Mineralocorticoid receptor antagonists in heart failure with reduced ejection fraction: a systematic review and network meta-analysis of 32 randomized trials.

INTRODUCTION: Several randomized controlled trials (RCTs) have examined mineralocorticoid receptor antagonists (MRAs) in heart failure (HF) with reduced ejection fraction (HFrEF). This systematic review and network meta-analysis (NMA) evaluated the comparative efficacy and safety of MRAs in HFrEF. MATERIALS AND METHODS: MEDLINE(Pubmed), Scopus, Cochrane and ClinicalTrials.gov were searched until April 8, 2024 for RCTs examining the efficacy and/or safety of MRAs in HFrEF. Double-independent study selection, extraction and quality assessment were performed. Random-effects frequentist NMA models were used. Evidence certainty was assessed via Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: Totally, 32 RCTs (15685 patients) were analyzed. Eplerenone ranked above spironolactone in all-cause mortality (hazard ratio {HR}=0.78, 95% confidence interval {CI} [0.66,0.91], GRADE:"Moderate"), cardiovascular death (HR=0.74, 95%CI [0.53, 1.04], GRADE:"Low") and in all safety outcomes. Spironolactone was superior to eplerenone in the composite of cardiovascular death or hospitalization (HR=0.67, 95%CI [0.50,0.89], GRADE:"Moderate"), HF hospitalization (HR=0.61, 95%CI [0.43,0.86], GRADE:"Moderate"), all-cause hospitalization (HR=0.51, 95%CI [0.26,0.98], GRADE:"Moderate") and cardiovascular hospitalization (HR=0.56, 95%CI [0.37,0.84], GRADE:"Moderate"). Canrenone ranked first in all-cause mortality, the composite outcome and HF hospitalization. Finerenone ranked first in hyperkalemia (risk ratio [RR]=1.56, 95%CI [0.89,2.74], GRADE:"Moderate"), renal injury (RR=0.56, 95%CI [0.24,1.29]), any adverse event (RR=0.84, 95%CI [0.75,0.94], GRADE:"Moderate"), treatment discontinuation (RR=0.89, 95%CI [0.64,1.23]) and hypotension (RR=1.06, 95%CI [0.12,9.41]). CONCLUSIONS: MRAs are effective in HFrEF with certain safety disparities. Spironolactone and eplerenone exhibited similar efficacy, however, eplerenone demonstrated superior safety. Finerenone was the safest MRA, while canrenone exhibited considerable efficacy, nonetheless, evidence for these MRAs were scarce.

Eplerenone reduces lymphangiogenesis in the contralateral kidneys of UUO rats.

Inflammation and fibrosis often occur in the kidney after acute injury, resulting in chronic kidney disease and consequent renal failure. Recent studies have indicated that lymphangiogenesis can drive renal inflammation and fibrosis in injured kidneys. However, whether and how this pathogenesis affects the contralateral kidney remain largely unknown. In our study, we uncovered a mechanism by which the contralateral kidney responded to injury. We found that the activation of mineralocorticoid receptors and the increase in vascular endothelial growth factor C in the contralateral kidney after unilateral ureteral obstruction could promote lymphangiogenesis. Furthermore, mineralocorticoid receptor activation in lymphatic endothelial cells resulted in the secretion of myofibroblast markers, thereby contributing to renal fibrosis. We observed that this process could be attenuated by administering the mineralocorticoid receptor blocker eplerenone, which, prevented the development of fibrotic injury in the contralateral kidneys of rats with unilateral ureteral obstruction. These findings offer valuable insights into the intricate mechanisms underlying kidney injury and may have implications for the development of therapeutic strategies to mitigate renal fibrosis in the context of kidney disease.

Chronic unpredictable mild stress increases serum aldosterone without affecting corticosterone levels and induces hepatic steatosis and renal injury in young adult male rats.

