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Chronic kidney disease (CKD) represents a global health concern, associated with an increased risk of cardiovascular morbidity and mortality and decreased quality of life. Many patients with type 1 diabetes (T1D) will develop CKD over their lifetime. Uncontrolled glucose levels, which occur in patients with T1D as well as type 2 diabetes (T2D), are associated with substantial mortality and cardiovascular disease burden. T2D and T1D share common pathological features of CKD, which is thought to be driven by haemodynamic dysfunction, metabolic disturbances, and subsequently an influx of inflammatory and profibrotic mediators, both of which are major interrelated contributors to CKD progression. The mineralocorticoid receptor is also involved, and, under conditions of oxidative stress, salt loading and hyperglycaemia, it switches from homeostatic regulator to pathophysiological mediator by promoting oxidative stress, inflammation and fibrosis. Progressive glomerular and tubular injury leads to macroalbuminuria a progressive reduction in the glomerular filtration rate and eventually end‐stage renal disease. Finerenone, a non‐steroidal, selective mineralocorticoid receptor antagonist, is approved for treatment of patients with CKD associated with T2D; however, the benefit of finerenone in patients with T1D has yet to be determined. This narrative review will discuss treatment of CKD in T1D and the potential future role of finerenone in this setting. [ABSTRACT FROM AUTHOR]

Hyperkalemia (HK) is associated with suboptimal renin–angiotensin system (RAS) inhibitor and mineralocorticoid receptor antagonist (MRA) use in heart failure with reduced ejection fraction (HFrEF). This study sought to assess characteristics and RAS inhibitor/MRA use in patients receiving patiromer during the DIAMOND (Patiromer for the Management of Hyperkalemia in Subjects Receiving RAASi Medications for the Treatment of Heart Failure) run-in phase. Patients with HFrEF and HK or past HK entered a run-in phase of ≤12 weeks with patiromer-facilitated RAS inhibitor/MRA optimization to achieve ≥50% recommended RAS inhibitor dose, 50 mg/d MRA, and normokalemia. Patients achieving these criteria (randomized group) were compared with the run-in failure group (patients not meeting the randomization criteria). Of 1,038 patients completing the run-in, 878 (84.6%) were randomized and 160 (15.4%) were run-in failures. Overall, 422 (40.7%) had HK entering run-in with a similar frequency in the randomized and run-in failure groups (40.3% vs 42.5%; P = 0.605). From start to the end of run-in, in the randomized group, an increase was observed in target RAS inhibitor and MRA use in patients with HK (RAS inhibitor: 76.8% to 98.6%; MRA: 35.9% to 98.6%) and past HK (RAS inhibitor: 60.5% to 98.1%; MRA: 15.6% to 98.7%). Despite not meeting the randomization criteria, an increase after run-in was observed in the run-in failure group in target RAS inhibitor (52.5% to 70.6%) and MRA use (15.0% to 48.1%). This increase was observed in patients with HK (RAS inhibitor: 51.5% to 64.7%; MRA: 19.1% to 39.7%) and past HK (RAS inhibitor: 53.3% to 75.0%; MRA: 12.0% to 54.3%). In patients with HFrEF and HK or past HK receiving suboptimal RAS inhibitor/MRA therapy, RAS inhibitor/MRA optimization increased during patiromer-facilitated run-in. [ABSTRACT FROM AUTHOR]

Objective: Here, we aimed to investigate the role of glucocorticoid and mineralocorticoid receptors (GRs and MRs, respectively) in the regulation of energy homeostasis. Methods: We used three mouse models with simultaneous deletion of GRs and MRs in either forebrain neurons, the paraventricular nucleus, or corticotropin‐releasing hormone (CRH) neurons and compared them with wild‐type controls or isolated knockout groups. In addition to body weight, food intake, energy expenditure, insulin sensitivity, fat/lean mass distribution, and plasma corticosterone levels, we also performed transcriptomic analysis of CRH neurons and assessed their response to melanocortinergic stimulation. Results: Similar to global double‐knockout models, deletion of GRs and MRs specifically in mature CRH neurons resulted in obesity. Importantly, the latter was accompanied by insulin resistance, but not increased plasma corticosterone levels. Transcriptomic analysis of these neurons revealed upregulation of several genes involved in postsynaptic signal transduction, including the Ptk2b gene, which encodes proline‐rich tyrosine kinase 2. Knockout of both nuclear receptors leads to upregulation of Ptk2b in CRH neurons, which results in their diminished responsiveness to melanocortinergic stimulation. Conclusions: Our data demonstrate the functional redundancy of GRs and MRs in CRH neurons to maintain energy homeostasis and prevent obesity. Simultaneous targeting of both receptors might represent an unprecedented approach to counteract obesity. [ABSTRACT FROM AUTHOR]

Aims: Sex differences in long‐term post‐discharge clinical outcomes in Asian patients hospitalized for acute decompensated heart failure (HF) persist despite the world‐wide implementation of guideline‐directed medical therapy for decades. The present study aims to elucidate the puzzling dilemma and to depict the directions of solution. Methods and results: Between 2011 and 2020, a total of 12 428 patients (6518 men and 5910 women, mean age 73.50 ± 14.85) hospitalized for acute decompensated HF were retrospectively enrolled from a university HF cohort. Compared with men, women hospitalized for acute decompensated HF were older in age (76.40 ± 13.43 vs. 71.20 ± 15.67 years old, P < 0.0001) with more coexisting hypertension, diabetes, hyperlipidaemia and moderate to severe chronic kidney disease, but less with ischaemic heart disease, cerebrovascular disease and chronic obstructive pulmonary disease (P < 0.0001). In echocardiography measurement parameters, women had smaller left ventricular and left atrial dimensions, higher left ventricular mass index, higher left ventricular ejection fraction (LVEF) and more in HF with preserved ejection fraction (EF) category (LVEF > 50%) than men (P < 0.0001). In HF therapy, women compared with men received more guideline‐directed medical HF therapies including angiotensin‐converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor–neprilysin inhibitors and sodium–glucose cotransporter‐2 inhibitors, but similar beta‐blockers and mineralocorticoid receptor antagonists (P < 0.0001). Post‐discharge long‐term clinical outcomes after multivariate‐adjusted analysis revealed that women compared with men had lower all‐cause mortality [adjusted hazard ratio (aHR): 0.89, 95% confidence interval (CI): 0.84–0.93], lower cardiovascular mortality (aHR: 0.89, 95% CI: 0.80–0.99) and lower 1 year mortality (aHR: 0.91, 95% CI: 0.84–0.99) but similar HF rehospitalization rate (aHR: 1.02, 95% CI: 0.95–1.09) over 8 years of follow‐up. The superiority of women over men in all‐cause mortality was shown in HF with preserved EF (>50%) and HF with mildly reduced EF (40%–50%), but not in HF with reduced EF (<40%) category. Subgroup forest plot analysis showed body mass index, coexisting hypertension and chronic obstructive pulmonary disease as significant interacting factors. Conclusions: With more coronary risk factors and medical comorbidities, less cardiac remodelling and better adherence to guideline‐directed HF therapy, women hospitalized for acute decompensated HF demonstrated superiority over men in long‐term post‐discharge clinical outcomes, including all‐cause mortality, cardiovascular mortality and 1 year mortality, and mainly in HF with preserved and mid‐range EF categories, in the Asian HF cohort. [ABSTRACT FROM AUTHOR]

Aims: A set of indicators to assess the quality of care for patients hospitalized for heart failure was developed by an expert working group of the Italian Health Ministry. Because a better performance profile measured using these indicators does not necessarily translate to better outcomes, a study to validate these indicators through their relationship with measurable clinical outcomes and healthcare costs supported by the Italian National Health System was carried out. Methods and results: Residents of four Italian regions (Lombardy, Marche, Lazio, and Sicily) who were newly hospitalized for heart failure (irrespective of stage and New York Heart Association class) during 2014–2015 entered in the cohort and followed up until 2019. Adherence to evidence‐based recommendations [i.e. renin–angiotensin–aldosterone system (RAS) inhibitors, beta‐blockers, mineralocorticoid receptor antagonists (MRAs), and echocardiograms (ECCs)] experienced during the first year after index discharge was assessed. Composite clinical outcomes (cardiovascular hospital admissions and all‐cause mortality) and healthcare costs (hospitalizations, drugs, and outpatient services) were assessed during the follow‐up. The restricted mean survival time at 5 years (denoted as the number of months free from clinical outcomes), the hazard of clinical outcomes (according to the Cox model), and average annual healthcare cost (expressed in euros per person‐year) were compared between adherent and non‐adherent patients. A non‐parametric bootstrap method based on 1000 resamples was used to account for uncertainty in cost‐effectiveness estimates. A total of 41 406 patients were included in this study (46.3% males, mean age 76.9 ± 9.4 years). Adherence to RAS inhibitors, beta‐blockers, MRAs, and ECCs were 64%, 57%, 62%, and 20% among the cohort members, respectively. Compared with non‐adherent patients, those who adhered to ECCs, RAS inhibitors, beta‐blockers, and MRAs experienced (i) a delay in the composite outcome of 1.6, 1.9, 1.6, and 0.6 months and reduced risks of 9% (95% confidence interval, 2–14%), 11% (7–14%), 8% (5–11%), and 4% (−1–8%), respectively; and (ii) lower (€262, €92, and €571 per year for RAS inhibitors, beta‐blockers, and MRAs, respectively) and higher costs (€511 per year for ECC). Adherence to RAS inhibitors, beta‐blockers, and MRAs showed a delay in the composite outcome and a saving of costs in 98%, 84%, and 93% of the 1000 bootstrap replications, respectively. Conclusions: Strict monitoring of patients with heart failure through regular clinical examinations and drug therapies should be considered the cornerstone of national guidelines and audits. [ABSTRACT FROM AUTHOR]

