RESUMEN
BACKGROUND: Eplerenone and spironolactone, recognized as mineralocorticoid receptor antagonists (MRAs), have been reported to improve clinical prognosis among individuals diagnosed with heart failure (HF). However, the difference in the clinical effects between eplerenone and spironolactone in individuals with HF remains uncertain. We aimed to assess the impact of eplerenone compared to spironolactone on clinical outcomes within the HF population. METHODS: An extensive search was executed in several databases (PubMed, Web of Science, Scopus, Cochrane Library). All relevant studies evaluating eplerenone compared to spironolactone in patients with HF were included. Dichotomous data were pooled as Hazard ratio (HR) or Risk ratio (RR) with a 95% confidence interval (CI). Our main outcome was all-cause mortality. Secondary outcomes included death from cardiovascular causes, treatment withdrawal, and gynecomastia. RESULTS: Ten studies, comprising 21,930 HF individuals, were included in our investigation. Eplerenone showed a lower risk of all-cause mortality (HR = 0.78, 95%CI [0.64 to 0.94], P = 0.009) and cardiovascular mortality (HR = 0.54, 95%CI [0.39, 0.74], P = 0.0001) compared to spironolactone. Furthermore, eplerenone exhibited a reduced risk of treatment withdrawal (RR = 0.69, 95% CI [0.62, 0.78], P = 0.0001) and gynecomastia (RR = 0.07, 95% CI [0.02 to 0.31], P = 0.0001) than spironolactone. CONCLUSION: Eplerenone revealed lower all-cause and cardiovascular mortality events in comparison to spironolactone. Moreover, eplerenone was associated with lower gynecomastia and treatment withdrawal events compared to spironolactone. Further well-designed randomized controlled trials are still warranted better to identify the clinical differences between eplerenone and spironolactone. TRIAL REGISTRATION: Protocol registration: https://doi.org/10.17605/OSF.IO/VNMGK.
Asunto(s)
Eplerenona , Ginecomastia , Insuficiencia Cardíaca , Antagonistas de Receptores de Mineralocorticoides , Espironolactona , Humanos , Eplerenona/uso terapéutico , Eplerenona/efectos adversos , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Antagonistas de Receptores de Mineralocorticoides/efectos adversos , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/fisiopatología , Espironolactona/uso terapéutico , Espironolactona/efectos adversos , Espironolactona/análogos & derivados , Resultado del Tratamiento , Masculino , Medición de Riesgo , Ginecomastia/inducido químicamente , Ginecomastia/mortalidad , Ginecomastia/tratamiento farmacológico , Ginecomastia/diagnóstico , Anciano , Factores de Riesgo , Femenino , Persona de Mediana Edad , Causas de Muerte , Factores de Tiempo , Recuperación de la Función , Anciano de 80 o más Años , AdultoRESUMEN
AIMS: Benefits of mineralocorticoid receptor antagonists (MRAs) in heart failure with preserved and mildly reduced ejection fraction (HFpEF/HFmrEF) have not been established. Conventional randomized controlled trials are complex and expensive. The Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure with Preserved Ejection Fraction (SPIRRIT-HFpEF) is a unique pragmatic registry-based randomized controlled trial. METHODS: SPIRRIT-HFpEF is a multicentre, prospective, randomized, open-label, blinded endpoint trial conducted on platforms in the Swedish Heart Failure Registry (SwedeHF) and the United States (US) Trial Innovation Network. Patients with HFpEF/HFmrEF are randomized 1:1 to spironolactone (or eplerenone) in addition to usual care, versus usual care alone. The primary outcome is total number of cardiovascular deaths and hospitalizations for heart failure. Outcomes are collected from Swedish administrative complete coverage registries and a US call centre and subsequently adjudicated. Simple eligibility criteria were based on data available in SwedeHF: heart failure as outpatient or at discharge from hospital, left ventricular ejection fraction ≥40%, N-terminal pro-B-type natriuretic peptide >300 ng/L (in sinus rhythm) or >750 ng/L (in atrial fibrillation), with pre-specified adjustment for elevated body mass index, and chronic loop diuretic use. Power and sample size assessments were based on an event-driven design allowing enrolment over approximately 6 years, and application of hazard ratios from the TOPCAT trial, Americas subset. The final sample size is expected to be approximately 2400 patients. CONCLUSION: SPIRRIT-HFpEF will be informative on the effectiveness of generic MRAs in HFpEF and HFmrEF, and on the feasibility of conducting pragmatic and registry-based trials in heart failure and other chronic conditions.
