Mineralocorticoid Receptor Antagonist Treatment Research Articles

Mineralocorticoid Receptor Antagonists in Patients With HeartFailure and ImpairedRenalFunction.

Kidney dysfunction often leads to reluctance to start or continue life-saving heart failure (HF) therapy. This study sought to examine the efficacy and safety of mineralocorticoid receptor antagonists (MRAs) in patients with HF with reduced ejection fraction experiencing significant kidney dysfunction. We pooled individual patient data from the RALES (Randomized Aldactone Evaluation Study) and EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in HeartFailure) trials. The association between MRA treatment and outcomes was assessed according to whether the estimated glomerular filtration rate (eGFR) declined to<30mL/min/1.73m2 or not. The primary outcome was cardiovascular death or HF hospitalization. Among 4,355 patients included, 295 (6.8%) experienced a deterioration of eGFR after randomization to<30mL/min/1.73m2. These patients had more impaired baseline cardiac and kidney function (eGFR 47.3 ± 13.4mL/min/1.73m2 vs 70.5 ± 21.8mL/min/1.73m2) and had a higher risk of the primary outcome than patients without eGFR deterioration (HR: 2.49; 95%CI: 2.01-3.08; P< 0.001). However, the risk reduction in the primary outcome with MRA therapy was similar in those who experienced a decrease in eGFR to<30mL/min/1.73m2 (HR: 0.65; 95%CI: 0.43-0.99) compared with those who did not (HR: 0.63; 95%CI: 0.56-0.71) (Pinteraction=0.87). In patients with a decrease in eGFR to<30mL/min/1.73m2, 21 fewer individuals (per 100 person-years) experienced the primary outcome with MRA treatment, vs placebo, compared with an excess of 3 more patients with severe hyperkalemia (>6.0mmol/L). Because patients experiencing a decrease in eGFR to<30mL/min/1.73m2 are at very high risk, the absolute risk reduction with an MRA in these patients is large and this decline in eGFR should not automatically lead to treatment discontinuation.

Subtype Identification of Surgically Curable Primary Aldosteronism During Treatment With Mineralocorticoid Receptor Blockade.

Current guidelines and consensus documents recommend withdrawal of mineralocorticoid receptor antagonists (MRAs) before primary aldosteronism (PA) subtyping by adrenal vein sampling (AVS), but this practice can cause severe hypokalemia and uncontrolled high blood pressure. Our aim was to investigate if unilateral PA can be identified by AVS during MRA treatment. We compared the rate of unilateral PA identification between patients with and without MRA treatment in large data sets of patients submitted to AVS while off renin-angiotensin system blockers and β-blockers. In sensitivity analyses, the between-group differences of lateralization index values after propensity score matching and the rate of unilateral PA identification in subgroups with undetectable (≤2 mUI/L), suppressed (<8.2 mUI/L), and unsuppressed (≥8.2 mUI/L) direct renin concentration levels were also evaluated. Plasma aldosterone concentration, direct renin concentration, and blood pressure values were similar in non-MRA-treated (n=779) and MRA-treated (n=61) patients with PA, but the latter required more antihypertensive agents (P=0.001) and showed a higher rate of adrenal nodules (82% versus 67%; P=0.022) and adrenalectomy (72% versus 54%; P=0.01). However, they exhibited no significant differences in commonly used AVS indices and the area under the receiving operating characteristic curve of lateralization index, both under unstimulated conditions and postcosyntropin. Several sensitivity analyses confirmed these results in propensity score matching adjusted models and in patients with undetectable, or suppressed or unsuppressed renin levels. At doses that controlled blood pressure and potassium levels, MRAs did not preclude the identification of unilateral PA at AVS. URL: https://www.clinicaltrials.gov; Unique identifier: NCT01234220.

Effect of Heart Failure Pharmacotherapies in Patients with Heart Failure with Mildly Reduced Ejection Fraction.

