Mineralocorticoid Receptor Antagonists Research Articles

Aldosterone synthase inhibitors for cardiorenal protection: ready for prime time?

Background: Aldosterone, through its genomic and non-genomic effects, plays an important role in cardiovascular and renal injury. Steroidal mineralocorticoid receptor antagonists (MRAs) are fundamental to offset the aldosterone-mediated cardiorenal damage, but side effects may limit their use in a substantial proportion of patients. On the other hand, non-steroidal mineralocorticoid receptor antagonists (NS-MRA) showed improved selectivity and safety profile. However, interfering with the MRA could only partially inhibit aldosterone mediated effect both because of escaping mechanisms and potential non-genomic activity. Summary: Inhibiting aldosterone synthesis could be a promising strategy to abolish aldosterone-mediated cardiovascular side effects. Aldosterone is primarily synthesized by the CYP11B2 enzyme, which is very similar to CYP11B1, a key enzyme involved in glucocorticoid production. Lack of specificity for CYP11B2 and consequent off-target effects hampered the development of first-generation aldosterone synthase inhibitors (ASIs). The subsequent development of highly specific ASIs led to successful clinical trials in patients with resistant and uncontrolled hypertension. Key Messages: A recent randomized clinical trial showed a significant benefit of ASIs in patients with chronic kidney disease and albuminuria. However, further outcome based clinical trials are needed to confirm the promising role of ASIs in cardiorenal damage.

Finerenone, Serum Potassium, and Clinical Outcomes in Heart Failure With Mildly Reduced or Preserved Ejection Fraction.

Treatment with finerenone, a nonsteroidal mineralocorticoid receptor antagonist (MRA), improved outcomes in patients with heart failure with mildly reduced or preserved ejection fraction in FINEARTS-HF, but was associated with increased levels of serum potassium in follow-up. To investigate the frequency and predictors of serum potassium level greater than 5.5 mmol/L and less than 3.5 mmol/L and examine the treatment effect associated with finerenone, relative to placebo, on clinical outcomes based on postrandomization potassium levels. Secondary analysis of the FINEARTS-HF multicenter, randomized clinical trial, performed between September 14, 2020, and January 10, 2023, with a median follow-up of 32 months (final date of follow-up: June 14, 2024). Patients with heart failure and left ventricular ejection fraction greater than or equal to 40%, New York Heart Association class II to IV symptoms, and elevated natriuretic peptides were included. Participants received finerenone or placebo. The primary outcome was a composite of total worsening heart failure events or cardiovascular death. A total of 6001 participants were included (3003 randomized to receive finerenone and 2998 randomized to receive placebo). The increase in serum potassium was greater in the finerenone group than the placebo group at 1 month (median [IQR] difference, 0.19 [0.17-0.21] mmol/L) and 3 months (median [IQR] difference, 0.23 [0.21-0.25] mmol/L), which persisted for the remainder of trial follow-up. Finerenone increased the risks of potassium level increasing to greater than 5.5 mmol/L (hazard ratio [HR], 2.16 [95% CI, 1.83-2.56]; P < .001) and decreased the risks for potassium level decreasing to less than 3.5 mmol/L (HR, 0.46 [95% CI, 0.38-0.56]; P < .001). Both low (< 3.5 mmol/L; HR, 2.49 [95% CI, 1.8-3.43]) and high (>5.5 mmol/L; HR, 1.64 [95% CI, 1.04-2.58]) potassium levels were associated with higher subsequent risks of the primary outcome in both treatment groups. Nevertheless, the risk of the primary outcome was generally lower in patients treated with finerenone compared with placebo, even in those whose potassium level increased to greater than 5.5 mmol/L. In patients with heart failure with mildly reduced or preserved ejection fraction, finerenone resulted in more frequent hyperkalemia and less frequent hypokalemia. However, with protocol-directed surveillance and dose adjustment, clinical benefit associated with finerenone relative to placebo was maintained even in those whose potassium level increased to greater than 5.5 mmol/L. ClinicalTrials.gov Identifier: NCT04435626.

Antihypertensive effects and changes in extracellular water content by mineralocorticoid receptor antagonists in patients with primary aldosteronism.

In primary aldosteronism (PA), non-suppressible excessive aldosterone secretion due to dietary salt intake significantly contributes to hypertension and cardiovascular complications. Blocking the overactivation of mineralocorticoid receptors (MRs) with mineralocorticoid receptor antagonists (MRAs) is a cornerstone for the medical treatment of PA. However, the role of MRAs in controlling hypertension remains unclear. This study aimed to explore the relationship between changes in body composition parameters (determined by bioelectrical impedance analysis), blood pressure (BP) levels, serum potassium (K+) levels and Study 36-Item Short-Form Health Survey (SF-36) scores after MRA treatment in 50 patients with PA. Treatment with MRAs significantly decreased the systolic BP (SBP) and diastolic BP (DBP) levels and extracellular water (ECW) volume, while it increased the serum K+ levels, active renin concentrations (ARCs), and scores on several SF-36-based quality of life (QOL) subscales. ECW change (ΔECW) and serum K+ change were not significantly associated with changes in SBP and DBP levels. ΔECW showed a significant inverse correlation with ΔARC, suggesting that ARC increases with decreasing ECW volume due to renal MR activity blockade and that ARC is a highly sensitive indicator of ECW volume. In the stratified analysis of patients with PA, ECW volume was significantly decreased in those aged ≥60 years and those with a body mass index of ≥25 kg/m2. In conclusion, MRA treatment showed antihypertensive, biochemical, and QOL improvement effects in patients with PA. The antihypertensive effect may not be related to the decrease in ECW volume due to renal MR activity blockade. Evaluation of ECW using BIA in patients with PA treated with MRAs. Abbreviations: ARC, active renin concentration; BIA, bioelectrical impedance analysis; BMI, body mass index; BP, blood pressure; ECW, extracellular water; K+, serum potassium; MRA, mineralocorticoid receptor antagonist; PA, primary aldosteronism; QOL; quality of life; Δ, parameter changes after MRA treatment.