Background: Duchenne muscular dystrophy (DMD) is a rare disease that causes progressive muscle degeneration resulting in life-threatening cardiac complications. The objective of this systematic literature review was to describe and grade the published evidence of predictors of cardiac disease in DMD. Methods: The review encompassed searches of Embase, MEDLINE ALL, and the Cochrane Database of Systematic Reviews from January 1, 2000, to December 31, 2022, for predictors of cardiac disease in DMD. The certainty of evidence (i.e., very low to high) was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework. Results: We included 33 publications encompassing 9,232 patients with DMD. We found moderate- to high-quality evidence that cardiac medication (i.e., ACE inhibitors [enalapril and perindopril], β-blockers [carvedilol], and mineralocorticoid receptor antagonists [eplerenone]) are significantly associated with preserved left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), and left ventricular circumferential strain (LVCS). DMD mutations in exons 51 and 52 were found to be significantly associated with lower risk of cardiomyopathy; deletions treatable by exon 53 skipping and mutations in the Dp116 coding region with improved LVEF and prolonged cardiac dysfunction-free survival; and exons 45–50 and 52 with early left ventricular systolic dysfunction (low/very low-quality evidence). We found high-quality evidence that glucocorticoids (deflazacort) are significantly associated with preserved LVEF and improved fractional shortening (FS), and low-quality evidence that glucocorticoids (deflazacort, prednisone, and/or prednisolone) are associated with improved ejection fraction (EF) and lower risk of cardiomyopathy, ventricular dysfunction, and heart failure-related mortality. Full-time mechanical ventilation was found to be significantly correlated with LVEF (low-quality evidence), muscle strength with FS (low-quality evidence), and genetic modifiers (i.e., LTBP4 rs10880 and ACTN3) with LVEF, lower risk of cardiomyopathy and left ventricular dilation (low-quality evidence). Conclusion: Several sources of cardiac disease heterogeneity are well-studied in patients with DMD. Yet, the certainty of evidence is generally low, and little is known of the contribution of non-pharmacological interventions, as well as the impact of different criteria for initiation of specific treatments. Our findings help raise awareness of prevailing unmet needs, shape expectations of treatment outcomes, and inform the design of future research. [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusion Real‐world data show that guidelines are insufficiently implemented, and particularly guideline‐directed medical therapies (GDMT) are underused in patients with heart failure and reduced ejection fraction (HFrEF) in clinical practice. The Council for Cardiology Practice and the Heart Failure Association of the European Society of Cardiology (ESC) developed a survey aiming to (i) evaluate the perspectives of the cardiology community on the 2021 ESC heart failure (HF) guidelines, (ii) pinpoint disparities in disease management, and (iii) propose strategies to enhance adherence to HF guidelines.A 22‐question survey regarding the diagnosis and treatment of HFrEF was delivered between March and June 2022. Of 457 physicians, 54% were general cardiologists, 19.4% were HF specialists, 18.9% other cardiac specialists, and 7.7% non‐cardiac specialists. For diagnosis, 52.1% employed echocardiography and natriuretic peptides (NPs), 33.2% primarily used echocardiography, and 14.7% predominantly relied on NPs. The first drug class initiated in HFrEF was angiotensin‐converting enzyme inhibitors/angiotensin receptor–neprilysin inhibitor (ACEi/ARNi) (91.2%), beta‐blockers (BB) (73.8%), mineralocorticoid receptor antagonists (MRAs) (53.4%), and sodium–glucose cotransporter 2 (SGLT2) inhibitors (48.1%). The combination ACEi/ARNi + MRA+ BB was preferred by 39.3% of physicians, ACEi/ARNi + SGLT2 inhibitors + BB by 33.3%, and ACEi/ARNi + BB by 22.2%. The time required to initiate and optimize GDMT was estimated to be <1 month by 8.3%, 1–3 months by 52%, 3–6 months by 31.8%, and >6 months by 7.9%. Compared to general cardiologists, HF specialists/academic cardiologists reported lower estimated time‐to‐initiation, and more commonly preferred a parallel initiation of GDMT rather than a sequential approach.Participants generally followed diagnostic and treatment guidelines, but variations in HFrEF management across care settings or HF specialties were noted. The survey may raise awareness and promote standardized HF care. [ABSTRACT FROM AUTHOR]

Mineralocorticoid receptor antagonists (MRAs) reduce hospitalisations and death in patients with heart failure and reduced ejection fraction (HFrEF), but the benefit in patients with heart failure and mildly reduced ejection fraction (HFmrEF) or heart failure and preserved ejection fraction (HFpEF) is unclear. We evaluated the effect of MRAs in four trials that enrolled patients with heart failure across the range of ejection fraction. This is a prespecified, individual patient level meta-analysis of the RALES (spironolactone) and EMPHASIS-HF (eplerenone) trials, which enrolled patients with HFrEF, and of the TOPCAT (spironolactone) and FINEARTS-HF (finerenone) trials, which enrolled patients with HFmrEF or HFpEF. The primary outcome of this meta-analysis was a composite of time to first hospitalisation for heart failure or cardiovascular death. We also estimated the effect of MRAs on components of this composite, total (first or repeat) heart failure hospitalisations (with and without cardiovascular deaths), and all-cause death. Safety outcomes were also assessed, including serum creatinine, estimated glomerular filtration rate, serum potassium, and systolic blood pressure. An interaction between trials and treatment was tested to examine the heterogeneity of effect in these populations. This study is registered with PROSPERO, CRD42024541487. 13 846 patients were included in the four trials. MRAs reduced the risk of cardiovascular death or heart failure hospitalisation (hazard ratio 0·77 [95% CI 0·72–0·83]). There was a statistically significant interaction by trials and treatment (p for interaction=0·0012) due to the greater efficacy in HFrEF (0·66 [0·59–0·73]) compared with HFmrEF or HFpEF (0·87 [0·79–0·95]). We observed significant reductions in heart failure hospitalisation in the HFrEF trials (0·63 [0·55–0·72]) and the HFmrEF or HFpEF trials (0·82 [0·74–0·91]). The same pattern was observed for total heart failure hospitalisations with or without cardiovascular death. Cardiovascular death was reduced in the HFrEF trials (0·72 [0·63–0·82]) but not in the HFmrEF or HFpEF trials (0·92 [0·80–1·05]). All-cause death was also reduced in the HFrEF trials (0·73 [0·65–0·83]) but not in the HFmrEF or HFpEF trials (0·94 [0·85–1·03]). With an MRA, the risk of hyperkalaemia was doubled compared with placebo (odds ratio 2·27 [95% CI 2·02–2·56]), but the incidence of serious hyperkalaemia (serum potassium >6·0 mmol/L) was low (2·9% vs 1·4%); the risk of hypokalaemia (potassium <3·5 mmol/L) was halved (0·51 [0·45–0·57]; 7% vs 14%). Steroidal MRAs reduce the risk of cardiovascular death or heart failure hospitalisation in patients with HFrEF and non-steroidal MRAs reduce this risk in patients with HFmrEF or HFpEF. None. [ABSTRACT FROM AUTHOR]