RESUMEN
Literature with regards to pregnancy related outcomes in persons with the presence of a solitary kidney of any cause is scarce. Most of the available information has been extrapolated from persons who have been renal donors. Unilateral renal agenesis affects 1 in 1500 people and can present with resistant hypertension. When a woman with a solitary kidney presents in pregnancy, it may be both a challenging diagnostic and therapeutic problem. Eplerenone, a selective aldosterone blocker has been prescribed for resistant hypertension and in the presence of pregnancy, been useful in persons with primary hyperaldosteronism and resistant hypertension due to obstructive sleep apnoea. We describe the use of Eplerenone in a patient with resistant hypertension in pregnancy, due to secondary hyperaldosteronism precipitated by renal agenesis.
RESUMEN
OBJECTIVES: Congenital adrenal hyperplasia (CAH) is an uncommon genetic disorder which affects cortisol production in the adrenal glands. It is usually treated with glucocorticoids. We present a case of non-classical CAH caused by the partial deficiency of 11 beta-hydroxylase (11ßOH) which was treated with aldosterone antagonist (eplerenone) monotherapy. CASE PRESENTATION: An adolescent male was diagnosed with 11 beta-hydroxylase deficiency (11ßOHD) at 13 years of age when he presented with hypertension, fatigue and headaches. He was initially treated with glucocorticoids, but requested an alternative therapy. Eplerenone was commenced at 25â¯mg with subsequent dose increases to 100â¯mg daily. His hypertension was controlled on this regimen, achieving a 24â¯h average blood pressure of 124/81â¯mmHg. CONCLUSIONS: CAH caused by 11ßOHD is a known cause of hypertension. It is usually managed with glucocorticoids, and antihypertensives are added if blood pressure remains uncontrolled. In this case, glucocorticoid therapy was not tolerated and treatment with aldosterone antagonist monotherapy was effective in controlling his hypertension.
RESUMEN
Introduction: Eplerenone is approved for the treatment of hypertension as well as symptomatic heart failure with reduced ejection fraction (HFrEF) following an acute myocardial infarction. However, the adverse events (AEs) have not been systematically analyzed. The aim of this study was to identify adverse drug reactions (ADRs) related to eplerenone using the FDA Adverse Event Reporting System (FAERS) database. By identifying previously unreported AEs, the study could potentially contribute to updating the drug's label. Methods: In order to find significant AEs, four algorithms, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN) and Empirical Bayesian Geometric Mean (EBGM), were used to analyze the signal strength of the ADRs connected to eplerenone that were gathered from the FAERS database over the previous 20 years. Results: From 2004Q1 to 2023Q4, a total of 20, 629, 811 reported cases were gathered from the FAERS database for this study. After processing the data and filtering, 1,874 case reports were analyzed. Of these cases, 1,070 AEs were identified, 128 of which were eplerenone-related ADRs. We investigated the occurrence of ADRs induced by eplerenone in 27 organ systems. Our study showed that the AEs listed in the medication's package insert correspond with those listed in the literature, including hyperkalemia and increased creatinine. Additionally, the prescription label for eplerenone does not include all system organ class (SOC) terms, like Vascular disorders, hepatobiliary Disorders, etc. Discussion: The study used multiple algorithms to quantify the signal strength and then identified any previously unrecognized ADRs, further studies are needed to confirm the association of ADRs with eplerenone. The findings of this study may provide important insights into the safety profile of eplerenone, ensure that healthcare providers have up-to-date information about their potential risks and help guide them in the correct use of the drug.