Effectiveness and safety of mineralocorticoid receptor antagonists in heart failure patients with and without diabetes: a systematic review and meta-analysis.

Mineralocorticoid receptor antagonists (MRAs) have been shown to improve outcomes in various populations of heart failure (HF) patients. However, the impact of concomitant diseases, such as diabetes mellitus (DM), on these outcomes remains unclear. This meta-analysis aimed to evaluate the efficacy and safety of MRAs in heart failure patients with and without diabetes mellitus. A systematic search was conducted on PubMed, Scopus, and Google Scholar databases up to April 30, 2024. Data analysis was performed using a random-effects model to account for variability across studies, and statistical analysis was carried out using Review Manager 5.4. Efficacy and safety parameters were evaluated in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. The meta-analysis included a total of 21,832 subjects from ten studies. The pooled results demonstrated that MRAs, compared to placebo, significantly reduced all-cause mortality in HF patients with and without DM (RR: 0.85; 95%CI 0.75-0.96; p = 0.009). A similar effect was observed in HF patients without DM (RR: 0.83; 95%CI 0.71-0.97; p = 0.02), while no significant effect was detected in the DM subgroup (RR: 0.87; 95%CI 0.69-1.11; p = 0.27). Both treatments had comparable effects on cardiovascular mortality in HF patients with and without DM (RR: 0.88; 95%CI 0.82-0.94; p = 0.0002), in HF patients with DM (RR: 0.90; 95%CI 0.81-1.01; p = 0.08), and in the non-DM subgroup (RR: 0.86; 95%CI 0.79-0.94; p = 0.0009). MRAs significantly reduced the risk of cardiovascular mortality in HF patients with and without DM (RR: 0.82; 95%CI 0.72-0.94; p = 0.005) and in HF patients with DM (RR: 0.79; 95%CI 0.63-0.98; p = 0.03), but no significant effect was observed in the non-DM subgroup (RR: 0.85; 95%CI 0.69-1.05; p = 0.13). Furthermore, compared to placebo, MRAs were associated with an increased risk of hyperkalemia (> 5.5 mEq/L) in HF patients with and without DM (RR: 1.63; 95%CI 1.18-2.24; p = 0.003), particularly in HF patients with DM (RR: 1.44; 95%CI 0.97-2.13; p = 0.07) and in the non-DM subgroup (RR: 1.87; 95%CI 1.34-2.61; p = 0.0002). MRAs are effective in reducing all-cause mortality, cardiovascular death, and cardiovascular mortality in heart failure patients. However, the use of MRAs is associated with an increased risk of hyperkalemia, necessitating careful monitoring, particularly in patients with diabetes mellitus.

Determining optimal pretreatment in cardiac surgery: an experimental study.

Heart failure patients with reduced ejection fraction are currently treated with four drug combinations: angiotensin receptor/neprilysin inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter 2 inhibitors, resulting in improved survival outcomes. Herein, we examined whether myocardial protection by esaxerenone or sacubitril/valsartan may present a counter-effect to the harm caused by cardioplegic arrest. Male Wistar rats fed a normal diet were orally administered esaxerenone (3mg/kg; Esax) or sacubitril/valsartan (68mg/kg; SaV) once a day for 2weeks from 6weeks of age. Age-matched, untreated male Wistar rats served as controls (Control). Isolated rat hearts were aerobically Langendorff-perfused and subjected to 2min of St Thomas' Hospital 2 cardioplegia (STH2) infusion and 28min of normothermic global ischemia followed by 60min of reperfusion. The recovery of function was measured during 60min of reperfusion. Additionally, troponin T levels were measured after reperfusion as myocardial injury. The final recovery of left ventricular developed pressure (presented as the percentage of preischemic value) in the Control, Esax, and SaV groups was 50.7 ± 6.2%, 68.5 ± 7.4%*, and 69.3 ± 14.3%*, respectively (*p < 0.05 vs. Control). Troponin T (ng per gram wet weight) levels in the Control, Esax, and SaV groups were 166.8 ± 78.1, 77.0 ± 14.6*, and 74.2 ± 36.6*, respectively (*p < 0.05 vs. Control). Oral administration of esaxerenone or sacubitril/valsartan to rats 2weeks prior to surgery enhanced the myocardial protection afforded by STH2 and may attenuate the myocardial injury caused by hyperkalemic cardioplegic arrest.