Every year millions die prematurely of complications related to chronic kidney disease (CKD). Main causes of death are connected with cardiovascular (CV) complications. There is no cure for CKD although current treatment can slow the progression of the disease if diagnosed early. Fortunately, last decades have witnessed an accelerating pace of discovery regarding the cellular and molecular basis for CKD and CV disease. Novel biomarkers, including amino-terminal type III procollagen peptide (PIIINP), carboxy-terminal type I procollagen peptide (PICP), FGF23, marinobufagenin, and several miRNAs, show promise for early detection and risk stratification. In this review, we provide an overview of recent advances in the "fibrotic concept" of the etiology and pathogenesis of CKD which involves system consisting of Na/K-ATPase and its endogenous ligands including marinobufagenin which inhibits Fli1 and stimulates synthesis of collagen-1 in the vasculature. A novel treatment of CKD already involves the use of mineralocorticoid receptor antagonists capable of impairing marinobufagenin-Na/K-ATPase interactions. [ABSTRACT FROM AUTHOR]

Inadequate blood supply to the expanding adipose tissue (AT) is involved in the unhealthy AT remodeling and cardiometabolic consequences of obesity. Because of the pathophysiological role of upregulated mineralocorticoid receptor (MR) signaling in the complications of obesity, this study tested the vasoactive properties of finerenone, a nonsteroidal MR antagonist, in arteries of human AT. Arteries isolated from the visceral AT of obese subjects were studied in a wire myograph. Finerenone resulted in a concentration‐dependent relaxation of arteries precontracted with either the thromboxane‐A2 analog U46619, ET‐1, or high‐K+ solution; the steroidal MR antagonist potassium canrenoate, by contrast, did not relax arteries contracted with either U46619 or high‐K+ solution. Finerenone‐induced relaxation after precontraction with U46619 was greater in the arteries of obese versus nonobese subjects. Mechanistically, the vasorelaxing response to finerenone was not influenced by preincubation with the nitric oxide synthase inhibitor L‐NAME or by endothelium removal. Interestingly, finerenone, like the dihydropyridine Ca2+‐channel blocker nifedipine, relaxed arteries contracted with the L‐type Ca2+‐channel agonist Bay K8644. In conclusion, finerenone relaxes arteries of human visceral AT, likely through antagonism of L‐type Ca2+ channels. This finding identifies a novel mechanism by which finerenone may improve AT perfusion, hence protecting against the cardiometabolic complications of obesity. [ABSTRACT FROM AUTHOR]

Aims Methods Conclusion 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.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.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. [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusion We analysed baseline characteristics and guideline‐directed medical therapy (GDMT) use and decisions in the European Society of Cardiology (ESC) Heart Failure (HF) III Registry.Between 1 November 2018 and 31 December 2020, 10 162 patients with acute HF (AHF, 39%, age 70 [62–79], 36% women) or outpatient visit for HF (61%, age 66 [58–75], 33% women), with HF with reduced (HFrEF, 57%), mildly reduced (HFmrEF, 17%) or preserved (HFpEF, 26%) ejection fraction were enrolled from 220 centres in 41 European or ESC‐affiliated countries. With AHF, 97% were hospitalized, 2.2% received intravenous treatment in the emergency department, and 0.9% received intravenous treatment in an outpatient clinic. AHF was seen by most by a general cardiologist (51%) and outpatient HF most by a HF specialist (48%). A majority had been hospitalized for HF before, but 26% of AHF and 6.1% of outpatient HF had de novo HF. Baseline use, initiation and discontinuation of GDMT varied according to AHF versus outpatient HF, de novo versus pre‐existing HF, and by ejection fraction. After the AHF event or outpatient HF visit, use of any renin–angiotensin system inhibitor, angiotensin receptor–neprilysin inhibitor, beta‐blocker, mineralocorticoid receptor antagonist and loop diuretics was 89%, 29%, 92%, 78%, and 85% in HFrEF; 89%, 9.7%, 90%, 64%, and 81% in HFmrEF; and 77%, 3.1%, 80%, 48%, and 80% in HFpEF.Use and initiation of GDMT was high in cardiology centres in Europe, compared to previous reports from cohorts and registries including more primary care and general medicine and regions more local or outside of Europe and ESC‐affiliated countries. [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

The proopiomelanocortin (Pomc)‐derived peptides, including adrenocorticotropic hormone and α‐melanocyte stimulating hormone (α‐Msh), play both a central and a peripheral role in modulating the stress response. The central role is predominantly associated with nutrient homeostasis, while peripherally they play an important role in the synthesis of glucocorticoids (GCs) in response to stress. Pomc mutations are a major risk factor in the development of early‐onset childhood obesity in humans. This is attributed primarily to their central effects on melanocortin receptor dysfunction leading to hyperphagia and reduced energy expenditure, while the peripheral mechanism contributing to obesity has largely been unexplored. Here, we tested the hypothesis that Pomc mutation‐mediated adrenal insufficiency and the associated changes in GC signaling contribute to postnatal adiposity using zebrafish as a model. We generated a ubiquitous Pomc knockout zebrafish that mimicked the mammalian mutant phenotype of adrenal insufficiency and enhanced adiposity. The loss of Pomc inhibited stress‐induced cortisol production and reprogrammed GC signaling by reducing glucocorticoid receptor responsiveness, whereas the mineralocorticoid receptor (Mr) signaling was enhanced. Larval feeding led to enhanced growth and adipogenesis in the Pomc mutants, and this was inhibited by eplerenone, an Mr antagonist. Altogether, our results underscore a key role for Mr signaling in early developmental adipogenesis and a possible target for therapeutic intervention for early‐onset childhood obesity due to Pomc dysfunction. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is one of the leading causes of chronic kidney disease and its progression to end-stage kidney disease (ESKD). Diabetic kidney disease (DKD) is characterized by glomerular hypertrophy, hyperfiltration, inflammation, and the onset of albuminuria, together with a progressive reduction in glomerular filtration rate. This progression is further accompanied by tubulointerstitial inflammation and fibrosis. Factors such as genetic predisposition, epigenetic modifications, metabolic derangements, hemodynamic alterations, inflammation, and inappropriate renin-angiotensin-aldosterone system (RAAS) activity contribute to the onset and progression of DKD. In this context, decades of work have focused on glycemic and blood pressure reduction strategies, especially targeting the RAAS to slow disease progression. Although much of the work has focused on targeting angiotensin II, emerging data support that the mineralocorticoid receptor (MR) is integral in the development and progression of DKD. Molecular mechanisms linked to the underlying pathophysiological changes derived from MR activation include vascular endothelial and epithelial cell responses to oxidative stress and inflammation. These responses lead to alterations in the microcirculatory environment, the abnormal release of extracellular vesicles, gut dysbiosis, epithelial-mesenchymal transition, and kidney fibrosis. Herein, we present recent experimental and clinical evidence on the MR in DKD onset and progress along with new MR-based strategies for the treatment and prevention of DKD. [ABSTRACT FROM AUTHOR]

Over the past decades, research has clearly established the important role of the mineralocorticoid receptor (MR) in both renal and extra-renal tissues. Recently, caveolin-1 (Cav-1) has emerged as a mediator of MR signaling in several tissues, with implications on cardiovascular and metabolic dysfunction. The main structural component of caveolae (plasma membrane invaginations with diverse functions), Cav-1 is a modulator of cardiovascular function, cellular glucose, and lipid homeostasis, via its effects on signal transduction pathways that mediate inflammatory responses and oxidative stress. In this review, we present evidence indicating an overlap between the roles of the MR and Cav-1 in cardiometabolic disease and the relevant signaling pathways involved. Furthermore, we discuss the potential use of Cav-1 as a biomarker and/or target for MR-mediated dysfunction. [ABSTRACT FROM AUTHOR]

Primary: aldosteronism is a frequent cause of secondary hypertension. With access to specialized care, an increasing number of patients with aldosteronism are being identified. Primary aldosteronism is treatable by adrenal surgery if aldosterone excess originates from one of the two, and not from both, adrenals. Bilateral hyperplasia requires lifelong mineralocorticoid receptor antagonist treatment. Up till now, adrenal venous sampling (AVS) has been widely used to distinguish between one-sided and two-sided aldosterone overproduction and patient selection for surgery. AVS is an invasive technique, and the unsuccessful sampling of the right adrenal vein during AVS often prevents side comparison, making the AVS procedure useless. Molecular imaging using [131I]6ß-iodomethyl-19-norcholesterol with SPECT CT imaging (SPECT/CT) may be a potential alternative. Methods: In 42 consecutive patients with confirmed primary aldosteronism, molecular imaging has been performed. After dexamethasone suppression of the non-affected adrenal tissue, 37 MBq [131I]6ß-iodomethyl-19-norcholesterol was injected i.v., and SPECT/CT images were taken 7 days later. Based on the visual evaluation of the images by two nuclear medicine specialists, patients with one-sided tracer accumulation underwent adrenalectomy. To identify a SPECT/CT parameter that best characterizes the side difference, the maximum counts and the mean counts of spherical VOIs were analyzed. Results: Of the 42 patients, 24 had one-sided aldosterone overproduction by SPECT/CT. After surgical removal of the involved adrenal, all 24 patients with SPECT/CT-identified unilateral aldosteronism achieved biochemical cure, defined as a normalized potassium level combined with an aldosterone-to-renin ratio ≤ 30. To identify the best measurable parameter of SPECT/CT side difference, the mean counts and maximum counts of a series of spherical VOIs of different diameters were analyzed. The ratio of the mean counts of 3 cm spherical VOIs of the right and left adrenal regions (lateralization index) was the best discriminator; a ratio of ≥1.29 was characteristic of one-sided disease, without overlap between the one-sided and two-sided patient groups. Conclusions: [131I]6ß-iodomethyl-19-norcholesterol SPECT/CT with a count-based image interpretation and side-ratio calculation may be an equipollent non-invasive substitute for adrenal venous sampling in the lateralization of mineralocorticoid overproduction. It reliably identifies unilateral disease and facilitates patients' selection for surgical intervention. If confirmed by others, this functional imaging may replace AVS when lateralization is required for management decisions in primary aldosteronism. [ABSTRACT FROM AUTHOR]

