Targeting the untargeted: Molecular insights and emerging therapeutic strategies for primary aldosteronism.

In clinical states of relative aldosterone excess, such as in patients with chronic kidney disease (CKD), blockade of the overactivated mineralocorticoid receptor (MR) is a mechanistically plausible target of therapy in order to improve long-term cardiovascular and kidney outcomes. However, in the recently completed Benefits of Aldosterone Receptor Antagonism in Chronic Kidney Disease (BARACK-D) trial, the addition of spironolactone to standard care was not superior to standard care alone in improving cardiovascular outcomes in high-risk patients with moderate CKD. The use of spironolactone over the course of the BARACK-D trial was commonly restricted by hyperkalemia and other side effects. In sharp contrast, finerenone is a novel, selective, non-steroidal MR antagonist with proven cardiorenal protective effects and a more favorable side-effect profile. In a prespecified, individual patient-level data synthesis of 3 large clinical trials, as compared with placebo, finerenone significantly reduced the risks of all-cause death, hospitalization for heart failure and progression of CKD in a broad spectrum of patients with cardio-kidney-metabolic diseases. Although the risk of hyperkalemia with finerenone is real, the permanent discontinuation of treatment due to hyperkalemia occurs rarely. Accordingly, finerenone appears to be a safer therapeutic option with well-documented benefits on cardiovascular and kidney outcomes. In this article, we provide a comparative evaluation of safety and efficacy of spironolactone with that of finerenone. We discuss differences in pharmacodynamic and pharmacokinetic properties as well as data for the safety and efficacy of these 2 MR antagonists. We conclude with a call for a trial aiming to provide a direct and head-to-head comparison between spironolactone and finerenone in high-risk patients with cardio-kidney-metabolic diseases in the future.

Characterisation and differential expression of Atlantic salmon, Salmo salar, corticosteroid receptor paralogues following poly I:C and Vibrio anguillarum stimulations.

Comparative effectiveness of mineralocorticoid receptor antagonists in cardiovascular, renal and metabolic disease.

Although doxorubicin (DOX) is a potent chemotherapeutic agent, its clinical use is limited by dose-dependent cardiotoxicity. Doxorubicin-induced cardiotoxicity (DIC) promotes cardiomyocyte apoptosis, which leads to cardiac dysfunction, remodeling, and even heart failure. Although Finerenone (Fin), a selective mineralocorticoid receptor antagonist, has demonstrated benefit in the treatment of heart failure, its role in DIC remains unclear. Our study found that Finerenone mitigated myocardial injury, cardiac dysfunction, fibrosis, and remodeling by attenuating DOX-induced cardiomyocyte apoptosis, and it improved survival in a DIC mouse model. Similarly, Finerenone reduced injury and apoptosis in DOX-treated H9c2 cells. We identified key targets of Finerenone in DIC using proteomics and network pharmacology and demonstrated that it prevented the upregulation of p38 phosphorylation induced by DOX. Through in vitro experiments, we confirmed that TAK1-p38 played a critical role in mediating the protective effects of Finerenone against DIC. Furthermore, we found that Finerenone inhibits TAK1-p38 phosphorylation and cardiomyocyte apoptosis by antagonizing MR to suppress ROS. Overall, these results suggested that Finerenone ameliorated DIC primarily by inhibiting cardiomyocyte apoptosis via the TAK1-p38 pathway. Our findings elucidate a key mechanism underlying the cardioprotective effect of Finerenone in DIC and provide a theoretical basis for expanding its clinical applications.