Molecular Mechanism of Finerenone in Treating Diabetic Nephropathy Based on Bioinformatics

Background: Diabetic Nephropathy (DN) is the leading cause of the end-stage renal disease (ESRD). Finerenone (with the molecular formula C21H22N4O3) is an oral non-steroidal mineralocorticoid antagonist (ns-MRA) that is both highly potent and has strong selectivity for the MR. At present, it has been used to treat DN. However, the molecular mechanism of finerenone in the treatment of diabetic nephropathy remains unclear. Objective: In this study, we employed bioinformatics approaches to investigate the molecular mechanism of finerenone as a novel therapeutic agent for the treatment of DN. Methods: We examined a number of databases, including GEO, DisGeNET, Genecards, and OMIM, to find putative genes linked to DN. We then employed the PubChem database and PharmMapper service platform to identify targets of finerenone. Further analysis was conducted using the DAVID database for enrichment analysis and the STRING database for protein-protein interaction (PPI) networks. Molecular docking (MD) was performed using AutoDockTools software, and results were visualized using PyMOL software. Results: In total, we identified 82 drug-disease targets, primarily associated with lipid and atherosclerosis, diabetic cardiomyopathy, MAPK signaling pathway, and PI3K-Akt signaling pathway. Our PPI network analysis and docking studies demonstrated good binding ability of finerenone to specific targets such as AKT1, MMP-9, IGF1, EGFR, CASP3, PPARG, ESR1, MMP-2, and KDR. Conclusion: Finerenone has the potential to reduce the progression of DN through various pathways, including lipid and atherosclerosis, diabetic cardiomyopathy, MAPK signaling pathway, and PI3KAkt signaling pathway. Moreover, it could exert anti-inflammatory and antifibrotic effects on specific targets, such as AKT1, MMP-9, IGF1, EGFR, CASP3, PPARG, ESR1, MMP-2, and KDR.

The potential for improving cardio-renal outcomes in chronic kidney disease with the aldosterone synthase inhibitor vicadrostat (BI 690517): a rationale for the EASi-KIDNEY trial.

Patients with chronic kidney disease (CKD) are at risk of progressive loss of kidney function, heart failure, and cardiovascular death despite current proven therapies, including renin-angiotensin system inhibitors (RASi), sodium glucose co-transporter-2 inhibitors (SGLT2i), and statin-based regimens. RASi and SGLT2i reduce risk of CKD progression irrespective of primary cause of kidney disease, suggesting they target final common pathways. Targeting aldosterone overactivity with a nonsteroidal mineralocorticoid receptor antagonist (MRA) also reduces cardiorenal risk in patients with albuminuric diabetic kidney disease already treated with RASi. Together, these observations provide the rationale for trials to assess effects of inhibiting the aldosterone pathway in a broader range of patients with CKD, including those with non-diabetic causes of CKD or low albuminuria. Aldosterone synthase inhibitors (ASi) have emerged as an alternative to MRAs for aldosterone pathway inhibition. Phase II data from 586 patients with albuminuric CKD have shown that 10 mg of an ASi, vicadrostat (BI 690517), reduced urine albumin-to-creatinine ratio by ∼40% compared to placebo with or without concurrent empagliflozin treatment. MRA and ASi increase risk of hyperkalaemia. Combining their use with an SGLT2i may mitigate some of this risk, improving tolerability, and allowing a wider range of patients to be treated (including those with higher levels of blood potassium than in previous trials). The EASi-KIDNEY (NCT06531824) double-blind placebo-controlled trial will test this approach by assessing the safety and cardiorenal efficacy of vicadrostat in combination with empagliflozin in ∼11,000 patients with CKD. It will be sufficiently large to assess effects in patients with and without diabetes separately.

Abstract 4136009: Adherence and Persistence to Guideline-Directed Medical Therapy in Patients with Heart Failure: A Systematic Review and Meta-Analysis

Introduction: Since individual adherence/persistence studies for heart failure (HF) guideline-directed medical therapy (GDMT) have mainly focused on single classes or had limited sample sizes, providing inconclusive estimates, a comprehensive analysis is needed to understand the magnitude of the problem. Hypothesis: Adherence and persistence to HF GDMT are suboptimal and are associated with increased risks of HF admission and mortality. Aims: To generate estimates of real-world HF medication adherence and persistence and associated clinical outcomes. Methods: We conducted a systematic review and meta-analysis, searching PubMed, EMBASE, and CINAHL for observational studies on adherence and persistence in HF GDMT from inception to 9/25/23. We evaluated bias using the Newcastle-Ottawa Scale. Primary outcomes were adherence and persistence rates using a restricted maximum-likelihood model. Adherence was summarized as the mean proportion of days covered (PDC) and medication possession ratio (MPR), proportion of patients with good adherence (PDC/MPR≥80%), and persistence. Secondary outcomes were all-cause mortality and HF readmission with summary hazard ratios (HRs) and 95% confidence intervals (CI) estimated. Heterogeneity and publication bias were assessed using Cochran’s Q, I squared statistics, funnel plots, and Egger's tests, while subgroup analyses explored variations across studies. Results: The 48 studies included comprised 1,614,985 patients (mean age 71; 57% men). The overall mean PDC/MPR was 76%, with good adherence of 54%, and persistence rates of 60%. Renin-angiotensin-aldosterone system inhibitors had the highest mean PDC/MPR of 78%, good adherence of 56%, and persistence of 64%, while mineralocorticoid receptor antagonists (MRAs) had the lowest at 71%, 47%, and 49% respectively. Nonadherence/nonpersistence to GDMT was associated with a higher rate of mortality (HR 1.27 [95% CI 1.19–1.35]) and HF admission (HR 1.25 [95% CI 1.14-1.37]). Conclusions: Suboptimal adherence/persistence to HF GDMT is common, with only half of patients showing good adherence. Given the association with worse clinical outcomes, clinicians should prioritize identifying barriers to and addressing nonadherence/nonpersistence to HF GDMT, particularly with MRAs.