Eplerenone is a medication used to manage hypertension and chronic heart failure by inhibiting aldosterone receptors. This study's objective is to prepare sublingual dissolving films containing Eplerenone, to enhance patient adherence, avoid first-pass metabolism, and minimize the need for repeated dosing. To achieve this goal, eight different formulations were prepared using a solvent-casting method. The study examined how various formulation factors influenced the physical and mechanical characteristics of the films, as well as their drug-release behavior. Notably, the results showed that the Eplerenone oral film, which included a combination of hydroxypropyl methylcellulose (HPMC E5) and polyvinyl alcohol (PVA), exhibited the fastest disintegration time, dissolving within just 27 seconds. Furthermore, formula F3, containing 25 mg of HPMC E5, 25 mg of PVA, and 30% glycerin, demonstrated a remarkable drug release rate of 72.4% within a 2-minute period with satisfactory mechanical properties. To summarize, this investigation successfully developed sublingual dissolving films for Eplerenone to improve patient adherence and decrease the necessity for frequent dosing. These films disintegrate rapidly and provide effective drug release, offering a patient-friendly alternative for managing conditions such as hypertension and chronic heart failure. [ABSTRACT FROM AUTHOR]

Stress and inflammation are risk factors for schizophrenia. Chronic psychosocial stress is associated with subcortical hyperdopaminergia, a core feature of schizophrenia. Hyperdopaminergia arises from midbrain neurons, leading us to hypothesise that changes in stress response pathways may occur in this region. To identify whether transcriptional changes in glucocorticoid and mineralocorticoid receptors (NR3C1/GR, NR3C2/MR) or other stress signalling molecules (FKBP4, FKBP5) exist in schizophrenia midbrain, we measured gene expression in the human brain (N = 56) using qRT-PCR. We assessed whether alterations in these mRNAs were related to previously identified high/low inflammatory status. We investigated relationships between stress-related transcripts themselves, and between FKBP5 mRNA, dopaminergic, and glial cell transcripts in diagnostic and inflammatory subgroups. Though unchanged by diagnosis, GR mRNA levels were reduced in high inflammatory compared to low inflammatory schizophrenia cases (p = 0.026). We found no effect of diagnosis or inflammation on MR mRNA. FKBP4 mRNA was decreased and FKBP5 mRNA was increased in schizophrenia (p < 0.05). FKBP5 changes occurred in high inflammatory (p < 0.001), whereas FKBP4 changes occurred in low inflammatory schizophrenia cases (p < 0.05). The decrease in mRNA encoding the main stress receptor (GR), as well as increased transcript levels of the stress-responsive negative regulator (FKBP5), may combine to blunt the midbrain response to stress in schizophrenia when neuroinflammation is present. Negative correlations between FKBP5 mRNA and dopaminergic transcripts in the low inflammatory subgroup suggest higher levels of FKBP5 mRNA may also attenuate dopaminergic neurotransmission in schizophrenia even when inflammation is absent. We report alterations in GR-mediated stress signalling in the midbrain in schizophrenia. • Stress and neuroinflammation are implicated in the pathophysiology of schizophrenia. • GR-mediated stress signalling is altered in the midbrain in schizophrenia. • Decreased GR and increased FKBP5 mRNAs may impair midbrain stress responsivity in the presence of heightened neuroinflammation. • Higher FKBP5 mRNA may contribute to dopamine dysregulation in the midbrain in schizophrenia in the absence of heightened neuroinflammation. • These findings suggest altered stress responsivity in the midbrain in schizophrenia consistent with a state of chronic stress. [ABSTRACT FROM AUTHOR]

Volume overload represents a hallmark clinical feature linked to the development and progression of heart failure (HF). Alleviating signs and symptoms of volume overload represents a foundational HF treatment target that is achieved using loop diuretics in the acute and chronic setting. Recent work has provided evidence to support guideline-directed medical therapies, such as sodium glucose cotransporter 2 (SGLT2) inhibitors and mineralocorticoid receptor (MR) antagonists, as important adjunct diuretics that may act synergistically when used with background loop diuretics in people with chronic HF. Furthermore, there is growing interest in understanding the role of SGLT2 inhibitors, carbonic anhydrase inhibitors, thiazide diuretics, and MR antagonists in treating volume overload in patients hospitalized for acute HF, particularly in the setting of loop diuretic resistance. Thus, the current review demonstrates that: (i) SGLT2 inhibitors and MR antagonists confer long-term cardioprotection in chronic HF patients but it is unclear whether natriuresis or diuresis represents the primary mechanisms for this benefit, (ii) SGLT2 inhibitors, carbonic anhydrase inhibitors, and thiazide diuretics increase natriuresis in the acute HF setting, but implications on long-term outcomes remain unclear and warrants further investigation, and (iii) a multi-nephron segment approach, using agents that act on distinct segments of the nephron, potentiate diuresis to alleviate signs and symptoms of volume overload in acute HF. [ABSTRACT FROM AUTHOR]

Context Primary aldosteronism is a form of low-renin hypertension characterized by dysregulated aldosterone production. Objective To investigate the contributions of renin-independent aldosteronism and ACTH-mediated aldosteronism in individuals with a low-renin phenotype representing the entire continuum of blood pressure. Design/Participants Human physiology study of 348 participants with a low-renin phenotype with severe and/or resistant hypertension, hypertension with hypokalemia, elevated blood pressure and stage I/II hypertension, and normal blood pressure. Setting 4 international centers. Interventions/Main Outcome Measures The saline suppression test (SST) to quantify the magnitude of renin-independent aldosteronism; dexamethasone suppression and ACTH-stimulation tests to quantify the magnitude of ACTH-mediated aldosteronism; adrenal venous sampling to determine lateralization. Results There was a continuum of nonsuppressible and renin-independent aldosterone production following SST that paralleled the magnitude of the blood pressure continuum and transcended conventional diagnostic thresholds. In parallel, there was a full continuum of ACTH-mediated aldosteronism wherein post-SST aldosterone levels were strongly correlated with ACTH-stimulated aldosterone production (r = 0.75, P <.0001) and nonsuppressible aldosterone production postdexamethasone (r = 0.40, P <.0001). Beyond participants who met the criteria for primary aldosteronism (post-SST aldosterone of ≥10 ng/dL or ≥277 pmol/L), the continuum of nonsuppressible and renin-independent aldosterone production persisted below this diagnostic threshold, wherein 15% still had lateralizing aldosteronism amenable to surgical adrenalectomy and the remainder were treated with mineralocorticoid receptor antagonists. Conclusion In the context of a low-renin phenotype, there is a continuum of primary aldosteronism and dysregulated aldosterone production that is prominently influenced by ACTH. A large proportion of individuals with low renin may benefit from aldosterone-directed therapy. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is a systemic disease associated with a high risk of morbidity, mortality, increased risk of hospitalizations, and low quality of life. Therefore, effective, systemic treatment strategies are necessary to mitigate these risks. In this manuscript, we emphasize the concept of high-intensity care to optimize guideline-directed medical therapy (GDMT) in HF patients. The document highlights the importance of achieving optimal recommended doses of GDMT medications, including beta-blockers, renin–angiotensin–aldosterone inhibitors, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter inhibitors to improve patient outcomes, achieve effective, sustainable decongestion, and improve patient quality of life. The document also discusses potential obstacles to GDMT optimization, such as clinical inertia, physiological limitations, comorbidities, non-adherence, and frailty. Lastly, it also attempts to provide possible future scenarios of high-intensive care that could improve patient outcomes. [ABSTRACT FROM AUTHOR]