The study sought to comprehensively investigate the effect of heart failure (HF) pharmacotherapies in patients with heart failure with mildly reduced ejection fraction (HFmrEF). In the absence of randomized controlled trials, guideline recommendations concerning HF-related therapies in patients with HFmrEF are limited. Consecutive patients hospitalized with HFmrEF were retrospectively included at one institution from 2016 to 2022. The prognostic value of treatment with beta-blockers (BB), angiotensin-converting enzyme inhibitors, receptor blockers or receptor-neprilysin inhibitor (ACEi/ARB/ARNI), mineralocorticoid receptor antagonists (MRA) and sodium-glucose transport protein 2 inhibitors (SGLT2i) was investigated for all-cause mortality at 30 months (median follow-up) and HF-related rehospitalization. 2,109 patients with HFmrEF were included. Treatment with BB (27.0% vs. 35%; HR = 0.737; 95% CI 0.617-0.881; p = 0.001), ACEi/ARB/ARNI (25.9% vs. 37.6%; HR = 0.612; 95% CI 0.517-0.725; p = 0.001) and SGLT2i (11.9% vs. 29.5%; HR = 0.441; 95% CI 0.236-0.824; p = 0.010) was associated with lower risk of 30-months all-cause mortality, which was still demonstrated after multivariable adjustment and propensity score matching. In contrast, MRA treatment was not associated with long-term prognosis. The risk of HF-related rehospitalization was not affected by HF pharmacotherapies. Finally, the lowest risk of long-term all-cause mortality was observed in patients with combined use of BB, ACEi/ARB/ARNI and SGLT2i (HR = 0.456; 95% CI 0.227-0.916; p = 0.027). BB, ACEi/ARB/ARNI and SGLT2i were independently associated with lower risk of all-cause mortality in patients with HFmrEF, specifically when applied as combined "HF triple therapy". Randomized studies are needed to investigate the effect of HF-related pharmacotherapies in patients with HFmrEF.

Real-world effectiveness of mineralocorticoid receptor antagonists in heart failure with reduced ejection fraction: a retrospective, non-interventional cohort analysis

Background and purpose: Mineralocorticoid receptor antagonists (MRAs) have been shown in clinical trials to improve outcomes in heart failure with reduced ejection fraction (HFrEF). Yet, it is still uncertain how effective they are in real-world patients with HFrEF. This study aimed to investigate the association between MRAs and outcomes in the overall population and a propensity score-matched cohort, based on patient-level data from the Swedish Heart Failure Registry (SwedeHF). Methods: Patients diagnosed with HFrEF were included from the SwedeHF spanning from 2003 to 2020. Enrollment was based on medication dispensation within 3 months before and 6 months after the index date recorded in the register. Endpoints included all-cause mortality, cardiovascular death, and hospital re-admissions, tracked from the index date until censoring or occurrence of an event. Results: Of 47,103 patients identified through the SwedeHF with HFrEF, 22,368 individuals were not treated with MRA (referred to as MRA naive patients), 21,893 were treated with MRA at a dosage of 25 mg, and 1,423 were treated with MRA at 50 mg once daily. In the overall cohort, the administration of MRA at 25 mg was associated with modest reductions in the risk of all-cause mortality (hazard ratio: 0.92 [0.89–0.95], P &lt; 0.0001) and cardiovascular death (hazard ratio: 0.93 [0.89–0.98], P &lt; 0.01) compared to the MRA naive group. However, both dosages of MRA (25 and 50 mg) were associated with a slight increase in the risk of hospital re-admissions due to heart failure 10% compared to MRA naive patients. These findings were consistent when examining a propensity score-matched cohort. Interaction analysis showed a significantly improved survival rate for patients receiving MRA at 25 mg compared to MRA naive individuals, particularly among those with an estimated glomerular rate ≥30 mL/min/1.73 m2 across all patients and in those aged 70 years and above. Conclusions: The administration of MRA treatment at 25 mg once daily was linked to a modestly improved survival in a real-life HFrEF population, with even more pronounced benefits observed within a specific subgroup. This finding highlights the importance of personalized medicine in providing customized therapeutic advantages.

Water and Electrolyte Content in Salt-Dependent HYpertension in the SKIn (WHYSKI): Effect of Surgical Cure of Primary Aldosteronism.

In skin biopsies, we will measure the content of Na+, K+, water, by physical-chemical methods and the osmotic-stress-responsive transcription factor Tonicity-responsive Enhancer Binding Protein (TonEBP, NFAT5) mRNA copy number by droplet digital PCR, in sex-balanced cohorts of 18 -75-year-old consecutive consenting patients with unilateral and bilateral PA, primary (essential) hypertension, and normotension. Before surgery, the patients with unilateral PA will receive the mineralocorticoid receptor antagonist (MRA) canrenone at doses that correct hypokalemia and high blood pressure values. They will be reassessed in an identical way one month after surgical cure, while off MRA. PA patients not selected for adrenalectomy will similarly be assessed at diagnosis and follow-up while on stable MRA treatment. Since a pilot study showed a direct correlation of dry weight (DW) with skin electrolytes and water content and significant differences of biopsy DW between surgery and follow-up, meaningful comparison of the skin cations and water content and TonEBP mRNA copy number, between specimen obtained at different time points, will require DW- and total mRNA-adjustment, respectively. This study will provide novel information on the skin Na+, K+ and water content in PA, the paradigm of salt-dependent hypertension, and novelknowledge on the effect of surgical cure of hyperaldosteronism. The TonEBP-mediated regulation of Na+, K+ and water content in the skin will also be unveiled. Trial Registration number: NCT06090617. Date of Registration: 2023-10-19.