Abstract 4119908: Outcomes for heart failure patients with reduced ejection fraction attending emergency department and discharged within 24 hours versus those admitted patients in heart failure unit.

Introduction: Heart failure (HF) is a clinical syndrome with increasing prevalence. Currently, there are extensive evidence-based therapies targeted at managing patients with heart failure and reduced ejection fraction (HFrEF) to improve outcomes. The National Heart Failure Audit shows the quality of inpatient care (specialist review, discharge medication etc) is related to outcome. This study aimed to evaluate the current practice at a London tertiary centre hospital in managing patients with heart failure and compared outcomes in patients who had a short course of admission (less than 1 day) with those who had a more prolonged course of admission. Method: Retrospective data was collected from a London tertiary centre hospital database for consecutive patients from Sep/2022 till Sep/2023. Statistical analysis was performed using Chi-Square test. The eligibility criteria included a new or previous diagnosis of HF with left ventricular ejection fraction (LVEF) &lt; 40%. Patients were divided into two groups: Group A included 40 eligible patients who were admitted and discharged from the emergency department (ED) within 24 hours. Group B included 37 eligible patients who were admitted and discharged from the dedicated heart failure unit after 10-15 days of hospital admission. Results: In Group A, prescribing guideline-directed medical therapy (GDMT) was lower compared to Group B; Renin-Angiotensin-Aldosterone Inhibitors (47.50% vs. 94.59%), beta blockers (55% vs. 91.89%), mineralocorticoid receptor antagonists (12.50 %vs. 94.59%), and sodium-glucose co-transporter 2 inhibitors (15% vs. 89.19%). More patients in Group B received all four pillars of GDMT (86.49%) compared to Group A (5%). At 6-month follow-up,18.75% were on 4 GDMT in Group A versus 92% in group Group B. Re-admission within 6 months was higher in Group A (30%) compared to Group B (16.22%); however, the difference was not statistically significant (P value: 0.153). Higher mortality rates were observed in Group A (mortality rate: 20%) compared to Group B (mortality rate: 2.70%), with statistical significance (P value: 0.018). Conclusion: This study showed that HFrEF patients admitted to a specialist heart failure unit achieve higher rates of GDMT and have significantly improved outcomes compared to those who had a shorter inpatient stay and discharged from the emergency department. These findings underscore the high risks associated with rapid discharge from hospital on incomplete medical therapy.

Evidence for Aldosterone Antagonism in Heart Failure

Activation of the renin–angiotensin–aldosterone system is the ultimate pathophysiological hallmark in heart failure. Though aldosterone primarily appears to regulate electrolyte homeostasis by acting on distal nephrons in the kidneys, its effects are far-reaching across the cardiovascular system as its receptors are also expressed in vascular smooth muscle cells, endothelial cells, macrophages and cardiomyocytes. Aldosterone excess leads to vascular stiffness, vasoconstriction, endothelial dysfunction, inflammation, oxidative stress, cardiac fibrosis and hypertrophy, atherogenesis and thrombosis. Hence, aldosterone antagonism is an attractive proposition for heart failure management. The first-generation non-selective mineralocorticoid receptor antagonist spironolactone produced a spectacular reduction of cardiovascular outcomes in the seminal RALES study, while the selective second-generation congener eplerenone boasts two positive studies: EPHESUS and EMPHASIS-HF. The TOPCAT trial indicated that a specific subgroup of patients with heart failure with preserved ejection fraction may benefit from targeted therapy of mineralocorticoid receptor antagonists. Newer-generation non-steroidal mineralocorticoid antagonists and aldosterone synthase inhibitors are being evaluated in randomised trials.

Abstract 4138662: Mineralocorticoid receptor antagonist in patients with acute myocardial infarction: An updated systematic review and meta-analysis of randomized trials