Corticosteroids are so vital for organ maturation that reduced corticosteroid signaling during postembryonic development causes death in terrestrial vertebrates. Indeed, death occurs at metamorphosis in frogs lacking proopiomelanocortin (pomc) or the glucocorticoid receptor (GR; nr3c1). Some residual corticosteroids exist in pomc mutants to activate the wild-type (WT) GR and mineralocorticoid receptor (MR), and the elevated corticosteroids in GR mutants may activate MR. Thus, we expected a more severe developmental phenotype in tadpoles with inactivation of 21-hydroxylase, which should eliminate all interrenal corticosteroid biosynthesis. Using CRISPR/Cas9 in Xenopus tropicalis , we produced an 11-base pair deletion in cyp21a2 , the gene encoding 21-hydroxylase. Growth and development were delayed in cyp21a2 mutant tadpoles, but unlike the other frog models, they survived metamorphosis. Consistent with an absence of 21-hydroxylase, mutant tadpoles had a 95% reduction of aldosterone in tail tissue, but they retained some corticosterone (∼40% of WT siblings), an amount, however, too low for survival in pomc mutants. Decreased corticosteroid signaling was evidenced by reduced expression of corticosteroid-response gene, klf9 , and by impaired negative feedback in the hypothalamus-pituitary-interrenal axis with higher messenger RNA expression levels of crh , pomc , star , and cyp11b2 and an approximately 30-fold increase in tail content of progesterone. In vitro tail-tip culture showed that progesterone can transactivate the frog GR. The inadequate activation of GR by corticosterone in cyp21a2 mutants was likely compensated for by sufficient corticosteroid signaling from other GR ligands to allow survival through the developmental transition from aquatic to terrestrial life. [ABSTRACT FROM AUTHOR]

BACKGROUND: Persistent mineralocorticoid receptor activation is a pathologic response in type 2 diabetes and chronic kidney disease. Whereas mineralocorticoid receptor antagonists are beneficial in reducing cardiovascular complications, direct mechanistic pathways for these effects in humans are lacking. METHODS: The MAGMA trial (Mineralocorticoid Receptor Antagonism Clinical Evaluation in Atherosclerosis) was a randomized, double-blind, placebo-controlled trial in patients with high-risk type 2 diabetes with chronic kidney disease (not receiving dialysis) on maximum tolerated renin-angiotensin system blockade. The primary end point was change in thoracic aortic wall volume, expressed as absolute or percent value (ΔTWV or ΔPWV), using 3T magnetic resonance imaging at 12 months. Secondary end points were changes in left ventricle (LV) mass; LV fibrosis, measured as a change in myocardial native T1; and 24-hour ambulatory and central aortic blood pressures. Tertiary end points included plasma proteomic changes in 7596 plasma proteins using an aptamer-based assay. RESULTS: A total of 79 patients were randomized to placebo (n=42) or 25 mg of spironolactone daily (n=37). After a modified intent-to-treat, including available baseline data of study end points, patients who completed the trial protocol were included in the final analyses. At the 12-month follow-up, the average change in PWV was 7.1±10.7% in the placebo group and 0.87±10.0% in the spironolactone group (P=0.028), and ΔTWV was 1.2±1.7 cm3 in the placebo group and 0.037±1.9 cm³ in the spironolactone group (P=0.022). Change in LV mass was 3.1±8.4 g in the placebo group and -5.8±8.4 g in the spironolactone group (P=0.001). Changes in LV T1 values were significantly different between the placebo and spironolactone groups (26.0±41.9 ms in the placebo group versus a decrease of -10.1±36.3 ms in the spironolactone group; P=6.33x10-4). Mediation analysis revealed that the spironolactone effect on thoracic aortic wall volume and myocardial mass remained significant after adjustment for ambulatory and central blood pressures. Proteomic analysis revealed a dominant effect of spironolactone on pathways involving oxidative stress, inflammation, and leukocyte activation. CONCLUSIONS: Among patients with diabetes with moderate to severe chronic kidney disease at elevated cardiovascular risk, treatment with spironolactone prevented progression of aortic wall volume and resulted in regression of LV mass and favorable alterations in native T1, suggesting amelioration of left-ventricular fibrosis. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02169089. [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusion Although the prevalence of heart failure (HF) increases markedly with advancing age, surprisingly little is known about HF in the very elderly. The aim of this study was to describe the clinical characteristics and outcomes of octogenarians with HF.Individual participant meta‐analysis of patients with HF and reduced, mildly reduced, and preserved ejection fraction (HFrEF, HFmrEF, and HFpEF, respectively) enrolled in eight large randomized trials. Overall, the proportion of octogenarians was 1518 of 20 168 patients (7.5%) with HFrEF, 610 of 4609 (13.2%) with HFmrEF, and 3130 of 15 354 (20.4%) with HFpEF. Regardless of HF phenotype, octogenarian patients were more often female and had more comorbidities, more symptoms and signs of congestion, and worse health status (but not quality of life), in comparison to patients aged <80 years. The incidence (per 100 person‐years) of the composite of cardiovascular death or HF hospitalization was 13.3 (95% confidence interval [CI] 12.7–14.0) in octogenarians versus 9.5 (95% CI 9.3–9.7) in non‐octogenarians (adjusted hazard ratio [aHR] 1.40, 95% CI 1.32–1.48). Each component of the composite was more frequent in octogenarians with rates of cardiovascular mortality of 7.0 (95% CI 6.5–7.4) per 100 person‐years versus 4.9 (95% CI 4.8–5.1) in non‐octogenarians (aHR 1.60, 95% CI 1.48–1.72, p < 0.001). Octogenarians received less evidence‐based therapy, especially mineralocorticoid receptor antagonists, than younger patients.Despite worse health status and higher hospitalization and mortality rates, octogenarians were undertreated compared to younger patients. [ABSTRACT FROM AUTHOR]

Excessive activation of the mineralocorticoid receptor (MR) is implicated in cardiovascular and renal disease. Decreasing MR activation with MR antagonists (MRA) is effective to slow chronic kidney disease (CKD) progression and its cardiovascular comorbidities in animal models and patients. The present study evaluates the effects of the MR modulator balcinrenone and the MRA eplerenone on kidney damage in a metabolic CKD mouse model combining nephron reduction and a 60% high-fat diet. Balcinrenone and eplerenone prevented the progression of renal damages, extracellular matrix remodeling and inflammation to a similar extent. We identified a novel mechanism linking MR activation to the renal proteoglycan deposition and inflammation via the TLR4 pathway activation. Balcinrenone and eplerenone similarly blunted this pathway activation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is associated with alterations in neuroendocrine function, primarily the hypothalamic–pituitary–adrenal axis, including lower expression of the glucocorticoid receptor (GR) and its target genes in peripheral blood mononuclear cells (PBMC) or full blood. We previously found reduced mineralocorticoid receptor (MR) expression in MS patients' peripheral blood. MS is being treated with a widening variety of disease-modifying treatments (DMT), some of which have similar efficacy but different mechanisms of action; body-fluid biomarkers to support the choice of the optimal initial DMT and/or to indicate an unsatisfactory response before clinical activity are unavailable. Using cell culture of volunteers' PBMCs and subsequent gene expression analysis (microarray and qPCR validation), we identified the mRNA expression of OTUD1 to represent MR signaling. The MR and MR target gene expression levels were then measured in full blood samples. In 119 MS (or CIS) patients, the expression of both MR and OTUD1 was lower than in 42 controls. The expression pattern was related to treatment, with the MR expression being particularly low in patients treated with fingolimod. While MR signaling may be involved in the therapeutic effects of some disease-modifying treatments, MR and OTUD1 expression can complement the neuroendocrine assessment of MS disease course. If confirmed, such assessment may support clinical decision-making. [ABSTRACT FROM AUTHOR]