Mineralocorticoid receptor antagonist treatment in patients with renal insufficiency and the associated risk of hyperkalemia and death.

Mineralocorticoid receptor antagonist (MRA) treatment is kidney protective but not recommended to patients with advanced renal failure due to the risk of hyperkalemia and death. This study aimed to examine the impact of MRA treatment in patients with chronic kidney disease on risk of hyperkalemia and subsequent mortality. Rates of hyperkalemia were compared across strata of estimated glomerular filtration rate (eGFR) and MRA treatment based on cox regression using a nested case-control framework with 1 : 4 matching of patients with hyperkalemia (K + ≥6.0 mmol/l) with controls from the Danish general population on age, sex, diabetes, and hypertension. Risk of subsequent 30-day mortality was assessed in a cohort study with comparisons across strata of eGFR and MRA treatment based on multiple Cox regression. Thirty-two thousand four hundred twenty-six cases with hyperkalemia were matched with 127 038 controls. MRA treatment was associated with an increased rate of hyperkalemia with hazard ratios [95% confidence interval (95% CI)] of 8.28 (7.78-8.81), 5.12 (4.67-5.62), 3.58 (3.23-3.97), and 1.89 (1.60-2.23) in patients with eGFR at least 60, 45-59, 30-44, and less than 30 ml/min/1.73 m 2 , respectively (Reference: No MRA).However, MRA-exposed patients had a lower 30-day mortality risk following hyperkalemia with absolute risks (95% CI) of 29.3% (27.8-31.1), 20.3% (18.7-22.4), 19.5% (17.9-21.7), and 19.7% (17.4-22.5) compared to 39.8% (38.8-40.8), 32.0% (30.7-33.1), 28.8% (27.5-31.2), and 22.5% (21.4-23.4) in patients without MRA exposure in patients with GFR at least 60, 45-59, 30-44, and less than 30 ml/min/1.7 3m 2 , respectively. MRA treatment was associated with an increased rate of hyperkalemia but decreased risk of subsequent 30-day mortality across all stages of renal impairment.

Reversal of arterial stiffness in medically and surgically treated unilateral primary aldosteronism.

Hyperaldosteronism has adverse effects on cardiovascular structure and function. Laparoscopic adrenalectomy is the gold standard for patients with unilateral primary aldosteronism. For unilateral primary aldosteronism patients unable or unwilling to undergo surgery, the effects of mineralocorticoid receptor antagonists (MRAs) on the reversibility of arterial stiffness and other clinical data remain unclear. We aimed to compare the reversibility of arterial stiffness using pulse wave velocity (PWV) and other clinical parameters between surgically and medically treated unilateral primary aldosteronism patients. We prospectively enrolled 306 unilateral primary aldosteronism patients, of whom 247 received adrenalectomy and 59 received medical treatment with MRAs. Detailed medical history, basic biochemistry and PWV data were collected in both groups before treatment and 1 year after treatment. After propensity score matching (PSM) for age, sex, SBP and DBPs, 149 patients receiving adrenalectomy and 54 patients receiving MRAs were included for further analysis. After PSM, the patients receiving adrenalectomy had a greater reduction in blood pressure, increase in serum potassium, and change in PWV (ΔPWV, -53 ± 113 vs. -10 ± 140 cm/s, P  = 0.028) than those receiving MRAs 1 year after treatment. Multivariable regression analysis further identified that surgery (compared with MRA treatment), baseline PWV, baseline DBP, the change in DBP and the use of diuretics were independently correlated with ΔPWV. Adrenalectomy is superior to MRA treatment with regards to vascular remodeling when treating unilateral primary aldosteronism patients.

Abstract 18220: Does Mineralocorticoid Receptor Blockade Affect the Occurrence of Perioperative Atrial Fibrillation in Cardiac Surgery Patients? - A Systematic Review and Meta-Analysis

Background: Mineralocorticoid receptor antagonists (MRAs) have emerged as potential therapy to prevent atrial fibrillation (AF). However, inconsistent results of MRAs effect on perioperative AF have been reported in the literature in patients undergoing cardiac surgery. To our knowledge, this is the first metanalysis to assess the effect of MRAs on occurrence of perioperative AF in patients undergoing cardiac surgery. Method: We searched different electronic databases from inception to April 30th, 2023, for randomized controlled trials (RCTs) and observational studies that evaluated the use of MRAs in patients with heart failure and left ventricular ejection fraction (LVEF) 30-50% who were referred for Coronary Artery Bypass Grafting (CABG) and/or valve surgery without any AF history. Primary outcome was occurrence of perioperative AF. Three independent reviewers selected and appraised the data. A random-effects meta-analysis was performed to estimate pooled odds ratios (OR) and 95% confidence intervals (CI). Result: We included 4 studies, 1 RCT and 3 observational cohorts, with a cumulative number of 1,128 patients with mean age 65.15 years. 412(36.5%) received an MRA (spironolactone or eplerenone). The follow up duration was 5 days to 1 month. During follow-up, 118 (28.64%) patients treated with MRAs, developed AF, compared to 224 (31.28%) patients, without MRA treatment. However, metanalysis showed that there is no significant reduction in occurrence of perioperative AF in MRA treated patients (OR: 0.88 CI: 0.58-1.33 p=0.55), I2 53%; Figure] Conclusion: Experimental data have shown that MRA blockade prevents perioperative AF in animal models but our metanalysis demonstrated that MRAs were not protective for perioperative AF in patients undergoing cardiac surgery. Larger trials in humans are warranted to evaluate its efficacy, particularly in patients undergoing cardiac surgery.