Background: While mineralocorticoid antagonists (MRA) reduce mortality in patients developing heart failure post myocardial infarction (MI), it is unclear whether they are beneficial in an unselected post-MI population. Aims: Using a systematic review and meta-analysis, we aim to determine the effect of MRA treatment versus no MRA treatment on all-cause mortality in unselected post-MI patients from randomized data, simultaneously with the presentation of the largest randomized controlled trial on the topic, the CLEAR SYNERGY trial. Methods/Approach: We completed a systematic review of all randomized controlled trials comparing MRA treatment to no MRA treatment in post-MI patients. We will perform our primary analysis using fixed effects with the Peto odds ratio method and use random effects as a sensitivity analysis. The primary outcome will be all-cause mortality, and secondary outcomes will include cardiovascular mortality, new or worsening heart failure, recurrent myocardial infarction and stroke. Results/Data: Our systematic review of Pubmed, Embase, and CENTRAL from inception until April 30, 2024, yielded 456 records. A total of 11,199 participants from 11 randomized clinical trials will be included in addition to the late-breaking CLEAR SYNERGY trial. The CLEAR SYNERGY trial is a 2 x 2 factorial randomized controlled trial of low-dose colchicine 0.5mg daily versus placebo and spironolactone 25mg daily versus placebo in 7,062 post-MI patients who were within 72h of the index percutaneous coronary intervention. The results of the spironolactone factorial will be presented in the fall of 2024 with an expected median follow-up of 3.5 years. As the investigators of the CLEAR SYNERGY trial, we will combine our data with the other 11 trials for a total of 12 trials and 18,261 participants. Conclusions: CLEAR SYNERGY is the largest randomized controlled trial with the longest follow-up of spironolactone in the post-MI population. Our meta-analysis will provide updated effect estimates of post-MI MRA treatment, leveraging the late-breaking CLEAR SYNERGY data to reflect the totality of the evidence.

Abstract 4139191: ETX-258 - A GalOmic™ siRNA for the Treatment of Heart Failure Following Myocardial Infarction

Introduction: Heart failure with reduced ejection fraction (HFrEF) remains a significant clinical challenge, evidenced by high hospitalization rates and five-year mortality. Current treatments are limited by side effects, poor patient compliance, and the necessity for gradual drug titration. These challenges highlight the need for new therapies that are both safe and effective in targeting the structural remodeling pivotal to disease progression post-myocardial infarction (MI). e-therapeutics (ETX) uniquely combines computation and RNAi to discover life-transforming medicines. ETX’s RNAi platform, GalOmic™, enables generation of specific, potent, and long-acting siRNA therapies that effectively silence novel gene targets in hepatocytes. This highly specific mechanism of action limits unwanted side effects, positioning it as a promising approach to HFrEF treatment. Methods: Potent siRNAs against a hepatic target with cardioprotective potential were designed in silico. Candidate siRNAs were screened in vitro in HEK293 cells and in vivo in C57BL/6J mice to select the lead GalOmic™ siRNA, ETX-258. MI was induced by ligation of the left anterior descending artery in C57BL/6J mice after which ETX-258 was injected subcutaneously weekly for 6 weeks. Eplerenone, a mineralocorticoid receptor antagonist which is part of the current treatment regimen for HFrEF, was used as a comparator. Cardiac function was assessed by echocardiography at 2-, 4- and 6-weeks post-MI. Cardiac damage and structural remodeling were evaluated using circulating biomarkers of cardiac function and histological assessment. Results: ETX-258 was selected as a highly active siRNA for the treatment of heart failure with a long duration of action. Post-MI treatment with ETX-258 significantly improved key echocardiographic parameters of cardiac function, including ejection fraction and total cardiac output, achieving results comparable to eplerenone. Additionally, both structural cardiac parameters and markers of damage and remodeling showed significant improvements, reaching similar levels in both ETX-258 and eplerenone-treated mice. Conclusions: High unmet need remains for HFrEF patients despite existing therapies. These results highlight the potential of ETX-258 to improve cardiac function and pathogenic structural remodeling post-MI. This, paired with the long duration of action and favorable safety profile of GalOmic™ siRNAs, makes ETX-258 a promising candidate for further clinical development.

Abstract 4132062: Early changes in albuminuria and their interaction with eplerenone treatment in patients hospitalized for acute heart failure: findings from the EARLIER trial

Background: Patients hospitalized for acute heart failure (AHF) have high degrees of congestion, which may be associated with albuminuria. Mineralocorticoid receptor antagonists (MRAs) have natriuretic effects, possibly diminishing the degree of albuminuria. However, early changes in albuminuria, their prognostic value and interaction with MRA therapy remain unclear in AHF. Methods: The EARLIER trial included patients with AHF who were randomized to receive eplerenone or placebo over 6 months. Urine albumin-to-creatinine ratio (UACR) at admission and week 1 were measured, and Cox proportional hazards models were used for analyses. Results: Among 296 patients (mean age, 67±13years; 72% male), median B-type natriuretic peptide was 386 (190-660) pg/ml, and mean left ventricular ejection fraction was 30±8%. Patients with an UACR of ≥30 mg/g at admission had more severe congestion and poorer exercise capacity compared to those without (all-P&lt;0.01). From admission to week 1, UACR levels significantly decreased (P&lt;0.01), without significant differences between treatment groups (P&gt;0.10). UACR levels at both admission (adjusted-HR [95% CI]=1.23 [1.03-1.47]) and week 1 (adjusted-HR [95% CI]=1.23 [1.01-1.50]) were associated with the risk of cardiovascular death and hospitalization. Additionally, eplerenone vs. placebo reduced the risk of a composite of all-cause mortality, HF re-hospitalization, investigator-reported worsening HF, and/or out-of-hospital diuretic intensification (HR [95% CI]= 0.53 [0.29-0.97]), irrespective of the severity of albuminuria (P-for-interaction&gt;0.10). Conclusion: In patients with AHF, the degree of albuminuria at both admission and week 1 was associated with post-discharge prognosis. Although eplerenone did not reduce albuminuria levels, the benefit from eplerenone was consistent regardless of the albuminuria severity.