Stress is often associated with anxiety and depressive symptoms in adolescents. Stress is associated with components of metabolic syndrome and inflammation. The present study hypothesizes that aldosterone, more than corticosterone, promotes chronic stress-hepatic steatosis and fibrosis, as well as renal inflammation and fibrosis in young adult rats. Thirty-two young adult male Wistar rats of 51 days old were divided into four groups (n = 8 per group): Control (C), chronic unpredictable mild stress (CUMS), control plus vehicle (C plus veh), CUMS plus eplerenone, a selective aldosterone blocker (CUMS plus EP). On postnatal day 51, eplerenone was administered orally through a gastric tube two hours before the start of the stress test. The CUMS paradigm was administered once daily at different times, with no repetition of the stressor sequence for four weeks. Renal inflammation and fibrosis were measured, as well as liver glycogen, triacylglycerol, and fibrosis levels. The serum concentrations of corticosterone, aldosterone, sodium, and creatinine were measured in urine and serum. The CUMS group showed a high level of serum aldosterone without affecting the level of corticosterone, increased urinary sodium, tubular atrophy, glomerular sclerosis, the presence of inflammation, and fibrosis, without affecting creatinine, increased glycogen content, triacylglycerol, and moderate fibrosis in the liver, and treatment with eplerenone prevented the inflammation, fibrosis, glycogen, and triacylglycerol. Our results show that chronic stress-induced aldosterone promotes hepatic steatosis and renal injury more than corticosterone. The prevention by eplerenone supports our hypothesis.

Aldosterone synthase inhibitor (BI 690517) therapy for people with diabetes and albuminuric chronic kidney disease: A multicentre, randomized, double-blind, placebo-controlled, Phase I trial.

AIM: This Phase I study evaluated the safety and early efficacy of an aldosterone synthase inhibitor (BI 690517) in people with diabetes and albuminuric chronic kidney disease. METHODS: Double-blind, placebo-controlled study (NCT03165240) at 40 sites across Europe. Eligible participants [estimated glomerular filtration rate ≥20 and <75 ml/min/1.73 m2; urine albumin/creatinine ratio (UACR) ≥200 and <3500 mg/g] were randomized 6:1 to receive once-daily oral BI 690517 3, 10 or 40 mg, or eplerenone 25-50 mg, or placebo, for 28 days. The primary endpoint was the proportion of participants with drug-related adverse events (AEs). Secondary endpoints included changes from baseline in the UACR. RESULTS: Fifty-eight participants were randomized and treated from 27 November 2017 to 16 April 2020 (BI 690517: 3 mg, n = 18; 10 mg, n = 13; 40 mg, n = 14; eplerenone, n = 4; placebo, n = 9) for 28 days. Eight (13.8%) participants experienced drug-related AEs [BI 690517: 3 mg (two of 18); 10 mg (four of 13); 40 mg (two of 14)], most frequently constipation [10 mg (one of 13); 40 mg (one of 14)] and hyperkalaemia [3 mg (one of 18); 10 mg (one of 13)]. Most AEs were mild to moderate; one participant experienced severe hyperkalaemia (serum potassium 6.9 mmol/L; BI 690517 10 mg). UACR responses [≥20% decrease from baseline (first morning void urine) after 28 days] were observed for 80.0% receiving BI 690517 40 mg (eight of 10) versus 37.5% receiving placebo (three of eight). Aldosterone levels were suppressed by BI 690517, but not eplerenone or placebo. CONCLUSIONS: BI 690517 was generally well tolerated, reduced plasma aldosterone and may decrease albuminuria in participants with diabetes and albuminuric chronic kidney disease.

Mineralocorticoid promotes intestinal inflammation through receptor dependent IL17 production in ILC3s.

Aldosterone is a key mineralocorticoid involved in regulating the concentration of blood electrolytes and physiological volume balance. Activation of mineralocorticoid receptor (MR) has been recently reported to participate in adaptive and innate immune responses under inflammation. Here, we evaluated the role of aldosterone and MR in inflammation bowel diseases (IBD). Aldosterone elevated in the colon of DSS-induced colitis mice. Aldosterone addition induced IL17 production and ROS/RNS level in group 3 innate lymphoid cells (ILC3s) and exacerbated intestinal injury. A selective mineralocorticoid receptor antagonism, eplerenone, inhibited IL17-producing ILC3s and its ROS/RNS production, protected mice from DSS-induced colitis. Mice lacking Nr3c2 (MR coding gene) in ILC3s exhibited decreased IL17 and ROS/RNS production, which alleviated colitis and colitis-associated colorectal cancer (CAC). Further experiments revealed that MR could directly bind to IL17A promoter and facilitate its transcription, which could be enhanced by aldosterone. Thus, our findings demonstrated the critical role of aldosterone-MR-IL17 signaling in ILC3s and gut homeostasis, indicating the therapeutic strategy of eplerenone in IBD clinical trial.