RESUMEN
BACKGROUND: Eplerenone is a selective aldosterone receptor blocker that is effective in preventing the progression of chroinic kidney disease (CKD). However, its mechanism and role in CKD pregnancy still remain uncertain. The aim of this study was to evaluate whether eplerenone could attenuated the fibrosis of unilateral ureteral obstruction (UUO) pregnant rats' contralateral kidney, improved pregnancy outcome and explore its therapeutic mechanisms. METHODS: A pregnancy rat model of UUO established, female Wistar rats were randomly assigned into sham-operated group (Sham group),sham-operated combined pregnancy group (SP group), unilateral ureteral obstruction combined pregnancy group (UUO + Pregnancy group), unilateral ureteral obstruction combined pregnancy, administered eplerenone (UUO + Pregnancy+Eplerenone group). On the 18th day of pregnancy, the rats were placed in a metabolic cage, 24 h urine was collected and stored at -80 °C. Next day, all animals were euthanized, and serum was collected by centrifugation and stored at -20 °C. Then the right kidney was extracted, a part of the kidney was placed in 4% paraformaldehyde for morphology, immunohistochemical staining, and immunofluorescence staining, and the other part was placed in a - 80 °C refrigerator for RNA and protein extraction. In vitro, HUVECs was treated with aldosterone, progesterone and estradiol, VEGFA and its receptor blocker bevacizumab. The ability of proliferation, migration and tubularization of HUVECs was detected by CCK-8, scratch wound assay and endothelial tube formation assay. And the co-expression of CD34 and α-SMA of HUVECs was detected by Flow cytometry. RESULTS: Immunofluorescence results showed that the co-expression of CD34 and α-SMA increased in the UUO + Pregnancy group was significantly increased. The expression of SGK-1, TGFß-1, Smad2, Smad3, VEGF-A, VEGFR2, CD34, α-SMA and Collagen I was significantly higher in the kidneys of the UUO + Pregnancy group compared to the Sham group and SP group. Eplerenone inhibited the expression of those results. In vitro, the ability of proliferation, migration and tubularization was increased after treated with aldosterone, aldosterone with progesterone and estradiol or VEGFA. Similarly, the expression of α-SMA on the surface of HUVECs treated with aldosterone, aldosterone with progesterone and estradiol were increased, while eplerenone supressed its expression. CONCLUSION: Eplerenone inhibits renal angiogenesis by blocking the SGK-1/TGFß signal transduction pathway, thereby inhibiting the phenotypic transformation of endothelial cells, slowing down renal fibrosis, and reducing kidney damage caused by pregnancy.
Asunto(s)
Eplerenona , Proteínas Inmediatas-Precoces , Riñón , Proteínas Serina-Treonina Quinasas , Ratas Wistar , Insuficiencia Renal Crónica , Factor de Crecimiento Transformador beta , Animales , Femenino , Embarazo , Eplerenona/farmacología , Eplerenona/uso terapéutico , Ratas , Proteínas Inmediatas-Precoces/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/patología , Riñón/metabolismo , Riñón/patología , Riñón/efectos de los fármacos , Factor de Crecimiento Transformador beta/metabolismo , Transducción de Señal/efectos de los fármacos , Humanos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Proliferación Celular/efectos de los fármacos , Espironolactona/farmacología , Espironolactona/análogos & derivados , Espironolactona/uso terapéutico , Obstrucción Ureteral/metabolismo , Obstrucción Ureteral/tratamiento farmacológico , Obstrucción Ureteral/patología , Obstrucción Ureteral/complicaciones , Antagonistas de Receptores de Mineralocorticoides/farmacología , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/metabolismo , Movimiento Celular/efectos de los fármacos , Neovascularización Patológica/metabolismo , Neovascularización Patológica/tratamiento farmacológico , AngiogénesisRESUMEN
Mineralocorticoid receptor antagonists (MRAs) are one of the renin-angiotensin-aldosterone system inhibitors widely used in clinical practice. While spironolactone and eplerenone have a long-standing profile in clinical medicine, finerenone is a novel agent within the MRA class. It has a higher specificity for mineralocorticoid receptors, eliciting less pronounced adverse effects. Although approved for clinical use in patients with chronic kidney disease and heart failure, intensive non-clinical research aims to further elucidate its mechanism of action, including dose-related selectivity. Within the field, animal models remain the gold standard for non-clinical testing of drug pharmacological and toxicological properties. Their role, however, has been challenged by recent advances in in vitro models, mainly through sophisticated analytical tools and developments in data analysis. Currently, in vitro models are gaining momentum as possible platforms for advanced pharmacological and pathophysiological studies. This article focuses on past, current, and possibly future in vitro cell models research with clinically relevant MRAs.