Abstract 4122650: 1-year comparison of quadruple therapy sequencing strategies for heart failure with reduced ejection fraction using an individual-based state-transition microsimulation model

Introduction: Guidelines recommend quadruple therapy (angiotensin receptor blocker-neprilysin inhibitor [ARNI]), beta-blocker, mineralocorticoid receptor antagonist (MRA), and sodium-glucose co-transporter 2 inhibitor [SGLT2I]) as the cornerstone of heart failure (HF) with reduced ejection fraction (HFrEF) management. Yet, guidelines do not propose a specific order of initiation and titration (or “sequencing strategy”) of these agents, due to the absence of trial evidence. Aims: To model the 1-year efficacy and harms of proposed HFrEF quadruple therapy sequencing strategies using a microsimulation model. Methods: We conducted an individual-based state-transition microsimulation modeling study to compare the 1-year cumulative incidence of death, total HF hospitalization, and adverse events with 6 different HFrEF medication sequencing strategies (emulating 2 different traditional strategies, 2 two-drug combinations, a "cluster" strategy, and four-drug "simultaneous" strategy), each with two versions (weekly or biweekly medication adjustments), applied to treatment-naïve outpatients with HFrEF. We modeled death as an incidence at 1 year, and total HF hospitalization (first and recurrent events) and adverse events (bradycardia, hyperkalemia, hypotension, and renal impairment) as incidence rates per 100 patient-years. Results: At 1 year, an estimated 15.5% died without treatment compared to 6.9% with the traditional sequence adjusted biweekly, and 5.2-6.3% with other sequencing strategies. Similarly, the HF hospitalization rate decreased from 32.8 per 100 patient-years with no treatment to 11.1 per 100 patient-years traditional sequencing adjusted biweekly, and 6.9-9 per 100 patient-years with other strategies. The incidence rates of medication-related adverse events per 100 patient-years were: hypotension (5.8-6.9), renal impairment (4.6-6.0), bradycardia (2.9-3.2), and hyperkalemia (approximately 0.5). Conclusions: For treatment-naïve outpatients with HFrEF, pharmacotherapy sequencing strategies that started 2 to 4 medications on the first visit reduced the risk of death and hospitalization at 1 year compared to a traditional sequencing strategy. Weekly medication adjustments did not outperform biweekly adjustments when &gt;=2 medications were started on the initial visit. These findings can inform clinicians and policymakers in developing HFrEF medication optimization programs with sequencing strategy protocols that fit the local practical context.

Abstract 4138745: Blockade of Mineralocorticoid Receptor by Esaxerenone Improves Insulin Sensitivity in Obese Mice

Background: Aldosterone regulates blood pressure and electrolyte balance. However, overactivation of the mineralocorticoid receptor (MR) and elevated aldosterone levels are implicated in the pathogenesis of cardiometabolic disorders, though the underlying mechanisms are not fully understood. In this study, we investigated whether a novel, non-steroidal selective MR blocker, esaxerenone, ameliorates the development of metabolic disorders in obese mice models and examined the underlying mechanism. Methods: Esaxerenone (3 mg/kg/day) was orally administered to high-fat diet (HFD)-fed C57BL/6J or normal chow-fed db/db mice. Metabolic parameters, tissue morphology, and effects of esaxerenone on insulin sensitivity were assessed. Gene expression and insulin signaling, determined by Akt phosphorylation, were examined using quantitative RT-PCR and western blotting, respectively. In in-vitro experiments, insulin targets cell lines such as 3T3-L1 adipocytes, HepG2 cells, and C2C12 myotubes were used. Insulin-responsive cells were treated with 10 nM or 100 nM esaxerenone or eplerenone for 30 minutes before 4-hour 1000 nM aldosterone stimulation. Insulin signaling was assessed 15 minutes after stimulation with 17 nM insulin. Results: Esaxerenone improved insulin sensitivity (P&lt;0.05) without altering metabolic parameters in HFD-induced obese and db/db mice. Esaxerenone suppressed fat accumulation, adipocyte size, and liver lipid droplets compared with the vehicle-treated group (P&lt;0.01). In adipose tissue, esaxerenone reduced macrophage infiltration (P&lt;0.01) and the expression of inflammatory molecules (P&lt;0.05). In in-vitro experiments, aldosterone significantly decreased the expression levels of PPARγ and adiponectin in 3T3-L1 adipocytes. Moreover, aldosterone attenuated insulin-induced Akt phosphorylation in 3T3-L1 adipocytes, HepG2 cells, and C2C12 myotubes in a dose-dependent manner (P&lt;0.01). Pretreatment with esaxerenone reversed the effect of aldosterone, whereas eplerenone, an MR antagonist, did not show a similar effect at the same dose. Conclusion: Inhibition of MR by esaxerenone improved insulin sensitivity in HFD-induced obese and genetically diabetic mice. The reduction of inflammation and fat accumulation and enhancement of insulin signaling were suggested to be underlying mechanisms. Esaxerenone might be a beneficial therapeutic approach for managing metabolic disorders.

