated with each doubling of serum aldosterone. Current pharmacological interventions for hypertension, including mineralocorticoid receptor antagonists, were not reported to restore normal aldosterone levels. No literature was found on the economic burden of excess aldosterone or the association between excess aldosterone production and clinical outcomes independent of blood pressure control. Conclusions: Currently available literature emphasizes the broad impact of excess aldosterone production on CV, kidney, hepatic, and metabolic outcomes. The impact on outcomes indicates that excess aldosterone production is underappreciated, with prognostic implications beyond primary aldosteronism. Current hypertension treatments do not address excess aldosterone production. These findings underscore the unmet need for novel management strategies that target excess aldosterone production.

Abstract P218: Resistant hypertension is associated with elevated 24-hour cortisol to cortisone ratios in black patients.

Background: RHTN is defined as blood pressure above goal despite using ≥3 antihypertensive medications. Patients with RHTN are at an increased risk for cardiovascular (CVD) compared to those with more easily controlled hypertension (HTN). Blacks With RHTN are at a specifically high risk for CVD. Mineralocorticoid receptor activation has been found as an important mechanism of RHTN. However, aldosterone levels are not different in blacks versus whites. The role of 24-hour cortisol-to-cortisone ratios in this group has not been investigated. Methods: We conducted a cross-sectional analysis of a large cohort of 2397 black and white patients with RHTN who were referred to the RHTN Clinic at the University of Alabama at Birmingham and who underwent 24-hour urine collection including cortisol and cortisone. Patients with HTN served as a control group. Results: Black patients with RHTN compared to whites had a trend to higher 24h cortisol levels (17.7±27.6 vs 16.9±14.9, p =0.70, significantly lower 24h cortisone levels (60.45±37.7 vs 75.3±40.0, p 0.000234), and significantly higher 24h cortisol-to-cortisone ratios (0.23±0.14 vs 0.20 ±0.10, p=0.027). They were younger (53.3±11.6 vs 59.4±12.9 years), more obese (BMI 34.9±7.6 vs 30.8±6.1 kg/m2, p&lt;0.001), had earlier onset of HTN (35.6±12.5 vs 41.4±11.6 years of age, p&lt;0.001), higher 24-hour urinary sodium excretion (188.2±92.5 vs 174.9±83.1 mmol, p=0.006) and lower potassium excretion (54.5 ±28.6 vs 65.5 ±30.5 mmol, p&lt;0.001). Furthermore, they had a significantly higher rate of heart failure (p=0.000455) and diabetes (p=0.0006). Conclusion: Cortisol dysregulation and a higher cortisol-to-cortisone ratio as an index of 11beta HSD2 activity may play a role in black patients with RHTN and may be related to adverse outcomes in this population.

Abstract P301: A Meta-Analysis of Randomized Controlled Trials: Aldosterone Synthase Inhibitors as a Therapeutic Strategy for Hypertension

Introduction: Hypertension is a widespread health concern globally, often associated with excessive aldosterone production. Aldosterone synthase inhibitors (ASIs) have been proposed as potential therapeutic agents. Yet, their effectiveness and safety in managing blood pressure in hypertensive adults are not definitively established. This study aims to elucidate this matter through a comprehensive systematic review and meta-analysis of Randomized Controlled Trials (RCTs). Hypothesis: We hypothesize that ASIs could be a safe and effective strategy for managing blood pressure in adults diagnosed with hypertension. Methods: A systematic review and meta-analysis of seven RCTs were conducted to assess the impact of ASIs versus placebo in hypertensive patients. The studies were systematically sourced from MEDLINE and EMBASE until March 30 th , 2024. Continuous outcomes were pooled using the mean difference (MD), and dichotomous outcomes were pooled using the risk ratio (RR), both with their respective confidence intervals (CI). Results: Our meta-analysis incorporated data from seven randomized studies, averaging 7.7 ± 2.4 weeks in duration, and involving a total of 1440 patients. Compared to placebo, ASIs showed effectiveness in controlling systolic blood pressure (MD: -6.12 mm Hg; 95% CI [−4.32, −7.92]; p &lt; 0.0001; I 2 = 0%) and diastolic blood pressure (MD: −2.71; 95% CI [−1.07, −4.36]; p = 0.001; I 2 = 0%). Notably, the incidence of adverse events did not significantly differ from that observed with placebo (RR: 1.11; 95% CI 0.95 to 1.29; p = 0.18; I 2 = 0%). Conclusions: Our findings suggest that ASIs could be a safe and effective approach for managing blood pressure in hypertensive adults, with no significant difference in the incidence of adverse events compared to placebo. These results advocate for further investigation of ASIs in larger, long-term trials to confirm their safety and efficacy, and to explore any additional therapeutic benefits over mineralocorticoid receptor antagonists. Future research should also thoroughly examine the potential benefits of these inhibitors in diverse patient populations, including those with obesity-associated hypertension and suppressed plasma renin activity.