Rationale: Sarcoidosis is a granulomatous disorder of unclear cause notable for abnormal elevation of blood and tissue ACE1 (angiotensin converting enzyme 1) levels and activity. ACE1 regulates the renin-angiotensin-aldosterone system (RAAS), the terminal product of which is aldosterone, which selectively engages mineralocorticoid receptors to promote inflammation. Objectives: We sought to determine whether the RAAS promotes sarcoidosis granuloma formation and related inflammatory responses. Methods: Using an established ex vivo model, we first determined whether aldosterone was produced by sarcoidosis granulomas and verified the presence of CYP11B2, the enzyme required for its production. We then evaluated the effects of selective inhibitors of ACE1 (captopril), angiotensin type 1 receptor (losartan), and mineralocorticoid receptors (spironolactone, eplerenone) on granuloma formation, reflected by computer image analysis–generated granuloma area, and selected cytokines incriminated in sarcoidosis pathogenesis. Measurements and Main Results: Aldosterone was spontaneously produced by sarcoidosis peripheral blood mononuclear cells, and both intra- and extracellular levels steadily increased during granuloma formation. In parallel, peripheral blood mononuclear cells were shown to express more CYP11B2 during granuloma formation. Significant inhibition of sarcoidosis granulomas and related cytokines (TNFα, IL-1β, IFNγ, IL-10) was observed in response to pretreatments with captopril, losartan, spironolactone, or eplerenone, comparable to that of prednisone. Conclusions: The RAAS is intact in sarcoidosis granulomas and contributes significantly to early granuloma formation and to related inflammatory mediator responses, with important implications for clinical management. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) is one of the leading causes of end-stage renal disease worldwide and significantly increases the risk of premature death due to cardiovascular diseases. Elevated urinary albumin levels are an important clinical feature of DKD. Effective control of albuminuria not only delays glomerular filtration rate decline but also markedly reduces cardiovascular disease risk and all-cause mortality. New drugs for treating DKD proteinuria, including sodium-glucose cotransporter two inhibitors, mineralocorticoid receptor antagonists, and endothelin receptor antagonists, have shown significant efficacy. Auxiliary treatment with proprietary Chinese medicine has also yielded promising results; however, it also faces a broader scope for development. The mechanisms by which these drugs treat albuminuria in patients with DKD should be described more thoroughly. The positive effects of combination therapy with two or more drugs in reducing albuminuria and protecting the kidneys warrant further investigation. Therefore, this review explores the pathophysiological mechanism of albuminuria in patients with DKD, the value of clinical diagnosis and prognosis, new progress and mechanisms of treatment, and multidrug therapy in patients who have type 2 diabetic kidney disease, providing a new perspective on the clinical diagnosis and treatment of DKD. [ABSTRACT FROM AUTHOR]

Introduction: From 2008 and following the withdrawal of rosiglitazone, obligatory cardiovascular outcomes trials are performed for glucose lowering drugs introduced to the market to ensure their cardiovascular (CV) safety. Paradoxically, these studies have demonstrated CV safety but also shown additional cardio-reno-vascular protection of some therapeutic agents. Additionally, nonsteroidal mineralocorticoid receptor antagonists (ns-MRA) have emerged as novel drugs for cardio – and renoprotection in type 2 diabetes (T2D) and chronic kidney disease (CKD). In addition to atherosclerotic CV disease, heart failure (HF) and CKD are important clinical problems in T2D leading to poor quality of life and premature death as such cardio-reno-vascular protection is an important clinical issue. Areas covered: We provide new insights into pharmacotherapeutic cardio-reno-vascular protection in T2D based on the new glucose lowering drugs and ns-MRA. PUB MED/CINAHL/Web of Science/Scopus were searched (May 2024). Expert opinion: The conventional glucose lowering approach alone which was implemented for decades is now replaced by the use of disease modifying drugs which lower the rates of CV events, HF decompensation, hospitalization due to HF, slow progression of CKD and all-cause mortality. Indeed, the choice of medications in T2D should be focused on underlying co-morbidities with cardio-reno-vascular protection rather than a gluco-centric approach. [ABSTRACT FROM AUTHOR]

Spironolactone, a potassium-sparing diuretic, is used to treat hypertension, heart failure, and certain hyperandrogenic disorders. Its use during pregnancy is not recommended due to the risk of feminizing male fetuses, primarily because of its antiandrogenic activity. However, human data remain scarce and largely inconclusive. Here, we present the first case of a 25-year-old pregnant woman, at 16 weeks of gestation, who was inadvertently exposed to spironolactone (240 mg/day) for 1 week due to a pharmacy dispensing error. The patient subsequently delivered a healthy male infant with normal genitalia at 38 weeks of gestation following vaginal delivery. Current follow-up shows that the infant is healthy and developing normally. This article summarizes the potential causes of spironolactone-induced anomalous genital development and explores the safety of new-generation mineralocorticoid receptor antagonists (MRAs) during pregnancy. The mechanisms behind spironolactone-induced anomalous genital development in male fetuses have not been fully elucidated. Spironolactone competes with dihydrotestosterone for binding to androgen receptors and inhibits enzymes involved in androgen biosynthesis, which may partly explain its antiandrogenic effects. Recent advancements in MRAs have led to the development of compounds with higher selectivity for the mineralocorticoid receptor, thereby reducing the incidence of antiandrogen side effects. These new-generation MRAs may be effective alternatives during pregnancy, but more data are needed to establish their safety in pregnant women. This case contributes to the limited but growing body of literature on the safety profile of spironolactone in pregnancy, providing insights into its effects during a critical period of fetal development. [ABSTRACT FROM AUTHOR]

Background: The hypothalamic–pituitary–adrenal (HPA) and -gonadal (HPG) axes are two major pathways that connect the neural and endocrine systems in vertebrates. Factors such as prenatal stress and maternal exposure to exogenous steroids have been shown to affect these pathways during fetal development. Another less studied factor is the transfer of hormones across fetuses in multifetal pregnancies. This form of transfer has been shown to influence the morphology, anatomy, physiology, and behavior of the offspring in litter-bearing mammals, an influence termed the intrauterine position (IUP) effect. In this study, we sought to delineate how the IUP effects HPA and HPG brain receptors, peptides, and enzymes (hereafter components) in utero and how these influences may differ between males and females. Methods: We utilized the unconventional model of culled free-ranging nutria (Myocastor coypus), with its large natural variation. We collected brain tissues from nutria fetuses and quantified the expression of key HPA and HPG components in three brain regions: prefrontal cortex, hypothalamus, and striatum. Results: We found an interaction between sex and IUP in the mineralocorticoid receptor (MR), gonadotropin-releasing hormone receptor (GNRHR), androgen receptor (AR), and estrogen receptor alpha (ESR1). IUP was significant in both gonadotropin-releasing hormone (GnRH) and its receptor GNRHR, but in different ways. In the hypothalamus, fetuses adjacent to same-sex neighbors had higher expression of GnRH than fetuses neighboring the opposite sex. Conversely, in the cortex, GNRHR exhibited the inverse pattern, and fetuses that were neighboring the opposite sex had higher expression levels than those neighboring the same sex. Regardless of IUP, in most components that showed significant sex differences, female fetuses had higher mRNA expression levels than male fetuses. We also found that HPA and HPG components were highly related in the early stages of gestation, and that there was an interaction between sex and developmental stage. In the early stages of pregnancy, female component expression levels were more correlated than males', but in the last trimester of pregnancy, male components were more related to each other than female's. Conclusions: This study suggests that there are sexually different mechanisms to regulate the HPA and HPG axes during fetal development. Higher mRNA expression levels of endocrine axes components may be a mechanism to help females cope with prolonged androgen exposure over a long gestational period. Additionally, these findings suggest different coordination requirements of male and female endocrine axes during stages of fetal development. Highlights: This study is the first to analyze HPA and HPG axes receptors, peptides, and enzyme mRNA expression levels in the brains of fetuses in the wild. Higher HPA and HPG axes receptors mRNA expression levels in females hint towards alternative sex-specific mechanisms that regulate endocrine axes during fetal development. Coordination of HPA and HPG axes components' expression levels is different between males and females at different stages of gestation. Plain language summary: In litter-bearing mammals, the positioning of a fetus in the uterus relative to other fetuses of the same or opposite sex has been shown to directly influence fetal morphology and physiology, and later behavior, reproductive success, and survival in adults. In this study, we sought to understand the mechanisms by which the location in the uterus influences two major neuroendocrine pathways in fetal brains. We quantified expression of multiple receptors and an enzyme (referred to as 'components') of the endocrine axes in three different brain regions in fetal free-ranging nutrias. Our results showed higher expression in females than in males for some endocrine axes components. The location inside the uterus was also related to the expression of some components. Lastly, coordination between the axes was higher earlier on in gestation, and females were more coordinated than males in the second trimester, whereas males were more coordinated than females in the third trimester. The results of this study point to the mechanisms by which the sexes regulate key neuroendocrine pathways during fetal development. [ABSTRACT FROM AUTHOR]