Abstract 4126262: The impact of angiotensin receptor neprilysin inhibitors on the elderly population with heart failure and reduced ejection fraction: data from the real world

Heart failure (HF) remains a disease of increasing prevalence and morbidity. Validation of new lines of therapy in the elderly are required due to the progressive ageing of the world's population and scarce evidence in elderly patients with HF with reduced ejection fraction (HFrEF). The purpose of our study is to analyse the effect of Angiotensin Receptor–Neprilysin Inhibitors (ARNI) in this subgroup of patients. We conducted a single-centre, real-world observational study. We consecutively enrolled all patients aged ≥75 years diagnosed with HFrEF (defined as an ejection fraction &lt;40%) and theorical indication for treatment with ARNI from November 2019 to January 2021. The main outcomes analysed were all cause mortality and admission due to HF. In order to avoid potential confounding factors, we performed a propensity-score (PS) matched analysis. Patients matching was performed in a 1:1 ratio with the nearest neighbour method. A total of 364 patients were recruited (total population). The mean age was 84.1 years of which 67% were male. 81% were hypertensive and 33.5% diabetic. The main cause of ventricular dysfunction was ischemic with 50.2%. At inclusion 55.8% were in NYHA functional class II and the mean LVEF was 29.8%. After PS matching, we selected 184 patients (study population), 92 with ARNI. As compared with non ARNI group, the ARNI patients showed higher use of mineralocorticoid receptor antagonists (MRA) (59.8% vs 43.5%, p&lt; 0.05) and SGLT2 inhibitors (40.2% vs 6%, p&lt;0.05). Other treatments were otherwise similar in both groups. There were not significant differences in relation with age, etiology or comorbidities between ARNI group and non-ARNI group. During a median follow-up of 39 months, total mortality was 31.5% (58 patients). After a Cox logistic regression analysis, ARNI therapy was shown to be an independent protective variable with respect to total mortality [HR 0.6 (0.4-1), p 0.05]. The figure shows the Kaplan-Meier survival curves for total mortality in patients with and without ARNI treatment. In summary, treatment of HFrEF remains a significant challenge in managing HF patients, especially in the elderly. According to our data, treatment with ARNI in elderly patients with HFrEF was associated with a lower rate of all-cause mortality. Our data show us that ARNI therapy could improve prognosis in the elderly with HFrEF in a real-world study.

Abstract 4125999: Elderly patients with HF with reduced ejection fraction and renal failure: are SGLT2i a good option?

SGLT-2 receptor inhibitors (SGLT-2i) have been shown to reduce cardiovascular mortality and hospitalisations for heart failure (HF) in patients with HF with reduced ejection fraction (HFrEF) and to have a nephroprotective role in patients with chronic kidney disease (CKD). However, the available evidence in patients older than 75 years and with CKD is limited. We conducted a retrospective, single-centre study including patients aged &gt;75 years diagnosed with HFrEF (defined as ejection fraction &lt;40%), CKD (eGFR &lt;60mL/min) and with an indication for treatment with SGLT-2i for HF between November 2019 and November 2022. Clinical, analytical, electrocardiographic and echocardiographic variables were collected. A total of 173 patients were included with a mean follow-up of 31.6 months (SD ±13.2). Mean age 84.7 years (SD ±4.9), 66.5% were male, 85.5% were hypertensive, 34.7% diabetic and 39.3% dyslipidaemic. Peripheral vascular disease was present in 11.6%. Mean glomerular filtration rate was 45.9 mL/min and only 2.3% were on haemodialysis. LVEF at inclusion was 29.5% (SD ±7.9), with 53.1% being of ischaemic aetiology and the most frequent functional class being NYHA II (53.2%). Thirty-seven percent had atrial fibrillation and 34.1% had complete left bundle branch block. At the end of follow-up 80.3% were on beta-blockers, 48.6% on ACE inhibitors, 37.6% on aldosterone antagonists, 23.7% on ARNI and only 11% on SGLT-2i. Survival analysis was performed using Cox logistic regression (multivariate analysis), where SGLT-2i was shown to be the only protective factor for all-cause mortality (HR 0.3 [0.1-0.9]). Male sex (HR 2.2 [1.3-3.9]) and diabetes (HR 1.6 [1.0-2.6]) were associated with higher mortality. The attached figure (figure 1) shows the Kaplan-Meier survival curves for total mortality in those patients with and without SGLT-2i (p log-rank 0.05). In our population, SGLT2i showed a significant reduction in total mortality in patients older than 75 years, with HFrEF and CKD. However, the treatment rate in this subgroup of patients is very low. Further implementation of SGLT2i treatment in this type of patient could be of significant clinical and prognostic benefit.

Social Determinants of Health and Disparities in Guideline-Directed Medical Therapy Optimization for Heart Failure.