Safety of continuing mineralocorticoid receptor antagonist treatment in patients with heart failure with reduced ejection fraction and severe kidney disease: Data from Swedish Heart Failure Registry.

Mineralocorticoid receptor antagonists (MRAs) improve outcomes in heart failure with reduced ejection fraction (HFrEF) but remain underused and are often discontinued especially in patients with chronic kidney disease (CKD) due to concerns on renal safety. Therefore, in a real-world HFrEF population we investigated the safety of MRA use, in terms of risk of renal events, any mortality and any hospitalization, across the estimated glomerular filtration rate (eGFR) spectrum including severe CKD. We analysed patients with HFrEF (ejection fraction <40%), not on dialysis, from the Swedish Heart Failure Registry. We performed multivariable logistic regression models to investigate patient characteristics independently associated with MRA use, and univariable and multivariable Cox regression models to assess the associations between MRA use and outcomes. Of 33 942 patients, 17 489 (51%) received MRA, 32%, 45%, 54%, 54% with eGFR <30, 30-44, 45-59 or ≥60 ml/min/1.73 m2 , respectively. An eGFR ≥60 ml/min/1.73 m2 and patient characteristics linked with more severe HF were independently associated with more likely MRA use. In multivariable analyses, MRA use was consistently not associated with a higher risk of renal events (i.e. composite of dialysis/renal death/hospitalization for renal failure or hyperkalaemia) (hazard ratio [HR] 1.04, 95% confidence interval [CI] 0.98-1.10), all-cause death (HR 1.02, 95% CI 0.97-1.08) as well as of all-cause hospitalization (HR 0.99, 95% CI 0.95-1.02) across the eGFR spectrum including also severe CKD. The use of MRAs in patients with HFrEF decreased with worse renal function; however their safety profile was demonstrated to be consistent across the entire eGFR spectrum.

Serum aldosterone in right ventricular failure versus left ventricular failure before and after mineralocorticoid receptor antagonists: case-control clinical trial

Background Heart failure (HF) is a global growing health threat. This case-control clinical trial aimed to detect the predictive value and difference in aldosterone level between right side heart failure, heart failure with decreased ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) and compare the efficacy and safety of adding mineralocorticoid receptor antagonist (MRA) for treatment. Patients and methods We recruited 151 participants, 135 HF patients divided equally into 45 patients in each group:(1) right side HF (2) HFrEF and (3) HFpEF and 16 healthy controls. Serum aldosterone, troponin and echocardiography were evaluated at the beginning of the study, three and six months after administration of MRA. Results Aldosterone level was significantly greater in HF patients relative to controls. Aldosterone level can detect HF with excellent accuracy. There were significantly lower levels of aldosterone in right side HF compared to left side HF. There was a significant decrease in right ventricle dimensions, pulmonary artery systolic pressure and pulmonary artery size and significant increase in tricuspid annular plane systolic excursion after treatment in patients with right side HF. In the HFrEF group, there was a significant decrease in left ventricular end diastolic dimension and a significant increase in left ventricular EF after treatment. In the HFpEF group, there was a significant decrease in E/A and E/e′ after treatment. Conclusions Aldosterone may have pathogenic role in HF. Measuring and follow-up of aldosterone levels should be considered in HF patients. MRA treatment gives a significant improvement in right side HF group.

Mineralocorticoid receptor antagonist initiation during admission is associated with improved outcomes irrespective of ejection fraction in patients with acute heart failure.