Effects of the mineralocorticoid receptor antagonist eplerenone in experimental autoimmune encephalomyelitis.

There is growing evidence indicating that mineralocorticoid receptor (MR) expression influences a wide variety of functions in metabolic and immune response. The present study explored if antagonism of the MR reduces neuroinflammation in the spinal cord of mice with experimental autoimmune encephalomyelitis (EAE). Eplerenone (EPLE) (100 mg/kg dissolved in 30% 2-hydroxypropyl-ß-cyclodextrin) was administered intraperitoneally (i.p.) daily from EAE induction (day 0) until sacrificed on day 17 post-induction. The MR blocker (a) significantly decreased the inflammatory parameters TLR4, MYD88, IL-1ß, and iNOS mRNAs; (b) attenuated HMGB1, NLRP3, TGF-ß mRNAs, microglia, and aquaporin4 immunoreaction without modifying GFAP. Serum IL-1ß was also decreased in the EAE+EPLE group. Moreover, EPLE treatment prevented demyelination and improved clinical signs of EAE mice. Interestingly, MR was decreased and GR remained unchanged in EAE mice while EPLE treatment restored MR expression, suggesting that a dysbalanced MR/GR was associated with the development of neuroinflammation. Our results indicated that MR blockage with EPLE attenuated inflammation-related spinal cord pathology in the EAE mouse model of Multiple Sclerosis, supporting a novel therapeutic approach for immune-related diseases.

Efficacy and safety of esaxerenone (CS-3150) in primary hypertension: a meta-analysis.

This study aimed to assess the efficacy and safety of esaxerenone (CS-3150) in treating primary hypertension. PubMed (Medline), Cochrane Central Register of Controlled Trials (CENTRAL), and Embase databases were searched for articles published until April 18, 2023. The outcomes included were diastolic blood pressure (DBP), systolic blood pressure (SBP), 24 h DBP, 24 h SBP, and adverse events. The meta-analysis was conducted using RevMan 5.3. This study included three trials. CS-3150 5 mg had a greater effect on lowering the SBP, DBP, 24 h SBP, and 24 h DBP than either CS-3150 2.5 mg or eplerenone 50 mg. In contrast, CS-3150 2.5 mg and eplerenone 50 mg showed no significant difference in lowering DBP, SBP, 24 h DBP, and 24 h SBP. Moreover, adverse events occurred at comparable rates in the three groups. CS-3150 (especially CS-3150 5 mg) is an effective and safe treatment for primary hypertension; which can reduce blood pressure and alleviate hypertensive symptoms.

Eplerenone improves hyperglycemia and sympathetic excitation in chronic renocardiac syndrome in rats.

We aimed to assess the efficacy of eplerenone, a steroidal mineralocorticoid receptor antagonist known to reduce blood pressure and mitigate cardiovascular disease (CVD) progression, in retarding the progression of chronic kidney disease (CKD) and CVD in a rat model of type 4 cardiorenal syndrome (CRS). We grouped rats into four experimental categories: sham surgery, sham treatment with eplerenone, nephrectomy without eplerenone (Nx), and nephrectomy with eplerenone (Nx + EP). For the Nx + EP group, rats received five-sixths nephrectomy, inducing CKD and CVD conditions such as renal hypertension and hyperglycemia, and were then treated with eplerenone (100 mg/kg/day, orally) over 4 weeks after an initial 4-week observation period. Heart rate, blood pressure, blood sugar levels, and sympathetic nerve excitation were monitored biweekly. In addition, assessments of renal and cardiac tissues, including evaluation of renal tubulointerstitial injury, glomerular injury, and cardiomyocyte hypertrophy, were conducted at week 8. Eplerenone administration mitigated CKD and CVD progression in the Nx + EP group, evident by improved blood pressure (217.3 ± 5.4 versus 175.3 ± 5.6), blood sugar (121.8 ± 1.3 versus 145.6 ± 6.0) level, reduced sympathetic nerve excitation, and cardiomyocyte hypertrophy compared to the Nx group. However, renal tubulointerstitial injury, glomerular injury, and cardiovascular dysfunction, which were increased in rats with type 4 CRS, did not show significant changes with eplerenone treatment. Our study demonstrated that eplerenone treatment did not exacerbate type 4 CRS but improved blood pressure, blood sugar levels, sympathetic nerve excitation, and cardiomyocyte hypertrophy in this model.