Asunto(s)
Antagonistas de Receptores de Mineralocorticoides , Receptores de Mineralocorticoides , Antagonistas de Receptores de Mineralocorticoides/farmacología , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Humanos , Animales , Receptores de Mineralocorticoides/metabolismo , Espironolactona/farmacología , Espironolactona/análogos & derivados , Espironolactona/uso terapéutico , Eplerenona/farmacología , Eplerenona/uso terapéutico , Naftiridinas/farmacología , Evaluación Preclínica de Medicamentos/métodos , Sistema Renina-Angiotensina/efectos de los fármacos , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/metabolismoRESUMEN
BACKGROUND: The guidelines recommend the initiation or up-titration of heart failure (HF) treatments following an HF hospitalization; however, concerns about adverse events may limit the use of mineralocorticoid receptor antagonists (MRAs). Patient profiles or disease severity might impact adverse events associated with MRA therapy in acute HF. METHODS: The EARLIER trial included patients with acute HF who were randomized to eplerenone or placebo over 6 months. Adverse events (i.e., worsening renal function [WRF], hyperkalemia, hypotension, and volume depletion/dehydration) were assessed. HF-related outcome included a composite of all-cause mortality, HF re-hospitalization, investigator-reported worsening HF and out-of-hospital diuretic intensification. RESULTS: In 297 patients (mean age: 67 ± 13 years; 73% males), adverse events were observed: 44.4% experienced WRF (>20% drop in estimated glomerular filtration rate[eGFR] and/or investigator-reported WRF), 8.4% had hyperkalemia (potassium >5.5 mmol/L and/or investigator-reported hyperkalemia), 27.9% experienced hypotension (systolic blood pressure[SBP] <90 mmHg and/or investigator-reported hypotension), and 16.8% had investigator-reported volume depletion/dehydration. Eplerenone vs. placebo did not elevate the incidence of these events (all-p-values>0.0 5). Multivariable analyses revealed that, irrespective of treatment allocation, older age (>7 5 years), prevalent diabetes, symptomatic congestion, and microalbuminuria were associated with increased risk of WRF. Baseline eGFR<60 ml/min/1.73m2 and SBP < 90 mmHg predicted hyperkalemia and hypotension, respectively, while older patients were more likely to experience volume depletion/dehydration. However, these patient profiles did not alter the benefit of eplerenone on outcomes (HR [9 5%CI] = 0.53 [0.29 to 0.97], P = 0.04; all-p-for-interaction>0.10). CONCLUSION: Eplerenone did not increase adverse events compared with placebo in acute HF. Importantly, disease severity and comorbidity burden greatly influence adverse events, but not benefit from eplerenone.
Asunto(s)
Eplerenona , Insuficiencia Cardíaca , Hospitalización , Antagonistas de Receptores de Mineralocorticoides , Humanos , Eplerenona/uso terapéutico , Eplerenona/administración & dosificación , Eplerenona/efectos adversos , Masculino , Femenino , Anciano , Insuficiencia Cardíaca/tratamiento farmacológico , Antagonistas de Receptores de Mineralocorticoides/efectos adversos , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Antagonistas de Receptores de Mineralocorticoides/administración & dosificación , Persona de Mediana Edad , Enfermedad Aguda , Espironolactona/efectos adversos , Espironolactona/análogos & derivados , Espironolactona/uso terapéutico , Espironolactona/administración & dosificación , Método Doble Ciego , Anciano de 80 o más Años , Resultado del Tratamiento , Hiperpotasemia/inducido químicamente , Hiperpotasemia/epidemiologíaRESUMEN
Background Clinical and translational research suggests that mineralocorticoid receptor antagonists (MRAs) may prevent atrial fibrosis and electrical remodeling associated with atrial fibrillation (AF). This study aimed to consolidate existing evidence from randomized controlled trials (RCTs) evaluating the effect of MRAs on incident or recurrent AF. Methods Medline, Cochrane Library and Scopus were searched until February 12, 2024. Triple-independent study selection, data extraction and quality assessment were performed. Evidence was pooled using both pairwise and Bayesian and frequentist network meta-analyses. Results Twenty-three RCTs (13,358 participants) were identified. Based on the pairwise random effects meta-analysis, MRAs were associated with a significant reduction in AF events compared to placebo or usual care (risk ratio {RR}= 0.75; 95% confidence interval {CI}= [0.66, 0.87]; P< 0.001; I2= 3%). This protective effect was robust both for new-onset and recurrent AF episodes (subgroup p-value= 0.69), while the baseline HF status was not a significant effect modifier (subgroup p-value= 0.58). MRAs demonstrated a significantly higher reduction in AF events for patients with chronic renal disease compared to placebo (RR= 0.78; 95% CI= [0.62, 0.98]; P= 0.03; I2= 0%). The network meta-analyses revealed that only spironolactone was associated with a significant reduction in AF events (Bayesian RR= 0.76; 95% CI= [0.65, 0.89]; P< 0.001; level of evidence moderate; SUCRA 0.731), while eplerenone and finerenone showed a neutral effect. Conclusion MRAs confer a significant benefit in terms of reducing incident or recurrent AF episodes, irrespective of HF status. In this context, spironolactone may be preferable compared to eplerenone or finerenone.