Suppressed Renin Status Is a Risk Factor for Cardiocerebrovascular Events in Bilateral Primary Aldosteronism Treated With Mineralocorticoid Receptor Antagonists

ObjectiveMineralocorticoid receptor antagonists are the recommended medical therapy for bilateral primary aldosteronism (BPA). Patients with BPA have higher risk of cardiocerebrovascular disease (CCVD) than those with essential hypertension. There is no consensus on the criteria to assess the effectiveness of medical therapy for BPA. This study aimed to investigate the incidence of and risk factors for CCVD after medical therapy of BPA. MethodsWe conducted a retrospective cohort study including 240 patients with BPA treated with mineralocorticoid receptor antagonists. The posttreatment plasma renin activity (PRA) was defined as unsuppressed (PRA, ≥1 ng/mL/h); otherwise, it was defined as suppressed. We analyzed the association of posttreatment PRA status with CCVD outcomes. ResultsOf patients with BPA, 7.1% (17/240) developed CCVD at a median follow-up of 5.0 (range, 2.96-7.66) years. Moreover, 57.1% of patients had a PRA of ≥1 ng/mL/h after treatment. Patients with a PRA of <1 ng/mL/h had a higher incidence of CCVD (12.6% vs 2.9%, P < .05) and were at higher risk than those with a PRA of ≥1 ng/mL/h (hazard ratio, 4.50 [95% CI, 1.47-13.83; P < .05]; adjusted hazard ratio, 3.98 [95% CI, 1.22-13.02; P < .05]). ConclusionPatients with BPA who receive pharmacologic treatment have a high incidence of CCVD. PRA may be an indicator that mineralocorticoids are being adequately antagonized.

Abstract P100: TRPM7 deficiency amplifies aldosterone signalling cardiac fibroblasts

Introduction: Transient Receptor Potential Melastatin 7 (TRPM7) channel is a channel bound to a kinase domain that influences cellular Mg 2+ with an important role in inflammatory response and cell metabolism. TRPM7 is regulated by aldosterone. Here, we investigated the importance of TRPM7-Mg2+ in pro-fibrotic responses and oxidative stress in cardiac fibroblasts (CF) in the context of hypertension and organ damage induced by aldosterone. Methods: Wild-type (WT) and TRPM7-deficient (M7+/Δ) mice were treated with aldosterone (600µg/Kg/day) plus NaCl (1% drinking water), 4 weeks. Mechanisms were investigated in primary culture of CF. Ca 2+ and Mg 2+ influx was assessed by fluorescence microscopy and flow cytometry. Gene and protein expression was assessed by real-time PCR and immunoblotting. Proteomic analysis was performed in two-dimensional liquid chromatography and mass spectrometry (LC/LC-MS/MS). Results: M7+/Δ mice exhibited reduced tissue [Mg 2+ ] (28%) and increased cardiac collagen deposition (2-fold). Aldosterone-induced fibrosis and hypertension were enhanced in M7+/Δ. CF M7+/Δ had reduced aldosterone-induced calcium influx (136±6 vs WT:166±7) and Mg 2+ influx (1.05±0.05 vs WT 1.14±0.02). CF M7+/Δ exhibit increased expression of calpain-1(300%), α-SMA(80%), collagen-1 (50%), mineralocorticoid receptor target proteins ENaC(70%) and SGK1(30%) and reduced proliferation(33%) vs WT(p&lt;0.05). Aldosterone reduced TRPM7 (44%) and increased expression of ENaC (150%) and collagen-1 (93%) in CF WT to similar levels observed in CF M7+/Δ. CF M7+/Δ exhibit increased Nox2(70%), Nox4(120%) and ROS production (1,362 vs WT: 899 RLU/mg protein). Increased mRNA for the antioxidant catalase, NQO1 and Prdx1 (1.7-2.6-fold) was found in M7+/Δ CF. Mg 2+ supplementation normalised Ca 2+ and Mg 2+ influx, proliferation and expression of SGK1, Nox4, catalase and NQO1, whereas other effects might be mediated by the kinase domain. Proteomic analysis showed that CF M7+/Δ exhibit reduced expression of proteins related to cell migration and proliferation (Tnc, Cdcc80, Crip1, Ggt5) cell cycle and differentiation (AnxA8, Rpl22, Prickle2) and cell metabolism (Marcks, Mtab, Ces1d, Serpina3n, Afap1l1). Conclusion: Our findings demonstrate that in aldosterone-treated mice TRPM7 expression and tissue Mg 2+ levels are decreased. These processes are associated with cardiac fibrosis and oxidative stress. Our findings suggest a cardio-protective role for TRPM7/Mg2+ in aldosterone-induced hypertension.