Mineralocorticoid Receptor Antagonism by Eplerenone and Arterial Inflammation in HIV: The MIRABELLA HIV Study.

Importance: The risk for atherosclerotic disease is increased 1.5- to 2.0-fold among persons with HIV (PWH). Increased activation of the renin-angiotensin-aldosterone system may contribute to increased arterial inflammation in this population. Objective: To determine the effects of eplerenone on arterial inflammation among well-treated PWH without known cardiovascular disease (CVD). Design, Setting, and Participants: Well-treated PWH who participated in the double-blinded, placebo-controlled, Mineralocorticoid Receptor Antagonism for Cardiovascular Health in HIV (MIRACLE HIV) study between February 2017 and March 2022 assessing the effects of eplerenone on myocardial perfusion were invited to participate in the Mineralocorticoid Receptor Antagonism By Eplerenone to Lower Arterial Inflammation in HIV (MIRABELLA) substudy if there was no current statin use. Participants were enrolled in the MIRABELLA study and underwent additional 18F-fludeoxyglucose-positron emission tomography/computed tomography (18F-FDG PET/CT) imaging of the aorta and carotid arteries to assess arterial inflammation over 12 months of treatment with eplerenone vs placebo. Interventions: Eplerenone, 50 mg, twice a day vs identical placebo. Main Outcomes and Measures: The primary outcome was change in target to background ratio (TBR), a measure of arterial wall inflammation, in the index vessel after 12 months of treatment. The index vessel was defined as the vessel (aorta, left carotid artery, or right carotid artery) with the highest TBR at baseline in each participant. Results: A total of 26 participants (mean [SD] age, 54 [7] years; 18 male [69%]) were enrolled in the study. Treatment groups (eplerenone, 13 vs placebo, 13) were of similar age, sex, and body mass index. Eplerenone was associated with a reduction in TBR of the primary end point, the index vessel (eplerenone vs placebo: model treatment effect, -0.31; 95% CI, -0.50 to -0.11; P = .006; percentage change, -12.4% [IQR, -21.9% to -2.6%] vs 5.1% [IQR, -1.6% to 11.0%]; P = .003). We further observed a significant reduction of the TBR of the most diseased segment (MDS) of the index vessel (eplerenone vs placebo: -19.1% [IQR, -27.0% to -11.9%] vs 6.8% [IQR, -9.1% to 12.1%]; P = .007). A similar result was seen assessing the index vessel of the carotids (eplerenone vs placebo: -10.0% [IQR, -21.8% to 3.6%] vs 9.7% [IQR, -9.8% to 15.9%]; P = .046). Reduction in the TBR of MDS of the index vessel on 18F-FDG PET/CT correlated with improvement in the stress myocardial blood flow on cardiac magnetic resonance imaging (Spearman ρ = -0.67; P = .01). Conclusion and Relevance: In this small randomized clinical trial, eplerenone was associated with reduction in arterial inflammation among well-treated PWH without known CVD. In addition, reductions in arterial inflammation as measured by 18F-FDG PET/CT were related to improvements in stress myocardial perfusion. Further larger studies should explore whether eplerenone is a potential treatment strategy for inflammatory-mediated CVD in PWH. Trial Registration: ClinicalTrials.gov Identifier: NCT02740179.

Glomerular and tubular effects of dapagliflozin, eplerenone and their combination in patients with chronic kidney disease: A post-hoc analysis of the ROTATE-3 study.