Asunto(s)
Fibrilación Atrial , Teorema de Bayes , Antagonistas de Receptores de Mineralocorticoides , Metaanálisis en Red , Ensayos Clínicos Controlados Aleatorios como Asunto , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Humanos , Fibrilación Atrial/tratamiento farmacológico , Recurrencia , Resultado del TratamientoRESUMEN
Objectives: Evidence suggests that renal function increasingly deteriorates in patients with apparently treatment-resistant hypertension (ATRH) in comparison with those who have non-resistant arterial hypertension (NAH). We aimed to assess the long-term decline in renal function between these patient groups and identify specific risk factors contributing to the progression of renal dysfunction. Methods: Data for 265 patients with ATRH and NAH in a hypertension excellence centre were retrospectively evaluated. Demographic characteristics, co-morbidities, laboratory findings, secondary causes of hypertension, medication and exposure to contrast agents were assessed. To address differences between groups, adjustment with linear mixed-effect models was used. Results: Data from the first 4 years of follow-up were evaluated. After adjustment for age and diabetes, which were identified as independent risk factors for renal dysfunction progression in the study cohort, the mean decrease in estimated glomerular filtration rate per year was steeper with ATRH than with NAH (-1.49 vs. -0.65 mL/min/1.73 m2 per year; difference in slope, 0.83 mL/min/1.73 m2 per year; 95% confidence interval [CI]: 0.25-1.41, p = 0.005). In subgroup analyses, without Holm-Bonferroni correction, the prescription of MRA indicated a faster decline in renal function in ATRH. Following correction, no specific therapeutic risk factor was associated with faster progression of renal dysfunction. Conclusions: Renal function declines twice as fast with ATRH compared with NAH, independently of age and diabetes. Larger studies are needed to reveal risk factors for renal dysfunction in patients with hypertension.
High blood pressure (arterial hypertension) is a significant risk factor for kidney function decline. Resistant hypertension represents a subtype of hypertension that is difficult to treat and requires multiple antihypertensive agents to achieve effective blood pressure control. Recent research suggests that individuals with resistant hypertension are at greater risk of kidney dysfunction.This study analyses data from adult patients with arterial hypertension and resistant hypertension followed-up for a mean duration of 6.4 years.A faster decline in kidney function was observed in patients with resistant hypertension. This suggests that renal function in these patients should be closely monitored.After statistical evaluation, no medication was found to be associated with an increased risk of kidney failure progression. However, two specific medications, spironolactone and eplerenone, raised suspicion and require further exploration in larger prospective studies.
Asunto(s)
Tasa de Filtración Glomerular , Hipertensión , Humanos , Masculino , Hipertensión/fisiopatología , Hipertensión/tratamiento farmacológico , Hipertensión/complicaciones , Femenino , Persona de Mediana Edad , Factores de Riesgo , Anciano , Estudios Retrospectivos , Progresión de la Enfermedad , Antihipertensivos/uso terapéutico , Riñón/fisiopatología , Estudios de SeguimientoRESUMEN
BACKGROUND: Kidney dysfunction often leads to reluctance to start or continue life-saving heart failure (HF) therapy. OBJECTIVES: 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. METHODS: We pooled individual patient data from the RALES (Randomized Aldactone Evaluation Study) and EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) trials. The association between MRA treatment and outcomes was assessed according to whether the estimated glomerular filtration rate (eGFR) declined to <30 mL/min/1.73 m2 or not. The primary outcome was cardiovascular death or HF hospitalization. RESULTS: Among 4,355 patients included, 295 (6.8%) experienced a deterioration of eGFR after randomization to <30 mL/min/1.73 m2. These patients had more impaired baseline cardiac and kidney function (eGFR 47.3 ± 13.4 mL/min/1.73 m2 vs 70.5 ± 21.8 mL/min/1.73 m2) 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 <30 mL/min/1.73 m2 (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 <30 mL/min/1.73 m2, 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 (>6.0 mmol/L). CONCLUSIONS: Because patients experiencing a decrease in eGFR to <30 mL/min/1.73 m2 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.