Abstract P440: Discovery of clinical candidate GSC002219, a highly selective oral CYP11B2 inhibitor for hypertension

Background: Aldosterone is an important mediator of hypertension and its aberration could contribute to heart and kidney diseases. Aldosterone synthase inhibitors (ASI) attenuate the production of aldosterone directly and have been proposed as an alternative to mineralocorticoid receptor antagonists (MRA) for treatment of resistant hypertension and chronic renal disease. GSC002219 is a potent inhibitor of aldosterone synthase (CYP11B2) with high selectivity over the closely related enzyme CYP11B1. The aim of the study was to evaluate the effect of GSC002219 on aldosterone and blood pressure. Methods: The inhibitory effect of GSC002219 against CYP11B2 and CYP11B1 proteins was assessed in human renal leiomyoblastoma cells expressing recombinant human / cynomolgus CYP11B1or CYP11B2 enzymes, respectively. GSC002219 was further evaluated in Synacthen (ACTH) challenged cynomolgus monkey model for its effects against various related key biomarkers including cortisol, aldosterone and precursors. The effects of GSC002219 on systolic blood pressure (SBP) and diastolic blood pressure (DBP) were evaluated in stroke-prone spontaneously hypertensive rat (SHRSP) model. Results: GSC002219 potently inhibits CYP11B2 with an IC 50 of 27nM, while maintains a &gt;150-fold selectivity over CYP11B1. In ACTH challenged cynomolgus monkey model, single oral doses of GSC002219 at 0.03 mg/kg and 0.1 mg/kg could suppress aldosterone production to 80% and 93%, respectively, comparing to vehicle-treated animals without any effect towards cortisol levels. In the rat SHRSP hypertension model, GSC002219 could effectively lower both SBP and DBP. GSC002219 has an excellent in vitro ADME and toxicology profile as well as a balanced physicochemical property. In 14-day rat and monkey toxicology studies, GSC002219 displayed good tolerance, excellent PK profile and a great safety window (&gt;100 fold). Conclusions: Taken together, GSC002219 is a safe and potent inhibitor of CYP11B2 and efficacious in various disease models of hypertension. GSC002219 is under IND-enabling study and may enter the clinical development early 2025.

Finerenone in Patients With a Recent Worsening Heart Failure Event: The FINEARTS-HF Trial.

Patients with heart failure (HF) and a recent worsening heart failure (WHF) event are known to be at high risk of recurrent hospitalization and death, regardless of ejection fraction. This study examined the efficacy and safety of the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone in relation to the recency of a WHF event. FINEARTS-HF (FINerenone trial to investigate Efficacy and sAfety superioR to placebo in paTientS with Heart Failure) was a randomized, double-blind, placebo-controlled trial of finerenone in patients with HF and left ventricular ejection fraction≥40%. In this prespecified analysis, we assessed the risk of cardiovascular (CV) events and response to finerenone vs placebo in relation to the time from WHF to randomization (during or within 7days, 7days to 3months, >3months, or no prior WHF). The primary outcome was a composite of total (first and recurrent) WHF events and CV death, analyzed using a proportional rates method. Of 6,001 patients validly randomized to finerenone or placebo, 1,219 (20.3%) were enrolled during (749 [12.5%]) or within 7days (470 [7.8%]), 2,028 (33.8%) between 7days and 3months, and 937 (15.6%) >3months from a WHF event; 1,817 (30.3%) had no prior history of WHF. Rates of the primary composite outcome varied inversely with time since WHF, with >2-fold higher risk in those enrolled during or within 7days of WHF compared with those enrolled >3months from WHF or without prior WHF (risk ratio [RR]: 2.13; 95%CI: 1.82-2.55). Compared to placebo, finerenone appeared to lower the risk of the primary composite to a greater extent in those enrolled within 7days of WHF (RR: 0.74; 95%CI: 0.57-0.95) or between 7days and 3months of WHF (RR: 0.79; 95%CI: 0.64-0.97) than in those >3months from WHF or without prior WHF (RR: 0.99; 95%CI: 0.81-1.21); however, no definitive treatment-by-time interaction could be confirmed (P = 0.07). Greater absolute risk reductions with finerenone were accordingly seen in those with recent WHF (Ptrend=0.011). The risk of adverse events including hyperkalemia and worsening renal function among patients assigned to finerenone was not increased in those with recent WHF. Compared with those without recent WHF, patients with HF and mildly reduced or preserved ejection fraction who have experienced a recent WHF event are at higher risk for recurrent HF events and CV death; a possible signal of enhanced absolute treatment benefit with finerenone in this population requires further confirmation in future studies. (Study to Evaluate the Efficacy [Effect on Disease] and Safety of Finerenone on Morbidity [Events Indicating Disease Worsening] & Mortality [Death Rate] in Participants With HeartFailure and Left Ventricular Ejection Fraction [Proportion of Blood Expelled Per Heart Stroke] Greater or Equal to 40% [FINEARTS-HF], NCT04435626; A study to gather information on the influence of study drug finerenone on the number of deaths and hospitalizations in participants with heart failure EudraCT 2020-000306-29).