Heart failure (HF) guidelines recommend initiation and optimization of guideline-directed medical therapy, including mineralocorticoid receptor antagonists (MRAs), before hospital discharge. However, scientific evidence for this recommendation is lacking. Our objective was to determine whether initiation of MRA prior to hospital discharge is associated with improved outcomes. We performed a secondary analysis of 6197 patients enrolled in the RELAX-AHF-2 study. Patients were divided into four groups according to MRA therapy at baseline and discharge. At baseline 30% of patients received MRA therapy, which increased to 50% of patients at discharge. In-hospital initiation of an MRA was observed in 1690 (27%) patients, 1438 (23%) patients remained on MRA therapy, 418 (7%) patients discontinued MRA treatment, and 2651 (43%) patients did not receive an MRA during hospital stay. Compared with patients who did not receive MRA therapy, in-hospital initiation of an MRA was independently associated with lower risks of mortality (multivariable hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.60-0.96; p = 0.02), cardiovascular death (HR 0.77, 95% CI 0.59-1.01; p = 0.06), hospitalization for HF or renal failure (HR 0.72, 95% CI 0.60-0.86; p = 0.0003) and the composite endpoint of cardiovascular death and/or rehospitalization for HF or renal failure (HR 0.71, 95% CI 0.61-0.83; p < 0.0001) at 180 days. These results were independent of baseline left ventricular ejection fraction. In patients hospitalized for acute HF, in-hospital initiation of an MRA was associated with improved post-discharge outcomes, independent of left ventricular ejection fraction and other potential confounders.

MRAs may have lost their cornerstone position for heart failure treatment in the age of SGLT-2 inhibitors: A meta-analysis of randomized controlled trials.

Mineralocorticoid receptor antagonists (MRAs) are a cornerstone drug class for heart failure therapy. Several clinical studies have demonstrated its role in heart failure therapy. However, due to the recommendation of sodium-glucose cotransporter-2 (SGLT-2) inhibitors for the treatment of heart failure, there is a lack of sufficient evidence regarding whether MRAs can continue to play a cornerstone role in heart failure treatment. A meta-analysis was performed on subgroups of the DAPA-HF and EMPEROR-Reduced trials. Using trial-level data, we performed a meta-analysis to assess the effects of SGLT-2 inhibitors and MRAs on various clinical endpoints of heart failure. The incidence of cardiovascular-related death or heart failure hospitalization was the primary outcome. In addition, we assessed cardiovascular death, all-cause death, heart failure hospitalization, renal outcomes, and hyperkalemia. This study has already been registered with PROSPERO, CRD42022385023. Compared with SGLT-2 inhibitor monotherapy, combined treatment did not demonstrate more significant advantages in terms of heart failure or cardiovascular death (RR = 1.00; 95% CI: 0.78-1.28), cardiovascular death (RR = 0.96; 95% CI: 0.61-1.52), heart failure hospitalization (RR = 0.92; 95% CI: 0.79-1.07), all-cause death (RR = 1.00; 95% CI: 0.63-1.59) and composite kidney endpoint (RR = 0.85; 95% CI: 0.49-1.46). Moreover, in comparison to SGLT-2 inhibitors, combined therapy increased the risk of moderate-severe hyperkalemia (blood potassium > 6.0mmol/l) (RR = 4.13; 95% CI: 2.23-7.65). In patients with HFrEF who have started MRAs treatment, the addition of an SGLT-2 inhibitor provides significant clinical benefit. However, the addition of MRAs to SGLT-2 inhibitors to treat heart failure is not essential.

Initiation of eplerenone or spironolactone, treatment adherence, and associated outcomes in patients with new-onset heart failure with reduced ejection fraction: a nationwide cohort study.

The mineralocorticoid receptor antagonists (MRAs) eplerenone and spironolactone are beneficial in heart failure with reduced ejection fraction (HFrEF), but have not been prospectively compared. We compared clinical outcomes, daily dosages, and discontinuation rates for the two drugs in a nationwide cohort. We identified all patients with HFrEF in the period 2016-2020, who were alive and had initiated MRA treatment at study start, 180 days after HF diagnosis. We estimated the 2-year risk of a composite of death and HF hospitalization, as well as each component separately, using Kaplan-Meier, cumulative incidence functions, and Cox proportional hazards models adjusted for age, sex, and comorbidities. Secondly, we assessed treatment withdrawal, cross-over, and daily drug dosage. We included 7479 patients; 653 (9%) on eplerenone and 6840 (91%) on spironolactone. Patients in the eplerenone group were younger (median age 65vs. 69 years), and more often men (91%vs. 68%), both P<0.001. In adjusted analyses, with spironolactone as reference, there were no differences in the risk of the composite of all-cause death and HF hospitalization (HR 1.02, 95% CI 0.82-1.27), all-cause death (HR 0.93, 95% CI 0.67-1.30), or HF hospitalization (HR 1.10, 95% CI 0.84-1.42). Treatment withdrawal occurred in 34% in the eplerenone group and 53% in the spironolactone group (P<0.001), treatment cross-over in 3%, and 10%, respectively. Daily dose >25mg at 12 months, was observed in 230 patients (37%) in the eplerenone group and 771 patients (12%) in the spironolactone (P<0.001). In a contemporary nationwide cohort of patients with new-onset HFrEF who initiated MRA, we found no differences in clinical outcomes associated with initiation of eplerenone vs. spironolactone. Treatment was more frequently withdrawn, and daily drug dosage was lower among patients treated with spironolactone.