Asunto(s)
Tasa de Filtración Glomerular , Insuficiencia Cardíaca , Antagonistas de Receptores de Mineralocorticoides , Humanos , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Masculino , Femenino , Anciano , Tasa de Filtración Glomerular/efectos de los fármacos , Persona de Mediana Edad , Volumen Sistólico/fisiología , Volumen Sistólico/efectos de los fármacos , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Insuficiencia Cardíaca , Antagonistas de Receptores de Mineralocorticoides , Metaanálisis en Red , Ensayos Clínicos Controlados Aleatorios como Asunto , Volumen Sistólico , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Antagonistas de Receptores de Mineralocorticoides/efectos adversos , Humanos , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Volumen Sistólico/fisiología , Volumen Sistólico/efectos de los fármacos , Espironolactona/uso terapéutico , Espironolactona/análogos & derivados , Espironolactona/efectos adversos , Eplerenona/uso terapéutico , Resultado del TratamientoRESUMEN
OBJECTIVEï¼To elucidate the mechanism by which Huoxue Jiedu Huayu recipe (, HJHR) regulates angiogenesis in the contralateral kidney of unilateral ureteral obstruction (UUO) rats and the mechanism by which it reduces of renal fibrosis. METHODS: Male Wistar rats were randomly divided into 4 groups: the sham group, UUO group (180 d of left ureter ligation), UUO plus eplerenone (EPL) group, and UUO plus HJHR group. After 180 d of oral drug administration, blood and contralateral kidneys were collected for analysis. Angiogenesis- and fibrosis-related indexes were detected. RESULTS: HJHR and EPL improved structural damage and renal interstitial fibrosis in the contralateral kidney and reduced the protein expression levels of α-smooth muscle actin (α-SMA), vimentin and collagen I. Moreover, these treatments could reduce the expression of vascular endothelial growth factor-A (VEGFA) by inhibiting the infiltration of macrophages. Furthermore, HJHR and EPL significantly reduced the expression of CD34 and CD105 by downregulating VEGFA production, which inhibited angiogenesis. Finally, the coexpressions of CD34, CD105 and α-SMA were decreased in the HJHR and EPL groups, indicating that endothelial-to-mesenchymal transition was inhibited. CONCLUSIONS: These findings confirm that HJHR alleviates contralateral renal fibrosis by inhibiting VEGFA-induced angiogenesis, encourage the use of HJHR against renal interstitial fibrosis and provide a theoretical basis for the clinical management of patients with CKD.