Patients with difficult to control hypertension (HTN) are often referred by general practitioners to specialized centers to estimate global cardiovascular (CV) risk profile, evaluate hypertension-mediated organ damage (HMOD), and optimize antihypertensive therapy. This referral provides a unique opportunity to analyse patients with high CV risk and HTN in a real-world setting, characterized by the rigorous adoption of uniform and state-of-the-art procedures by expert personnel. To examine (1) global CV risk profile, office and out-of-office blood pressure (BP) levels, and markers of HMOD in adult patients referred to a high-volume European Hypertension center; (2) to evaluate how these clinical parameters impact on the choice of different antihypertensive therapies. An observational, cross-sectional study was conducted in adult patients of both sexes, aged ≥ 18 years, with essential treated hypertension, who were consecutively evaluated at the Excellence Hypertension Center at Sant'Andrea Hospital in Rome, Italy. Office and out-of-office BP levels were measured, and different hypertension phenotypes were set according to European guidelines. CV risk profile was estimated according using SCORE2. Only patients with treated HTN were selected for the analysis and stratified according to antihypertensive therapies: (1) angiotensin receptor blockers (ARBs); (2) angiotensin converting enzyme (ACE) inhibitors; (3) other drugs (including diuretics, beta-blockers, calcium channel blockers, alpha-blockers, mineralocorticoid receptor antagonists). From an overall database of 11,168 outpatients, a total of 5,677 patients with treated HTN were analysed (46.3% females, age 63.6 ± 13.1 years, BMI 27.4 ± 4.8kg/m2, office BP 140.6 ± 17.5/85.5 ± 11.5 mmHg, 24-hour BP 128.7 ± 13.7/77.2 ± 9.7 mmHg, SCORE2 5.4 ± 4.3%). Among these, 52.9% were treated with ARBs, 30.2% with ACE inhibitors and 17.0% with other drugs. Patients treated with ARBs were more frequently males, and significantly older, had more frequently obesity (P < 0.001), dyslipidaemia (p < 0.001), and diabetes (p < 0.001) than those treated with other drug classes. They also had more frequently CV comorbidities (P < 0.001) and resistant HTN (P < 0.001). They received more BP lowering agents (P < 0.001), being more frequently treated with triple (P < 0.001), quadruple (P < 0.001), or more complex (P < 0.001) combination therapies. Comparable office and out-of-office BP control were recorded between patients treated with ARBs and those patients managed with either ACE inhibitors or other drugs. Among adult outpatients referred to an excellence hypertension center, the majority were treated with ARBs, alone or in combination therapies. ARB-treated patients presented more frequently CV risk factors, comorbidities, and difficult-to-treat HTN.

Diabetes is the leading cause of chronic kidney disease (CKD) worldwide. Diabetic kidney disease (DKD) has traditionally been viewed as a progressive condition characterized by declining estimated glomerular filtration rate (eGFR) and worsening albuminuria, with affected individuals facing substantially elevated risks of major adverse cardiovascular events and kidney failure. However, recent advances in pharmacologic therapies have demonstrated dramatic improvements in both cardiovascular and kidney outcomes. The objective of this review is to summarize the evidence for contemporary pharmacologic therapies in DKD, and to examine the emerging concept of disease remission in DKD. Randomized controlled trials of sodium-glucose cotransporter 2 inhibitors, non-steroidal mineralocorticoid receptor antagonists, and glucagon-like peptide-1 receptor agonists have demonstrated significant attenuation of eGFR decline and reductions in albuminuria. These findings have given rise to the hypothesis that, with guideline-directed therapy, some patients with DKD may achieve disease remission, defined by physiologic declines in eGFR and minimal (or resolved) albuminuria. Emerging evidence not only highlights the promise of this paradigm but also underscores the lack of standardized definitions and long-term outcome data. Emerging pharmacologic therapies are transforming DKD. Reframing DKD management from one of slowing progression to achieving remission could have important implications for clinical practice worldwide.

Despite widespread use of renin-angiotensin-aldosterone system blockade, resistant and uncontrolled hypertension remain common, highlighting the need for novel therapeutic strategies. Growing recognition of aldosterone excess as a central driver of vascular, cardiac, and kidney injury has renewed interest in targeting this pathway. Recent advances in highly-selective aldosterone synthase inhibition (ASI) suggest this is a clinically viable approach. ASIs, including baxdrostat and lorundrostat, demonstrate consistent blood pressure reductions of approximately 8-12 mmHg when administered in addition to standard antihypertensive therapy across phase 2 and phase 3 trials. These drugs may overcome limitations of mineralocorticoid receptor antagonists by suppressing aldosterone production upstream, mitigating aldosterone escape, and reducing adverse effects. There may also be benefits among patients with chronic kidney disease, primary aldosteronism, and heart failure with preserved ejection fraction, supporting a broader cardiorenal role. Aldosterone synthase inhibition represents an advance in hypertension therapeutics. If ongoing and future outcome-driven trials confirm cardiovascular and renal benefit, ASIs may reshape treatment algorithms, complement existing renin-angiotensin-aldosterone-based strategies, and enable more precise targeting of aldosterone-mediated disease.