Efficacy and safety assessment of mineralocorticoid receptor antagonists in patients with chronic kidney disease

BackgroundThe objective of our study is to evaluate the efficacy and safety of mineralocorticoid receptor antagonists (MRAs) and determine the optimal MRA treatment regimen in patients with chronic kidney disease (CKD). MethodsWe searched PubMed, Embase, Web of Science, and the Cochrane Library from their inception to June 20, 2022. The composite kidney outcome, cardiovascular events, urinary albumin to creatinine ratio (UACR), estimated glomerular filtration rate (EGFR), serum potassium, systolic blood pressure (SBP), diastolic blood pressure (DBP), creatine and creatine clearance were included for analysis. We conducted pairwise meta-analyses and Bayesian network meta-analyses (NMA) and calculated the surface under the cumulative ranking curve (SUCRA). ResultsWe included 26 studies with 15,531 participants. By pairwise meta-analyses, we found that MRA treatment could significantly reduce UACR in CKD patients with or without diabetes. Notably, compared to placebo, Finerenone was associated with a lower risk of composite kidney outcome and cardiovascular events. Data from NMA demonstrated an overt UACR reduction without increasing serum potassium by Apararenone, Esaxerenone, and Finerenone in CKD patients. Spironolactone decreased SBP and DBP but elevated CKD patients' serum potassium. ConclusionsCompared to placebo, Apararenone, Esaxerenone, and Finerenone might ameliorate albuminuria in CKD patients without causing elevated serum potassium levels. Remarkably, Finerenone conferred a cardiovascular benefit, and Spironolactone lowered blood pressure in CKD patients.

Estimated glomerular filtration rate-dip after medical target therapy associated with increased mortality and cardiovascular events in patients with primary aldosteronism.

The correlation of the changes of estimated glomerular filtration rate (eGFR) with long-term cardiovascular complications in patients with primary aldosteronism (PA) following mineralocorticoid receptor antagonists (MRA) treatment remains ambiguous. This prospective study aims to determine factors associated with all-cause mortality and de novo cardiovascular events of PA patients against the eGFR-dip. A total of 208 newly diagnosed PA patients were enrolled from January 2017 to January 2019. MRA was administered with at least a 6-month follow-up. The 'eGFR-dip' was defined as the difference between eGFR at 6 months after MRA treatment and respective baseline eGFR divided by the baseline eGFR. After a mean 5.7 years follow-up, an eGFR-dip more than 12%, which was detected in 99 (47.6%) of the 208 patients, was a significant independent risk factor predicting composite outcomes (all-cause mortality, de-novo three-point major adverse cardiovascular events, and/or congestive heart failure). Multivariable logistic regression showed that age [odds ratio (OR), 0.94; P = 0.003], pretreatment plasma aldosterone concentration (PAC; OR, 0.98; P  = 0.004), and initial eGFR (OR, 0.97; P  < 0.001) had a positive linkage with the eGFR-dip more than 12%. Nearly half of PA patients had an eGFR-dip more than 12% after 6 months of MRA treatment. They had a higher incidence of all-cause mortality and de novo cardiovascular events. Elder age, higher pretreatment PAC, or higher initial eGFR could be associated with an elevated risk of an eGFR-dip more than 12%.

Recent progress in the diagnosis and treatment of primary aldosteronism.

Primary aldosteronism (PA) is caused by excessive secretion of aldosterone from the adrenal glands, with subsequent changes in the renin-angiotensin system. In Japan, chemiluminescent enzyme immunoassay is currently performed for aldosterone assay rather than the earlier method of radioimmunoassay. This change in aldosterone measurement methods has resulted in faster and more accurate measurement of blood aldosterone levels. Since 2019, esaxerenone, a mineralocorticoid receptor antagonist (MRA) with a non-steroidal skeleton, has been available in Japan for the treatment of hypertension. Esaxerenone has been reported to have various effects, such as strong antihypertensive and anti-albuminuric/proteinuric effects. Treatment of PA with MRAs has been reported to improve the patient's quality of life and to suppress the onset of cardiovascular events independent of their effects on blood pressure. Measuring renin levels is recommended for monitoring the extent of mineralocorticoid receptor blockade during MRA treatment. Patients receiving MRAs are prone to developing hyperkalemia, and combining MRAs with sodium/glucose cotransporter 2 inhibitors is expected to prevent severe hyperkalemia and provide additional cardiorenal protection. Mineralocorticoid receptor-associated hypertension is a broad concept of hypertension that includes not only PA, but also hypertension caused by borderline aldosteronism, obesity, diabetes, and sleep apnea syndrome. New findings on primary aldosteronism, which is part of MR-associated hypertension. Aldosterone measurements have been changed to the CLEIA method. Treatment of primary aldosteronism with MRAs has a variety of positive effects. CT-guided radiofrequency ablation and transarterial embolization are alternatives to surgery for aldosterone-producing adenomas. BP blood pressure, CLEIA chemiluminescent enzyme immunoassay, CT computed tomography, K serum potassium, MR mineralocorticoid receptor, MRA mineralocorticoid receptor antagonist, QOL quality of life, SGLT2i sodium/glucose cotransporter 2 inhibitor.