AIM: Sodium-glucose co-transporter 2 inhibitors and mineralocorticoid receptor antagonists reduce albuminuria and the risk of kidney failure. The aim of this study was to investigate the effects of both agents alone and in combination on markers of the glomerular endothelial glycocalyx and tubular function. METHODS: This post-hoc analysis utilized data of the ROTATE-3 study, a randomized cross-over study in 46 adults with chronic kidney disease and urinary albumin excretion ≥100 mg/24 h, who were treated for 4 weeks with dapagliflozin, eplerenone or its combination. The effects of dapagliflozin, eplerenone and the combination on outcome measures such as heparan sulphate, neuro-hormonal markers and tubular sodium handling were assessed with mixed repeated measures models. RESULTS: The mean percentage change from baseline in heparan sulphate after 4 weeks treatment with dapagliflozin, eplerenone or dapagliflozin-eplerenone was -34.8% (95% CI -52.2, -10.9), -5.9% (95% CI -32.5, 31.3) and -28.1% (95% CI -48.4, 0.1) respectively. The mean percentage change from baseline in plasma aldosterone was larger with eplerenone [38.9% (95% CI 2.8, 87.7)] and dapagliflozin-eplerenone [32.2% (95% CI -1.5, 77.4)], compared with dapagliflozin [-12.5% (95% CI -35.0, 17.8)], respectively. Mean percentage change from baseline in copeptin with dapagliflozin, eplerenone or dapagliflozin-eplerenone was 28.4% (95% CI 10.7, 49.0), 4.2% (95% CI -10.6, 21.4) and 23.8% (95% CI 6.6, 43.9) respectively. Dapagliflozin decreased proximal absolute sodium reabsorption rate by 455.9 mmol/min (95% CI -879.2, -32.6), while eplerenone decreased distal absolute sodium reabsorption rate by 523.1 mmol/min (95% CI -926.1, -120.0). Dapagliflozin-eplerenone decreased proximal absolute sodium reabsorption [-971.0 mmol/min (95% CI -1411.0, -531.0)], but did not affect distal absolute sodium reabsorption [-9.2 mmol/min (95% CI -402.0, 383.6)]. CONCLUSIONS: Dapagliflozin and eplerenone exert different effects on markers of glomerular and tubular function supporting the hypothesis that different mechanistic pathways may account for their kidney protective effects.

Cardioprotective and Antifibrotic Effects of Low-Dose Renin-Angiotensin-Aldosterone System Inhibitors in Type 1 Diabetic Rat Model.

Diabetic cardiovascular complications are associated with up to 50% mortality, and current therapies are not effective enough. Renin-angiotensin-aldosterone system inhibitors (RAASis) are the standard of care for diabetic patients with hypertension and albuminuria. Based on our previous studies reporting the renoprotective effects of low-dose RAASis, here, we hypothesized that low-dose RAASi treatment has cardioprotective and antifibrotic benefits in type 1 diabetes mellitus (T1DM). After five weeks of T1DM, adult male Wistar rats received low doses of ramipril, losartan, or eplerenone for two weeks. Heart rate, blood pressure, and pulse wave velocity (PWV) were recorded. Aortic intima-media thickness (IMT), collagen accumulation, and myocardial fibrosis were assessed. All RAASis reduced PWV elevation, prevented the progression of myocardial fibrosis, and normalized B-type natriuretic peptide, troponin I, and fibroblast growth factor 23 levels without affecting blood pressure. Interestingly, only eplerenone reversed the decline in Klotho levels and reduced IMT and fibrosis in the media of the aorta. Our comparative analysis suggests that mineralocorticoid receptor antagonists, particularly eplerenone, may offer superior efficacy in halting both the arterial and the myocardial injuries in T1DM compared to angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers.

Unilateral adrenalectomy for a drug-resistant bilateral primary aldosteronism with heart failure: pathophysiology and surgical indication.