Asunto(s)
Medicamentos Herbarios Chinos , Fibrosis , Riñón , Macrófagos , Ratas Wistar , Obstrucción Ureteral , Factor A de Crecimiento Endotelial Vascular , Animales , Masculino , Obstrucción Ureteral/metabolismo , Obstrucción Ureteral/tratamiento farmacológico , Obstrucción Ureteral/genética , Ratas , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Riñón/efectos de los fármacos , Riñón/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Medicamentos Herbarios Chinos/administración & dosificación , Humanos , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/metabolismo , Enfermedades Renales/etiología , Enfermedades Renales/genética , AngiogénesisRESUMEN
Background: The renin-angiotensin-aldosterone system (RAAS) members, especially Ang II and aldosterone, play key roles in the pathogenesis of diabetic cardiomyopathy (DCM). Angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers combined with aldosterone receptor antagonists (mineralocorticoid receptor antagonists) have substantially improved clinical outcomes in patients with DCM. However, the use of the combination has been limited due to its high risk of inducing hyperkalemia. Methods: Type 1 diabetes was induced in 8-week-old male C57BL/6J mice by intraperitoneal injection of streptozotocin at a dose of 55 mg/kg for 5 consecutive days. Adeno-associated virus 9-mediated short-hairpin RNA (shRNA) was used to knock down the expression of ADAM17 in mice hearts. Eplerenone was administered via gavage at 200 mg/kg daily for 4 weeks. Primary cardiac fibroblasts were exposed to high glucose (HG) in vitro for 24 h to examine the cardiac fibroblasts to myofibroblasts transformation (CMT). Results: Cardiac collagen deposition and CMT increased in diabetic mice, leading to cardiac fibrosis and dysfunction. In addition, ADAM17 expression and activity increased in the hearts of diabetic mice. ADAM17 inhibition and eplerenone treatment both improved diabetes-induced cardiac fibrosis, cardiac hypertrophy and cardiac dysfunction, ADAM17 deficiency combined with eplerenone further reduced the effects of cardiac fibrosis, cardiac hypertrophy and cardiac dysfunction compared with single therapy in vivo. High-glucose stimulation promotes CMT in vitro and leads to increased ADAM17 expression and activity. ADAM17 knockdown and eplerenone pretreatment can reduce the CMT of fibroblasts that is induced by high glucose levels by inhibiting TGFß1/Smad3 activation; the combination of the two can further reduce CMT compared with single therapy in vitro. Conclusion: Our findings indicated that ADAM17 knockout could improve diabetes-induced cardiac dysfunction and remodeling through the inhibition of RAAS overactivation when combined with eplerenone treatment, which reduced TGF-ß1/Smad3 pathway activation-mediated CMT. The combined intervention of ADAM17 deficiency and eplerenone therapy provided additional cardiac protection compared with a single therapy alone without disturbing potassium level. Therefore, the combination of ADAM17 inhibition and eplerenone is a potential therapeutic strategy for human DCM.
RESUMEN
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.
Asunto(s)
Aldosterona , Corticosterona , Ratas Wistar , Estrés Psicológico , Animales , Masculino , Aldosterona/sangre , Corticosterona/sangre , Ratas , Estrés Psicológico/sangre , Estrés Psicológico/complicaciones , Hígado Graso/sangre , Hígado Graso/etiología , Hígado Graso/patología , Eplerenona/farmacología , Riñón/patología , Riñón/metabolismo , Hígado/patología , Hígado/metabolismo , Fibrosis , Espironolactona/análogos & derivados , Espironolactona/farmacologíaRESUMEN
The biological or clinical significance of mineralocorticoid receptor (MR) in urothelial cancer remains largely unknown. The present study aimed to determine the functional role of MR in bladder cancer progression. In two of the human bladder cancer lines expressing MR, treatment with a natural MR ligand, aldosterone, significantly reduced cell proliferation and migration, which was restored by three MR antagonists clinically used, spironolactone (except colony formation of androgen receptor-positive cells cultured in the presence of androgens), eplerenone, and esaxerenone. Similarly, MR knockdown via shRNA virus infection resulted in significant increases in cell viability/migration, as well as colony formation, compared with control sublines. In addition, MR knockdown augmented the expression of ß-catenin, c-fos, and N-cadherin, and lowered that of E-cadherin and p53, indicating the induction of the cadherin switching. Immunohistochemistry in surgical specimens detected MR signals in 58 (92.1%; 36.5% weakly-positive/1+, 44.4% moderately-positive/2+, and 11.1% strongly-positive/3+) of 63 muscle-invasive bladder cancers, which was significantly lower than in adjacent non-neoplastic urothelial tissues (100%; 15.7% 1+, 37.3% 2+, and 47.1% 3+). Moreover, patients with MR-high (3+) tumor had a significantly lower risk of cancer-specific mortality (P=0.039). Multivariable analysis further showed that strong MR expression was an independent predictor of cancer-specific survival in patients with muscle-invasive bladder cancer (hazard ratio 0.117, P=0.039). These findings suggest that MR signaling functions as a tumor suppressor in urothelial carcinoma and prevents tumor growth. Accordingly, there is a possibility that the concurrent use of anti-mineralocorticoids, particularly eplerenone and esaxerenone, in patients with bladder cancer rather contributes to the promotion of disease progression.
RESUMEN
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.