Short- and long-term treatment with mineralocorticoid receptor antagonist improved heart failure with preserved ejection fraction in obese female mice with or without ovariectomy-induced post-menopausal condition

Obesity and metabolic syndrome are major risks for the development of heart failure with preserved ejection fraction (HFpEF), especially in women after menopause. Although mineralocorticoid receptor antagonists (MRAs) improve outcomes of HF with reduced EF, their beneficial effects on HFpEF remain to be established. We aimed to characterize the potential beneficial effects of an MRA treatment on HFpEF related to obesity in post-menopausal condition or not. After 12 weeks of a high fat diet (HFD), B6D2 female mice underwent an ovariectomy (OVX) followed by an MRA treatment (daily gavage) for a short- or long-term (1 or 12 weeks). The metabolic profile of the mice was analyzed by glucose and insulin tolerance tests. Echocardiography and hemodynamics measurements were performed to evaluate the left ventricular (LV) function. LV coronary perfusion and reserve were measured by MRI, and exercise capacity was evaluated on a treadmill. LV and adrenal gland remodeling were explored by histology and immunohistochemistry. After 12 weeks of HFD, the LV systolic fractional shortening, stroke volume and cardiac output in obese mice were not different to control mice. However, impairment of the LV diastolic compliance was significantly improved either by a short- or long-term MRA treatment (LV-End-Diastolic-Pressure-Volume-Relation, mmHG/RVU: CTL 1.00 ± 0.27, HFD 3.29 ± 0.56, HFD + OVX 7.33 ± 0.35; P < 0.01 vs. CTL; HFD + MRAshort 1.13 ± 0.35, HFD + OVX + MRAshort 0.95 ± 0.51; P < 0.01 vs. untreated). Furthermore, the long-term MRA treatment ameliorated glucose and insulin tolerance tests and reduced LV interstitial fibrosis (Fibrosis, %: CTL 7.03 ± 0.41, HFD 8.82 ± 0.36, HFD + OVX 9.80 ± 0.58; P < 0.01 vs. CTL; HFD + MRA 6.45 ± 0.51, HFD + OVX + MRA 8.26 ± 0.28; P < 0.01 vs. untreated). Moreover, in HFD + OVX mice, the long-term MRA treatment increased the coronary perfusion reserve as well as the running distance during the treadmill stress test. Obesity and post-menopausal condition affected adrenal gland organization with capsule thinning in all obese mice, spindles cortical extensions in the HFD group, cortical dysplasia and disorganized vascular network in the HFD + OVX group. Overall, our data demonstrate that both short- and long-term MRA treatment improved diastolic dysfunction in pre- and post-menopausal obese female mice with HFpEF.

Moderate dietary salt restriction improves blood pressure and mental well-being in patients with primary aldosteronism: The salt CONNtrol trial.

Primary aldosteronism (PA) is a frequent cause of hypertension. Aldosterone excess together with high dietary salt intake aggravates cardiovascular damage, despite guideline-recommended mineralocorticoid receptor antagonist (MRA) treatment. To investigate the antihypertensive impact of a moderate dietary salt restriction and associated physiological changes, including mental well-being. A total of 41 patients with PA on a stable antihypertensive regimen-including MRA-followed a dietary salt restriction for 12 weeks with structured nutritional training and consolidation by a mobile health app. Salt intake and adherence were monitored every 4 weeks using 24-h urinary sodium excretion and nutrition protocols. Body composition was assessed by bioimpedance analysis and mental well-being by validated questionnaires. Dietary salt intake significantly decreased from 9.1 to 5.2g/d at the end of the study. In parallel, systolic (130 vs. 121mmHg) and diastolic blood pressure (BP) (84 vs. 81mmHg) improved significantly. Patients' aptitude of estimating dietary salt content was refined significantly (underestimation by 2.4 vs. 1.4g/d). Salt restriction entailed a significant weight loss of 1.4kg, improvement in pulse pressure (46 vs. 40mmHg) and normalization of depressive symptoms (PHQD scale, p<0.05). Salt restriction, cortisol after dexamethasone suppression test and dosage of renin-angiotensin-aldosterone-system (RAAS) blockers were independently associated with BP reduction. A moderate restriction of dietary salt intake in patients with PA substantially reduces BP and depressive symptoms. Moreover, the findings underline that a sufficient RAAS blockade seems to augment the effects of salt restriction on BP and cardiovascular risk.