BACKGROUND: Patients with bilateral primary aldosteronism (PA) generally are treated with antihypertensive drugs, but optimal treatment for patients with complications due to refractory hypertension has not been established. In this report, we present a case with bilateral PA who presented with persistent hypertension, despite treatment with 6 drugs, and left-dominant heart failure, which was improved after unilateral adrenalectomy. CASE PRESENTATION: A 61-year-old man was admitted to our hospital because of severe left-dominant heart failure. His heart rhythm was atrial fibrillation and the left ventricle was diffusely hypertrophic and hypokinetic. Coronary arteries were normal on coronary arteriogram. Primary aldosteronism was suspected based on severe hypokalemia (2.5 mEq/L) and plasma aldosterone concentration (PAC; 1,410 pg/mL). Although computed tomography (CT) showed a single left cortical nodule, adrenal vein sampling (AVS) indicated bilateral PA. Early in the case, heart failure and hyperkalemia in this patient were improved by treatment with a combination of 6 antihypertensive drugs (spironolactone 25 mg/day, eplerenone 100 mg/day, azosemide 60 mg/day, tolvaptan 7.5 mg/day, enalapril 5 mg/day, and bisoprolol fumarate 10 mg/day); however, heart failure relapsed after four months of treatment. We hypothesized that hypertension caused by excess aldosterone was inducing the patient's heart failure. In order to reduce aldosterone secretory tissue, a laparoscopic adrenalectomy was performed for the left adrenal gland, given the higher level of aldosterone from the left gland compared to the right. Following surgery, the patient's heart failure was successfully controlled despite the persistence of high PAC. Treatment with anti-hypertensive medications was reduced to two drugs (eplerenone 100 mg/day and bisoprolol fumarate 10 mg/day). In order to elucidate the mechanism of drug resistance, immunohistochemistry (IHC) and real time-polymerase chain reaction (RT-PCR) assays were performed to assess the expression of steroidogenic factor 1 (SF-1), a regulator of steroid synthesis in adrenal tissue. IHC and RT-PCR demonstrated that the expression of SF-1 in this patient (at both the protein and mRNA levels) was higher than that observed in unilateral PA cases that showed good responsivity to drug treatment. CONCLUSIONS: Unilateral adrenalectomy to reduce aldosterone secretory tissue may be useful for patients with drug-refractory, bilateral PA. Elevated expression of SF-1 may be involved in drug resistance in PA.

Possible dose-dependent effect of eplerenone on intraocular pressure.

Purpose: Intraocular pressure (IOP) is the main modifiable risk factor for glaucoma. Current therapies target the anterior outflow of aqueous humor or its production. This study aims to demonstrate eplerenone could reduce IOP through a possible posterior outflow path via retinal pigment epithelium (RPE). Methods: In this retrospective study, IOP changes in patients undergoing eplerenone treatment were investigated. Inclusion criteria were IOP data immediately before and during treatment. Exclusion criteria included ophthalmic procedures, changes in topical glaucoma treatment, or taking systemic medications affecting IOP. After reviewing 162 charts, 41 subjects were eligible. Pearson correlation test was used to investigate the correlation between continuous IOP and eplerenone dosage. Results: The mean ± SD IOP before eplerenone treatment was 14.31 ± 3.73 mmHg and decreased to 13.50 ± 4.04 mmHg; however, this was not statistically significant (P = 0.39). In subset of patients with eplerenone dose of more than 25 mg/day and baseline IOP equal to or less than 15 mmHg, the mean IOP before eplerenone treatment was 12.33 ± 2.59 mmHg and decreased to 10.33 ± 2.99, which is a trend toward IOP reduction with a 16% reduction in IOP (P = 0.055). Conclusion: A possible dose-dependent decrease in IOP with eplerenone provides indirect evidence for the posterior flow model and suggests the mineralocorticoid receptors (MRs) in RPE play a role in the posterior flow of aqueous humor. It can be deduced that the RPE pumps responsible for the posterior flow of aqueous humor are MR-regulated and their function can be enhanced with MR antagonists.

Agoraphobia and panic attacks complicated by primary aldosteronism improved by treatment with eplerenone: a case report.

BACKGROUND: Primary aldosteronism (PA) is an adrenal gland disease, that induces increased secretion of the mineralocorticoid, aldosterone, resulting in symptoms such as hypertension. This study reports a patient with agoraphobia and panic attacks, associated with PA. This patient's psychiatric symptoms improved after treatment with eplerenone, a mineralocorticoid receptor antagonist. CASE PRESENTATION: The patient was a 40-year-old female with agoraphobia, which refers to the irrational fear of situations that may cause anxiety, and panic attacks characterized by profuse sweating, palpitations, and generalized weakness. She was diagnosed with hypertension from PA. Subsequently, she received treatment with eplerenone, which improved her agoraphobia and panic attacks. CONCLUSIONS: There have been no previous reports on PA associated with agoraphobia and panic attacks that improved with pharmacotherapy. Patients with agoraphobia and panic attacks should be evaluated for PA. In patients with PA, pharmacotherapy with eplerenone should be considered.