Patients with primary aldosteronism (PA) have an increased risk of developing cardiovascular disease. In patients with bilateral adrenal aldosterone hypersecretion, mineralocorticoid receptor antagonists (MRAs) are recommended; however, the benefit of these agents is observed only in cases that show a sufficient increase in post-treatment PRA (responders). Because renin secretion can be influenced by sodium intake, the increase in post-treatment PRA may be attributable to sodium restriction. A total of 90 patients who received eplerenone or esaxerenone for PA treatment were included in the study. Patients whose PRA was ≥ 1.0ng/mL/h at one year after the initiation of MRAs treatment were defined as responders. The predictors of responders and the effect of sodium intake were investigated. Both baseline and post-treatment PRA and PAC levels were higher in responders. In addition, baseline estimated sodium intake tended to be lower, and post-treatment estimated sodium intake was significantly lower in responders. The post-treatment PRA value was significantly correlated with the post-treatment estimated sodium intake, and the post-treatment estimated sodium intake was an independent predictor of responders, suggesting that post-treatment PRA elevation may be partially attributable to adequate sodium restriction. However, the change in the estimated glomerular filtration rate over the 3-year follow-up period was not different between responders and non-responders. Although sodium restriction is suggested to facilitate attainment of post-treatment PRA ≥ 1.0ng/mL/h, a marker of adequate aldosterone blockade, it remains uncertain whether achieving PRA ≥ 1.0ng/mL/h is associated with favorable renal outcomes.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasing global health challenge closely linked to obesity and the metabolic syndrome. This review explores the role of aldosterone as a central contributor to metabolic dysfunction, highlighting its association with adipose tissue dysfunction and systemic insulin resistance which can further influence MASLD development and progression. While aldosterone-related organ damage has been extensively studied in other contexts such as kidney disease, its involvement in MASLD has received less attention. Beyond classical renin-angiotensin-aldosterone system activation, aldosterone secretion can be directly stimulated by leptin and other adipogenic factors, creating a pathogenic link between obesity and metabolic impairment. Aldosterone amplifies chronic inflammation, oxidative stress and insulin resistance, primarily through mineralocorticoid receptor (MR)-dependent mechanisms. These involve both genomic actions regulating pro-inflammatory genes and rapid non-genomic signalling. Additionally, aldosterone MR-independent effects, can further contribute to oxidative stress and inflammatory responses. Significantly, the MR is expressed in liver cells, including hepatocytes, liver sinusoidal endothelial cells, Kupffer cells, and hepatic stellate cells. This expression can allow for direct aldosterone-mediated effect on hepatic inflammation, oxidative stress, and fibrosis, which can occur alongside or independently of systemic metabolic pathways. Such direct mechanisms may explain associations found in clinical studies correlating high aldosterone levels -even with low renin- with the prevalence and progression of MASLD. Recognizing aldosterone as a pleiotropic hormone that integrates metabolic and hepatic disease offers new insights into the cardio-kidney-metabolic syndrome and underscores the potential for targeted therapies.

Benign prostatic hyperplasia (BPH) is a widespread urological clinical case in aged men associated with troublesome lower urinary tract symptoms and cardiac dysfunction, but its medical treatment is still insufficient. Thus, searching for more effective medical regimens is an essential target. We tried in current experiment to explore the role of bosentan (BOS) and/or finerenone (FIN) in this lesion. BPH was adequately induced using testosterone propionate (TP) in a dose of (5mg/kg/day) for 28 days of subcutaneous injection and an oral administration of BOS (50mg/kg/day) and/or FIN (10mg/kg/day) for 10 days. We found typical histopathological changes of BPH, increased serum dihydrotestosterone (DHT), prostatic specific antigen (PSA), cardiac enzymes, tissue malondialdehyde (MDA), aldosterone, endothelin-A, nuclear factor kappa b (NF-κB), and proliferating cell nuclear antigen (PCNA). However, significant decreases in total antioxidant capacity (TAC), reduced glutathione (GSH), and caspase-3. The histological findings were augmented by special staining techniques, immunohistochemical and morphometric studies. There are histopathological alternations as the hyperplastic nodules in the prostate's transition zone expand, and the prostatic urethra was compressed, lengthened and distorted. Interestingly the co-administration of BOS and/or FIN significantly improved BPH induced changes. This is mostly attributed to its ability in modulating endothelin receptors by BOS, aldosterone receptors by FIN, improved the histopathological changes with anti-oxidant, anti-inflammatory, anti-fibrotic, antiproliferative, and apoptotic properties. BOS and/or FIN showed a significant ameliorative effect in BPH.