Effects of Mineralocorticoid Receptor Antagonists in Early-Stage Heart Failure With Preserved Ejection Fraction

BackgroundHospitalization with a first episode of heart failure (HF) is a serious event associated with poor clinical outcomes in HF with preserved ejection fraction (HFpEF). Identification of HFpEF via detection of elevated left ventricular filling pressure at rest or during exercise may allow early intervention. Benefits of treatment with mineralocorticoid receptor antagonists (MRAs) in established HFpEF have been reported, but use of MRAs is not well studied in early HFpEF without prior HF hospitalization. MethodsWe retrospectively studied 197 patients with HFpEF who did not have prior hospitalization but had been diagnosed by exercise stress echocardiography or catheterization. We examined changes in natriuretic peptide levels and echocardiographic parameters reflecting diastolic function following MRA initiation. ResultsOf the 197 patients with HFpEF, MRA treatment was initiated for 47 patients. After a median 3-month follow-up, reduction in N-terminal pro-B-type natriuretic peptide levels from baseline to follow-up was greater in patients treated with MRA than in those who were not (median, -200 pg/mL [interquartile range, -544 to -31] vs 67 pg/mL [interquartile range, -95 to 456], P < 0.0001 in 50 patients with paired data). Similar results were observed for the changes in B-type natriuretic peptide levels. Reduction in the left atrial volume index was also greater in the MRA-treated group than in the non-MRA-treated group after a median 7-month follow-up (77 patients with paired echocardiographic data). Patients with lower left ventricular global longitudinal strain experienced a greater reduction in N-terminal pro-B-type natriuretic peptide levels following MRA treatment. In the safety assessment, MRA modestly decreased renal function but did not change potassium levels. ConclusionsOur results suggest that MRA treatment has potential benefits for early-stage HFpEF.

PS-BPC08-10: IMPORTANCE OF DIETARY SALT RESTRICTION IN PRIMARY ALDOSTERONISM DURING TREATMENT WITH MINERALOCORTICOID RECEPTOR ANTAGONISTS: ROLE OF POSTTREATMENT PLASMA RENIN LEVELS

Objective: The purpose of this study is to measure the estimated dietary salt intake (eU-NaCl) when primary aldosteronism (PA) is treated with mineralocorticoid receptor antagonists (MRAs) and to evaluate whether it is important to reduce salt intake even while on MRA medications. Design and method: The eU-NaCl values were investigated in 26 PA patients who were treated with MRAs at pre-treatment and 6-month treatment. The eU-NaCl was calculated as follows: eU-NaCl (g/day) = 21.98 * {urinary sodium (mmol / L) / &lt;urinary creatinine (mg / dL) * 10&gt; * (Body Weight (kg) × 14.89 + Height (cm) × 16.14 - age × 2.043 - 2244.45)}. Results: Data are shown as median {first quartile - third quartile}. Various clinical parameters of 26 PA patients were compared between pre-treatment and 6 months MRA treatment; Systolic blood pressure (138 mmHg {124.5–157.7} vs 125 mmHg {117.8–130.8}, p &lt; 0.01) and diastolic blood pressure (86 mmHg {80.5–95.0} vs 78 mmHg {74.5–86.3}, p = 0.02) were decreased, serum potassium (3.9 mmol/L {3.8–4.3} vs 4.3 mmol/L {4.0–4.6}, p &lt; 0.01) and active renin concentration (ARC) (2.6 pg/mL {1.2–3.8} vs 6.1 pg/mL {3.5–10.3}, p &lt; 0.01) were increased significantly. The eU-NaCl (8.9 g/day {8.0–10.2} vs. 10.0 g/day {7.8–12.0}, p = 0.27) did not change. The correlation between the difference in eU-NaCl (ΔeU-NaCl) and the difference in ARC (ΔARC) before and after MRA treatment showed a significant inverse correlation (r = -0.418, p = 0.03). Furthermore, when the 26 patients were divided into 2 groups of ARC &gt;5 pg/mL and ARC &lt; 5 pg/mL after MRA treatment, ΔeU-NaCl and ΔARC showed no significant correlation in 16 patients with ARC ≧ 5 pg/mL (r = -0.481, p = 0.11), whereas a strong inverse correlation in 10 patients with ARC &lt; 5 pg/mL (r = -0.7599, p = 0.01). Conclusions: The present data indicate that post-MRA treatment ARC of less than 5pg/mL reflects insufficient improvement of salt sensitivity, suggesting the importance of dietary salt restriction even in the presence of MRA treatment.