PARAMETERS OF LEFT VENTRICULAR DIASTOLIC DYSFUNCTION IN PATIENTS WITH HYPERTENSION DISEASE WITH CONCOMITANT TYPE 2 DIABETES.

OBJECTIVE: The aim: To study the parameters of the left ventricular (LV) diastolic function in patients with HT with concomitant T2DM and without it before and after complex treatment with the inclusion of Eplerenone 50 mg per day and Trimetazidine 80 mg per day during 3 months. PATIENTS AND METHODS: Materials and methods: The study included 50 patients, aged 45-54 years (mean age 51.3«1.5 years), women - 24 and men 26 with HT stage II. All patients were divided into 2 groups: 1 group (n=25) - patients with HT stage II (HbA1c level of 5.01«0.13%) and 2 group (n=25) - patients with HT stage II and concomitant T2DM (HbA1c level of 7.6«0.34%). The control group consisted of 20 healthy individuals (HbA1c level of 4.68«0.49%). RESULTS: Results: When analyzing the findings on left atrial volume index (LAVI), the highest indicators were observed in patients with HT with T2DM, but slightly lower in HT, and even lower in the control group, but the differences at this stage were not significant. This suggests that functional changes in cardiomyocyte kinetics, which develop in patients with comorbid pathology and are caused by metabolic and hemodynamic disorders, can progress steadily. CONCLUSION: Conclusions: After a three-month course of treatment with Eplerenone and Trimetazidine, the rate of myocardial relaxation in diastole likely increased in both groups of those examined. The prescribed treatment with Eplerenone and Trimetazidine has led to a decrease in the rate of progression of heart failure and a reduction in cardiovascular risks.

The Mineralocorticoid Receptor Plays a Crucial Role in Macrophage Development and Function.

Stress and the attendant rise in glucocorticoids (GCs) results in a potent suppression of the immune system. To date, the anti-inflammatory role of GCs, via activation of the glucocorticoid receptor, has been well-characterized. However, cortisol, the primary GC in both fish and humans, also signals through the high-affinity mineralocorticoid receptor (MR), of which the immunomodulatory role is poorly understood. Here, we tested the hypothesis that MR is a key modulator of leukocyte function during inflammation. Using transgenic MR knockout zebrafish with fluorescently labelled leukocytes, we show that a loss of MR results in a global reduction in macrophage number during key development stages. This reduction was associated with impaired macrophage proliferation and responsivity to developmental distribution signals, as well as increased susceptibility to cell death. Using a tail fin amputation in zebrafish larvae as a model for localized inflammation, we further showed that MR knockout larvae display a reduced ability to produce more macrophages under periods of inflammation (emergency myelopoiesis). Finally, we treated wild-type larvae with an MR antagonist (eplerenone) during definitive hematopoiesis, when the macrophages had differentiated normally throughout the larvae. This pharmacological blockade of MR reduced the migration of macrophages toward a wound, which was associated with reduced macrophage Ccr2 signalling. Eplerenone treatment also abolished the cortisol-induced inhibition of macrophage migration, suggesting a role for MR in cortisol-mediated anti-inflammatory action. Taken together, our work reveals that MR is a key modulator of the innate immune response to inflammation under both basal and stressed conditions.

Differential Role of Aldosterone and Transforming Growth Factor Beta-1 in Cardiac Remodeling.

Angiotensin II, a major culprit in cardiovascular disease, activates mediators that are also involved in pathological cardiac remodeling. In this context, we aimed at investigating the effects of two of them: aldosterone (Ald) and transforming growth factor beta-1 (TGF-ß1) in an in vivo model. Six-week-old male wild-type (WT) and TGF-ß1-overexpressing transgenic (TGF-ß1-TG) mice were infused with subhypertensive doses of Ald for 2 weeks and/or treated orally with eplerenone from postnatal day 21. Thehearts' ventricles were examined by morphometry, immunoblotting to assess the intracellular signaling pathways and RT qPCR to determine hypertrophy and fibrosis marker genes. The TGF-ß1-TG mice spontaneously developed cardiac hypertrophy and interstitial fibrosis and exhibited a higher baseline phosphorylation of p44/42 and p38 kinases, fibronectin and ANP mRNA expression. Ald induced a comparable increase in the ventricular-heart-weight-to-body-weight ratio and cardiomyocyte diameter in both strains, but a less pronounced increase in interstitial fibrosis in the transgenic compared to the WT mice (23.6% vs. 80.9%, p < 0.005). Ald increased the phosphorylation of p44/42 and p38 in the WT but not the TGF-ß1-TG mice. While the eplerenone-enriched chow partially prevented Ald-induced cardiac hypertrophy in both genotypes and interstitial fibrosis in the WT controls, it completely protected against additional fibrosis in transgenic mice. Ald appears to induce cardiac hypertrophy independently of TGF-ß1, while in the case of fibrosis, the downstream signaling pathways of these two factors probably converge.