Chronic kidney disease (CKD) in persons with diabetes mellitus (DM) continues to be the leading cause of end-stage kidney disease (ESKD) worldwide. Despite the use of reninangiotensin system blockade, sodium-glucose transport protein 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists, and nonsteroidal mineralocorticoid receptor antagonists the risk of progression to ESKD and CV events persists in this high-risk population. For this reason, new or combined strategies for treating persons with CKD and DM are in constant development. This editorial discusses the results of a recent published trial, Combination Effect of Finerenone and Empagliflozin (EMP) in Participants with Chronic Kidney Disease and Type 2 Diabetes Using a Urinary Albumin-to-Creatinine Ratio (UACR) Endpoint (CONFIDENCE) in persons with DM and CKD focused in the mechanisms involved in the beneficial renal effect in terms of albuminuria reduction[1]. Whether there is related to the synergistic effect of the combination therapy (EMP + finerenone) or merely a manifestation secondary to systolic blood pressure (SBP) reduction remains to be determined[2].The CONFIDENCE trial, a double-blind, multicenter, study involving 800 patients with type 2 DM and CKD (eGFR 30 to 90 ml/min/1.73m 2 and urinary albumin-to creatinine ratio (UACR) 100 to < 5000 mg/g) tested the effect of combining finerenone and EMP on reducing albuminuria compared with monotherapy with either empagliflozin or finerenone alone, over 180 days. All patients were on maximum tolerated angiotensin II blockade at baseline. The primary endpoint was the relative change in the log-transformed mean UACR from baseline to 180 days, a surrogate marker for kidney disease progression in previous meta-analysis [3].

The effect of ARNI and SGLT2i therapies on the inflammasome pathway in myocardial heart transplantation biobank samples

Specialist pharmacist-led rapid optimisation of patients with heart failure with reduced ejection fraction in the outpatient setting

Guideline-directed medical therapy use in adults with duchenne muscular dystrophy and heart failure with reduced ejection fraction

Finerenone is a nonsteroidal mineralocorticoid receptor antagonist that has demonstrated cardiorenal benefits in patients with chronic kidney disease (CKD) associated with type 2 diabetes. CKD affects up to 40% of patients with type 2 diabetes and is associated with substantial cardiovascular morbidity and mortality. Despite renin-angiotensin system inhibitors and sodium-glucose cotransporter-2 inhibitor therapy, many patients experience worsening kidney function and cardiovascular events. This narrative review summarizes evidence published between 2014 and 2025, including Mineralocorticoid Receptor Antagonist Tolerability Study-Diabetic Nephropathy, Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease, Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease, pooled analysis of FIDELIO-DKD and FIGARO-DKD, and Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure, and relevant real-world studies. Finerenone provides organ protection by reducing mineralocorticoid receptor-mediated inflammation and fibrosis, offering benefits beyond blood pressure and glycemic control. Clinical trials have shown an approximate 30% drop in urine albumin-to-creatinine ratio within the first months of treatment, with a slower long-term decline in kidney function. The pooled analyses indicate a 23% reduction in serious kidney outcomes and a 14% reduction in major cardiovascular events compared with placebo, in patients receiving background angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy. Although hyperkalemia was more frequent with finerenone than placebo, discontinuation was uncommon under trial-based monitoring protocols. Overall, finerenone is an important addition to cardiorenal risk reduction in CKD associated with type 2 diabetes, although direct randomized endpoint comparisons with spironolactone or eplerenone remain lacking. Hyperkalemia risk should be interpreted in the context of trial eligibility criteria and structured potassium monitoring.

Temporal trends in mineralocorticoid receptor antagonist use among patients with heart failure in a community-based cohort