Background and Aims In patients with de novo heart failure with reduced ejection fraction (HFrEF), improvement of left ventricular ejection fraction (LVEF) is expected to occur when started on guideline-recommended medical therapy. However, improvement may not be completed within 90 days. Methods Patients with HFrEF and LVEF ≤ 35% prescribed a wearable cardioverter-defibrillator between 2017 and 2022 from 68 sites were enrolled, starting with a registry phase for 3 months and followed by a study phase up to 1 year. The primary endpoints were LVEF improvement > 35% between Days 90 and 180 following guideline-recommended medical therapy initiation and the percentage of target dose reached at Days 90 and 180. Results A total of 598 patients with de novo HFrEF [59 years (interquartile range 51–68), 27% female] entered the study phase. During the first 180 days, a significant increase in dosage of beta-blockers, renin–angiotensin system inhibitors, and mineralocorticoid receptor antagonists was observed (P <.001). At Day 90, 46% [95% confidence interval (CI) 41%–50%] of study phase patients had LVEF improvement > 35%; 46% (95% CI 40%–52%) of those with persistently low LVEF at Day 90 had LVEF improvement > 35% by Day 180, increasing the total rate of improvement > 35% to 68% (95% CI 63%–72%). In 392 patients followed for 360 days, improvement > 35% was observed in 77% (95% CI 72%–81%) of the patients. Until Day 90, sustained ventricular tachyarrhythmias were observed in 24 wearable cardioverter-defibrillator carriers (1.8%). After 90 days, no sustained ventricular tachyarrhythmia occurred in wearable cardioverter-defibrillator carriers. Conclusions Continuous optimization of guideline-recommended medical therapy for at least 180 days in HFrEF is associated with additional LVEF improvement > 35%, allowing for better decision-making regarding preventive implantable cardioverter-defibrillator therapy. [ABSTRACT FROM AUTHOR]

Diabetes mellitus induces a pathophysiological disorder known as diabetic cardiomyopathy and may eventually cause heart failure. Diabetic cardiomyopathy is manifested with systolic and diastolic contractile dysfunction along with alterations in unique cardiomyocyte proteins and diminished cardiomyocyte contraction. Multiple mechanisms contribute to the pathology of diabetic cardiomyopathy, mainly including abnormal insulin metabolism, hyperglycemia, glycotoxicity, cardiac lipotoxicity, endoplasmic reticulum stress, oxidative stress, mitochondrial dysfunction, calcium treatment damage, programmed myocardial cell death, improper Renin-Angiotensin-Aldosterone System activation, maladaptive immune modulation, coronary artery endothelial dysfunction, exocrine dysfunction, etc. There is an urgent need to investigate the exact pathogenesis of diabetic cardiomyopathy and improve the diagnosis and treatment of this disease. The nuclear receptor superfamily comprises a group of transcription factors, such as liver X receptor, retinoid X receptor, retinoic acid-related orphan receptor-α, retinoid receptor, vitamin D receptor, mineralocorticoid receptor, estrogen-related receptor, peroxisome proliferatoractivated receptor, nuclear receptor subfamily 4 group A 1(NR4A1), etc. Various studies have reported that nuclear receptors play a crucial role in cardiovascular diseases. A recently conducted work highlighted the function of the nuclear receptor superfamily in the realm of metabolic diseases and their associated complications. This review summarized the available information on several important nuclear receptors in the pathophysiology of diabetic cardiomyopathy and discussed future perspectives on the application of nuclear receptors as targets for diabetic cardiomyopathy treatment. [ABSTRACT FROM AUTHOR]

Background: The fundamental role of the renin–angiotensin–aldosterone system in the pathophysiology of chronic kidney disease, congestive heart failure, hypertension and proteinuria is well established in pre‐clinical and clinical studies. Mineralocorticoid receptor antagonists are among the primary options for renin–angiotensin–aldosterone system blockage, along with angiotensin‐converting enzyme inhibitors and angiotensin receptor blockers. Methods: In this narrative review, we aim to evaluate the efficiency and safety of mineralocorticoid receptor antagonists in kidney transplant recipients, including the potential underlying pathophysiology. Results: The efficiency and safety of mineralocorticoid receptor antagonists in managing chronic kidney disease and proteinuria, either non‐nephrotic or nephrotic range, have been demonstrated among nontransplanted patients, though studies investigating the role of mineralocorticoid receptor antagonists among kidney transplant recipients are scarce. Nevertheless, promising results have been reported in pre‐clinical and clinical studies among kidney transplant recipients regarding the role of mineralocorticoid receptor antagonists in terms of ischaemia–reperfusion injury, proteinuria, or calcineurin inhibitor‐mediated nephrotoxicity without considerable adverse events such as hypotension, hyperkalaemia or worsening renal functions. Conclusion: Even though initial results regarding the role of mineralocorticoid receptor antagonist therapy for kidney transplant recipients are promising, there is clear need for large‐scale randomized clinical trials with long‐term follow‐up data. [ABSTRACT FROM AUTHOR]

The article discusses the need for reliable biomarkers to detect pulmonary congestion in patients with heart failure (HF) in order to prevent hospitalizations and improve patient outcomes. The current biomarkers used in clinical practice, B-type natriuretic peptides (NPs), have limitations such as being affected by comorbidities and having inconsistent measurement intervals. The article presents the BioMEMS study, which aims to identify alternative biomarkers that accurately reflect worsening congestion and can be easily measured. The study collects blood samples from HF patients and analyzes them using the Olink Cardiovascular III panel to evaluate the relationship between biomarkers and pulmonary artery pressures. The ultimate goal is to develop a biomarker-based management strategy for HF patients that is decentralized, manageable, and economically sustainable. [Extracted from the article]

Aims: Many patients with heart failure (HF) have chronic kidney disease (CKD) and may not tolerate mineralocorticoid receptor antagonists. We investigated the efficacy and safety of the novel mineralocorticoid receptor modulator balcinrenone in combination with dapagliflozin in a phase 2b study. Methods and results: From January 2021 to October 2023, we randomized 133 adults with symptomatic HF, ejection fraction <60%, estimated glomerular filtration rate (eGFR) ≥30 to ≤60 ml/min/1.73 m2 and urinary albumin‐to‐creatinine ratio (UACR) ≥30 to <3000 mg/g, to receive balcinrenone 15, 50 or 150 mg/day plus dapagliflozin 10 mg/day, or dapagliflozin 10 mg/day plus placebo, for 12 weeks. Enrolment was stopped early because of slow recruitment. Relative reductions in UACR from baseline to week 12 (primary endpoint) were not significantly different between the balcinrenone plus dapagliflozin groups versus dapagliflozin plus placebo. There was no clear balcinrenone dose–response relationship. There were possible dose‐dependent increases in serum potassium levels, reduced eGFR in the highest dose group, and non‐significant trends towards reduced N‐terminal pro‐B‐type natriuretic peptide levels. Hyperkalaemia adverse events led to discontinuation in two participants receiving balcinrenone plus dapagliflozin and none in those receiving dapagliflozin plus placebo. Conclusion: While the smaller than planned sample size limits interpretation, we did not see significant reduction in UACR in patients treated with balcinrenone plus dapagliflozin compared with dapagliflozin plus placebo. [ABSTRACT FROM AUTHOR]

Aims: Although recent randomized clinical trials have demonstrated the advantages of heart failure (HF) therapy in both frail and not frail patients, there is insufficient information on the use of HF therapy based on frailty status in a real‐world setting. The aim was to examine how frailty status in HF patients associates with use of HF therapy and with clinical outcomes. Methods and results: Patients with new‐onset HF between 2014 and 2021 were identified using the nationwide Danish registers. Patients across the entire range of ejection fraction were included. The associations between frailty status (using the Hospital Frailty Risk Score) and use of HF therapy and clinical outcomes (all‐cause mortality, HF hospitalization, and non‐HF hospitalization) were evaluated using multivariable‐adjusted Cox models adjusting for age, sex, diagnostic setting, calendar year, comorbidities, pharmacotherapy, and socioeconomic status. Of 35 999 participants (mean age 69.1 years), 68% were not frail, 26% were moderately frail, and 6% were severely frail. The use of HF therapy was significantly lower in frailer patients. The hazard ratio (HR) for angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker initiation was 0.74 (95% confidence interval 0.70–0.77) and 0.48 (0.43–0.53) for moderate frailty and severe frailty, respectively. For beta‐blockers, the corresponding HRs were 0.74 (0.71–0.78) and 0.51 (0.46–0.56), respectively, and for mineralocorticoid receptor antagonists, 0.83 (0.80–0.87) and 0.58 (0.53–0.64), respectively. The prevalence of death and non‐HF hospitalization increased with frailty status. The HR for death was 1.55 (1.47–1.63) and 2.32 (2.16–2.49) for moderate and severe frailty, respectively, and the HR for non‐HF hospitalization was 1.37 (1.32–1.41) and 1.82 (1.72–1.92), respectively. The association between frailty status and HF hospitalization was not significant (HR 1.08 [1.02–1.14] and 1.08 [0.97–1.20], respectively). Conclusion: In real‐world HF patients, frailty was associated with lower HF therapy use and with a higher incidence of clinical outcomes including mortality and non‐HF hospitalization. [ABSTRACT FROM AUTHOR]