Underutilization of Mineralocorticoid Antagonists in Patients With Heart Failure With Reduced Ejection Fraction.

BACKGROUND: It is unknown how the efficacy and safety of mineralocorticoid receptor antagonists vary according to duration of heart failure with reduced ejection fraction (HFrEF). OBJECTIVES: In this study, we sought to evaluate the safety and efficacy of eplerenone according to duration of HFrEF. METHODS: In the EMPHASIS-HF trial, 3 patient groups were created according to HFrEF duration: <1 year, 1 to <5 years, and ≥5 years. The primary outcome was the composite of heart failure (HF) hospitalization or cardiovascular death. Outcomes were adjusted for prespecified prognostic variables and examined with the use of Cox regression models. RESULTS: The numbers of patients in each group were: 975, <1 year; 769, 1 to <5 years; and 988, ≥5 years. Patients with longer-standing HF were older and more frequently had cardiovascular and noncardiovascular comorbidities. The rate of the primary outcome (per 100 person-years) increased with HFrEF duration: 9.8 (95% CI: 8.4-11.4) for <1 year, 13.5 (95% CI: 11.6-15.7) for 1 to <5 years, and 17.6 (95% CI: 15.6-19.8) for ≥5 years. The benefits of eplerenone were consistent across HF duration: HRs for the primary outcome were 0.57 (95% CI: 0.42-0.79) for <1 year, 0.81 (95% CI: 0.60-1.10) for 1 to <5 years, and 0.61 (95% CI: 0.48-0.78) for ≥5 years; Pinteraction = 0.24. The absolute benefit was greatest in the longest-duration group: the number needed to treat for the primary outcome was 14 for <1 year, 13 for 1 to <5 years, and 10 for ≥5 years duration. CONCLUSIONS: Patients with longer-standing HFrEF had worse clinical status and a higher rate of events, but the benefit of eplerenone was consistent regardless of HFrEF duration. (A Comparison of Outcomes in Patients in NYHA Class II Heart Failure When Treated With Eplerenone or Placebo in Addition to Standard Heart Failure Medicines [EMPHASIS-HF]; NCT00232180).

Effects of Corticosterone on the Excitability of Glutamatergic and GABAergic Neurons of the Adolescent Mouse Superficial Dorsal Horn.

Stress evokes age-dependent effects on pain sensitivity and commonly occurs during adolescence. However, the mechanisms linking adolescent stress and pain remain poorly understood, in part due to a lack of information regarding how stress hormones modulate the function of nociceptive circuits in the adolescent CNS. Here we investigate the short- and long-term effects of corticosterone (CORT) on the excitability of GABAergic and presumed glutamatergic neurons of the spinal superficial dorsal horn (SDH) in Gad1-GFP mice at postnatal days (P)21-P34. In situ hybridization revealed that glutamatergic SDH neurons expressed significantly higher mRNA levels of both glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) compared to adjacent GABAergic neurons. The incubation of spinal cord slices with CORT (90 min) evoked select long-term changes in spontaneous synaptic transmission across both cell types in a sex-dependent manner, without altering the intrinsic firing of either Gad1-GFP+ or GFP- neurons. Meanwhile, the acute bath application of CORT significantly decreased the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs), as well as the frequency of miniature inhibitory postsynaptic currents (mIPSCs), in both cell types leading to a net reduction in the balance of spontaneous excitation vs. inhibition (E:I ratio). This CORT-induced reduction in the E:I ratio was not prevented by selective antagonists of either GR (mifepristone) or MR (eplerenone), although eplerenone blocked the effect on mEPSC amplitude. Collectively, these data suggest that corticosterone modulates synaptic function within the adolescent SDH which could influence the overall excitability and output of the spinal nociceptive network.