Many drugs influence blood potassium levels and are often prescribed to older adults. Aim of this study was to estimate the extend of potassium level changes of drugs in the case of older, multi-medicated patients respecting renal function. Data of patients from an outpatient clinic (polypharmacy consultations hours) at the University Hospital RWTH Aachen and from a prospective, multicenter study on adverse drug reactions in emergency departments (ADRED) was used. Data of patients aged ≥ 70 years taking ≥ 3 drugs with available blood potassium levels were included. Quantile regression models were used to analyze drug effects in the context of multi-medication. In total, N = 1097 patient cases were included with hypokalemia in 28.4% (n = 311) and hyperkalemia in 20.3% (n = 223). Male sex, use of low-ceiling diuretics, loop diuretics, mineralocorticoid receptor antagonists (MRAs), angiotensin-converting-enzyme inhibitors/ angiotensin II receptor blockers, number of other drugs, and CKD stage were associated with serum potassium levels and included in quantile regression models. In CKD stages 1 and 2, the use of MRAs (+ 0.49, p = 0.002), together with low-ceiling diuretics (-0.54, p < 0.001) had highest impact on serum potassium levels. In CKD stage 3, use of low-ceiling diuretics (-0.52, p < 0.001) and in CKD stages 4 and 5, the use of MRAs (+ 0.86, p < 0.001) had highest impact on serum potassium levels. Hypo- as well as hyperkalemia occur frequently in geriatric, multi-medicated patients. While renal function is an important predictor of blood potassium levels, drug effects can differ per drug class in the context of multi-medication. The ADRED-study is registered at the German Clinical Trials Register under: DRKS00008979. The cohort study of the polypharmacy consultation hours at the University Hospital RWTH Aachen is registered at the ClinicalTrials.gov under: NCT05247814.

The Fontan circulation is defined by unique physiological constraints that limit preload, elevate systemic venous pressure, and reduce the capacity to compensate for stress or injury. Traditional paradigms for managing biventricular heart failure are often misaligned with the pathophysiology of this preload-limited, non-pulsatile system. In this editorial, we propose a conceptual reframing of medical therapy in the Fontan circulation, centred on preserving physiological reserve and long-term durability rather than reversing established failure. We introduce a serial constraints model that emphasises the interconnected roles of the pulmonary vascular bed, ventricular filling, systemic output, venous and lymphatic function, and end-organ tolerance. As limitations shift over time, therapeutic focus must also evolve from pulmonary vasodilation in early stages to addressing ventricular dysfunction, venous congestion, and fibrosis later in the trajectory. We review emerging applications of phosphodiesterase type 5 inhibitors, sodium-glucose cotransporter-2 inhibitors, nonsteroidal mineralocorticoid receptor antagonists and exercise within this framework, while cautioning against routine use of conventional renin-angiotensin-aldosterone system inhibition or beta-blockers in the absence of clear comorbid indications. Antithrombotic strategies remain important due to a persistent thrombo-inflammatory milieu. We advocate for a shift from reactive to trajectory-preserving therapy, targeting flow under stress, organ protection, and reserve conservation. This physiology-aligned, evidence-informed approach provides a rationale for earlier intervention and testable hypotheses for future Fontan-specific trials.

Heart failure with reduced ejection fraction (HFrEF) remains a leading cause of morbidity, hospitalization, and mortality in low- and middle-income countries (LMICs). Guideline-directed medical therapy (GDMT) including angiotensin receptor-neprilysin inhibitors (ARNIs), evidence-based beta-blockers, mineralocorticoid receptor antagonists (MRAs), and sodium-glucose co-transporter 2 (SGLT2) inhibitors has consistently demonstrated reductions in mortality and heart failure (HF) hospitalizations. Despite strong evidence, real-world implementation of GDMT in LMICs remains suboptimal. This article synthesizes published evidence and expert experience to identify barriers to GDMT implementation in India and comparable LMIC settings and to propose pragmatic, resource-aligned strategies to improve uptake. Relevant English-language literature (2015-2025) was identified through PubMed, Google Scholar, and guideline repositories (ESC, ACC/AHA/HFSA, CSI). Search terms included "heart failure," "GDMT," "LMIC," "India," "implementation barriers," and "pharmacist-led care." Key guidelines, randomized trials, observational studies, registries, and relevant reviews were included. Barriers span economic constraints, limited insurance coverage, high out-of-pocket costs, low health literacy, cultural beliefs, fragmented follow-up, limited access to specialized HF services, inconsistent drug availability, and clinician-level knowledge-practice gaps. Evidence from observational studies and implementation reports supports early low-dose combination GDMT, simplified titration pathways, pharmacist- and nurse-led follow-up models, task-shifting, and telemedicine-enabled monitoring as feasible strategies in LMIC settings. Bridging the evidence-practice gap for GDMT in LMICs requires coordinated, multi-level interventions tailored to resource constraints. Strengthening team-based care and aligning policy with essential HF therapies can substantially improve outcomes and equity.