Fewer than 20% of eligible patients with heart failure with reduced ejection fraction receive all 4 pillars of guideline-directed medical therapy. Understanding disparities by race, ethnicity, sex, and adverse social determinants of health is necessary to equitably optimize quadruple therapy. Utilizing the American Heart Association's Get With The Guidelines-Heart Failure registry, we examined associations between race and ethnicity, sex, and adverse social determinants of health (insurance type and documented social need [any barrier to accessing health care]) with quadruple therapy optimization (QTO) in patients with heart failure with reduced ejection fraction hospitalized between July 1, 2021, and September 30, 2023, with complete medication data at discharge. We calculated adjusted mean differences (AMDs) in the discharge QTO score (range, 0%-100%) reflecting the proportion of eligible use of renin-angiotensin system inhibitors, β-blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter-2 inhibitors and compared across demographic and adverse social determinants of health groups. Among 82 637 patients (median age, 66 years; 32.5% female; 57.0% non-Hispanic White; 76.4% prior heart failure with reduced ejection fraction), the overall mean QTO score was 56.2% (SD, 25.5). After adjustment, compared with non-Hispanic White individuals, Black (AMD, 2.56 percentage points [95% CI, 2.16-2.96]) and Hispanic individuals (AMD, 0.71 percentage points [95% CI, 0.11-1.31]) had higher QTO scores. Females had higher QTO scores than males (AMD, 1.94 percentage points [95% CI, 1.58-2.31]). Patients with no insurance (AMD, -4.90 percentage points [-5.62 to -4.17]), Medicaid (AMD, -0.45 percentage points [-0.89 to -0.01]), and Medicare (AMD, -1.64 percentage points [-2.10 to -1.18]) had lower QTO scores versus private insurance. Those with an identified social need (n=24 651) had lower QTO scores than those without (AMD, -3.40 percentage points [95% CI, -4.10 to -2.71]). Disparities in QTO were most evident for patients with no insurance, Medicaid, Medicare, or potentially an identified social need. Future efforts should focus on reducing gaps to improve equitable guideline-directed medical therapy use.

Autonomous cortisol secretion promotes vascular calcification in vivo and in vitro under hyperaldosteronism.

Autonomous cortisol secretion (ACS) is not uncommon in patients with primary aldosteronism (PA). However, the cardiovascular burden of ACS due to its dysregulated cortisol secretion remains poorly understood. Thus, we examined the effects of ACS on vascular calcification in a hyperaldosteronism environment in vitro and in vivo. A total of 339 patients with PA with adrenal incidentaloma and low-dose dexamethasone suppression test data (cutoff level: cortisol > 1.8 μg/dL) from a prospectively maintained database were enrolled; abdominal aortic calcification (AAC) scores were quantitatively estimated. Human aortic smooth muscle cells (HAOSMCs) were used as in vitro model of vascular calcification. In this study, 65 of the 339 patients with PA had ACS; 274 did not. Patients with PA/ACS had a higher AAC score (1171.0 ± 2434.0 vs. 489.5 ± 1085.3, P = 0.012) than patients without ACS. ACS was independently associated with AAC score (β = 0.139, P = 0.004) in multivariate analysis, and post-suppression cortisol level was significantly correlated with the AAC score (P = 0.004). In the HAOSMC model, co-treatment with cortisol synergistically stimulated alkaline phosphatase activity and calcium deposition in a hyperaldosteronism environment. The stimulatory effect of cortisol was abolished by the mineralocorticoid receptor (MR) antagonist eplerenone, but not glucocorticoid receptor antagonist mifepristone, indicating a MR-dependent mechanism. In conclusion, the presence of ACS is associated with heavier vascular calcification in patients with PA. Aldosterone and cortisol synergistically activate HAOSMC calcification via MR signaling, via a process that can be attenuated by eplerenone.

Mineralocorticoid Receptor in Endothelial Cells Contributes to VEGF Receptor Inhibitor-Induced Vascular and Kidney Damage.

Vascular endothelial growth factor receptor inhibitors (VEGFRis) improve cancer patient survival by inhibiting tumor angiogenesis. However, VEGFRis induce treatment-limiting hypertension which has been associated with impaired vascular endothelial cell (EC) function and kidney damage. The mineralocorticoid receptor (MR) regulates blood pressure via effects on the vasculature and the kidney. Thus, we interrogated the role of the MR in EC dysfunction, renal impairment, and hypertension in a mouse model of VEGFRi-induced hypertension using sorafenib. EC dysfunction in mesenteric arterioles was assessed by immunoblotting for phosphorylation of endothelial nitric oxide synthase (eNOS) at serine 1177. Renal damage was measured by assessing glomerular endotheliosis histologically. Blood pressure (BP) was measured using implanted radiotelemetry. Six days of sorafenib treatment significantly impaired mesenteric resistance vessel EC function, induced renal damage, and increased BP. Pharmacologic MR blockade with spironolactone prevented the sorafenib-induced decline in eNOS phosphorylation and the renal glomerular endotheliosis, without affecting systolic or diastolic BP. Mice with the MR knocked out specifically in ECs (EC-MR-KO) were protected from sorafenib-induced EC dysfunction and glomerular endotheliosis, whereas smooth muscle cell-specific MR (SMC-MR) knockout mice were not. Neither EC-MR knockout nor SMC-MR knockout affected the degree to which sorafenib increased systolic or diastolic BP. These results reveal that the MR, specifically in EC but not in SMCs, is necessary for VEGFRi-induced renal and vascular injury. While ineffective at lowering SBP, these data suggest potential therapeutic benefits of MR antagonists, like spironolactone, to protect the vasculature and the kidneys from VEGFRi-induced injury.