Aim: The management of patients with type 2 diabetes is asynchronous, i.e. not coordinated in time, resulting in delayed access to care and low use of guideline‐directed medical therapy (GDMT). Methods: We retrospectively analysed consecutive patients assessed in the 'synchronized' DECIDE‐CV clinic. In this outpatient clinic, patients with type 2 diabetes and cardiovascular or chronic kidney disease are simultaneously assessed by an endocrinologist, cardiologist and nephrologist in the same visit. The primary outcome was use of GDMT before and after the assessment in the clinic, including sodium‐glucose cotransporter 2 inhibitors, glucagon‐like peptide 1 receptor agonists, renin‐angiotensin system blockers and mineralocorticoid receptor antagonists. Secondary outcomes included the baseline‐to‐last‐visit change in surrogate laboratory biomarkers. Results: The first 232 patients evaluated in the clinic were included. The mean age was 67 ± 12 years, 69% were men and 92% had diabetes. In total, 73% of patients had atherosclerotic cardiovascular disease, 65% heart failure, 56% chronic kidney disease and 59% had a urinary albumin‐to‐creatinine ratio ≥30 mg/g. There was a significant increase in the use of GDMT:sodium‐glucose cotransporter 2 inhibitors (from 44% to 87% of patients), glucagon‐like peptide 1 receptor agonists (from 8% to 45%), renin‐angiotensin system blockers (from 77% to 91%) and mineralocorticoid receptor antagonists (from 25% to 45%) (p <.01 for all). Among patients with paired laboratory data, glycated haemoglobin, urinary albumin‐to‐creatinine ratio and N‐terminal proB‐type natriuretic peptide levels significantly dropped from baseline (p <.05 for all). Conclusions: Joint assessment of patients with diabetes in a synchronized cardiometabolic clinic holds promise for enhancing GDMT use and has led to significant reductions in surrogate cardiovascular and renal laboratory biomarkers. [ABSTRACT FROM AUTHOR]

Background: Vascular smooth muscle cell (VSMC) injury caused by the inflammatory response plays a key role in cardiovascular disease (CVD), and the vasoprotective effects of mineralocorticoid receptor blockers (MRBs) support the role of mineralocorticoid receptor (MR) activation. Methods: C57BL/6 mice and VSMCs isolated from rats were treated with aldosterone and esaxerenone. Caspase-1, GSDMD-N, IL-1β, and NR3C2 expression and DNA damage in aortic VSMCs were detected using immunohistochemistry, Western blotting, and TUNEL staining. Mitochondrial changes were detected by transmission electron microscopy (TEM). Reactive oxygen species (ROS), MitoTracker, JC-I, mitochondrial respiratory chain complexes I–V, and NR3C2 were detected using immunofluorescence and flow cytometry. Pyroptosis was detected with scanning electron microscopy (SEM). Results: After aldosterone treatment, the number of TUNEL-positive cells increased significantly, and the expression of caspase-1, GSDMD-N, and IL-1β increased. TEM revealed mitochondrial damage, and SEM revealed specific pyroptotic changes, such as cell membrane pore changes and cytoplasmic extravasation. Increased ROS levels and nuclear translocation of NR3C2 were also observed. These pyroptosis-related changes were reversed by esaxerenone. Conclusions: Aldosterone activates the MR and mediates mitochondrial damage, thereby inducing pyroptosis in VSMCs via the NLRP3/caspase-1 pathway. Esaxerenone inhibits MR activation and reduces mitochondrial damage and oxidative stress, thereby inhibiting pyroptosis. [ABSTRACT FROM AUTHOR]

Activation of the renin–angiotensin–aldosterone system (RAAS) plays an important pathophysiological role in hypertension. Increased mRNA levels of the angiotensinogen angiotensin-converting enzyme, angiotensin type 1 receptor gene, Agtr1a, and the aldosterone synthase gene, CYP11B2, have been reported in the heart, blood vessels, and kidneys in salt-sensitive hypertension. However, the mechanism of gene regulation in each component of the RAAS in cardiovascular and renal tissues is unclear. Epigenetic mechanisms, which are important for regulating gene expression, include DNA methylation, histone post-translational modifications, and microRNA (miRNA) regulation. A close association exists between low DNA methylation at CEBP-binding sites and increased AGT expression in visceral adipose tissue and the heart of salt-sensitive hypertensive rats. Several miRNAs influence AGT expression and are associated with cardiovascular diseases. Expression of both ACE and ACE2 genes is regulated by DNA methylation, histone modifications, and miRNAs. Expression of both angiotensinogen and CYP11B2 is reversibly regulated by epigenetic modifications and is related to salt-sensitive hypertension. The mineralocorticoid receptor (MR) exists in cardiovascular and renal tissues, in which many miRNAs influence expression and contribute to the pathogenesis of hypertension. Expression of the 11beta-hydroxysteroid dehydrogenase type 2 (HSD11B2) gene is also regulated by methylation and miRNAs. Epigenetic regulation of renal and vascular HSD11B2 is an important pathogenetic mechanism for salt-sensitive hypertension. [ABSTRACT FROM AUTHOR]

The global burden of chronic kidney disease (CKD) is high and increasing. Early diagnosis and intervention are key to improve outcomes. Single-nephron glomerular hyperfiltration is an early pathophysiologic manifestation of CKD that may result in absolute glomerular hyperfiltration, i.e. a high glomerular filtration rate (GFR), or be associated with normal or low GFR because of nephron loss (relative glomerular hyperfiltration). Even though compensatory glomerular hyperfiltration may contribute to maintain kidney function after the loss of kidney mass, the associated increased glomerular capillary pressure and glomerular and podocyte size drive podocyte loss, albuminuria and proximal tubular overload, contributing to CKD progression. In this regard, all kidney protective drugs in clinical use so far, from renin–angiotensin system blockers to mineralocorticoid receptor blockers to sodium–glucose co-transporter 2 inhibitors to tolvaptan, induce an early dip in glomerular filtration that is thought to represent reversal of hyperfiltration. As glomerular hyperfiltration may be present early in the course of kidney disease, its recognition may provide an effective intervention window that may predate current criteria based on high albuminuria or loss of GFR. Nevertheless, there is no diagnostic method with high sensitivity and specificity to identify single-nephron glomerular hyperfiltration, except when it leads to obvious absolute glomerular hyperfiltration, as observed in the early stages of diabetic kidney disease when nephron mass is still preserved. We now review the concept of glomerular hyperfiltration as an indicator of CKD risk, including definitions, challenges in diagnosis and evaluation, underlying pathophysiological mechanisms, potential therapeutic approaches and unanswered questions. [ABSTRACT FROM AUTHOR]

Aims: Heart failure with reduced ejection fraction (HFrEF) significantly impacts health‐related quality of life (HR‐QoL). Existing HR‐QoL questionnaires can show inconsistencies, potentially misrepresenting patient self‐reports. This study examines the variation in HR‐QoL measurement tools for HFrEF patients, identifying related determinants. Methods and results: We retrospectively analysed 134 hospitalized patients with acute decompensated HFrEF at a Taiwanese tertiary centre's Heart Failure Post‐Acute‐Care (HF‐PAC) programme. Participants completed the EuroQol‐5 dimension (EQ‐5D) questionnaire, the EQ‐5D visual analogue scale (VAS), and the Minnesota Living with Heart Failure Questionnaire (MLHFQ). Utility values were obtained from the EQ‐5D questionnaire. Demographic features were depicted using descriptive statistics, while multivariate regression was used to ascertain relationships between HR‐QoL measurements and determinants. Average scores for EQ‐5D, MLHFQ, EQ‐5D utility, and VAS were 6.1 ± 1.6, 21.8 ± 21.3, 81.7 ± 27.0, and 59.5 ± 14.6, respectively. Significant correlations were observed among the three tools. The New York Heart Association functional class showed a notable association with all tool scores. Other associations encompassed EQ‐5D with coronary artery disease, mineralocorticoid receptor antagonists, and the 6 min walk test; EQ‐5D VAS with chronic kidney disease; and MLHFQ with age. Conclusions: This study illuminates the variance in HR‐QoL measurement tools for Taiwanese HFrEF patients. Using a range of these tools is beneficial in unveiling diverse determinants and approaching comprehensive patient‐centred care. However, for a more precise HR‐QoL assessment in Taiwanese HFrEF patients, recalibrating the EQ‐5D‐derived utility scores might be necessary, emphasizing the importance of patient‐specific considerations within the HF‐PAC programme. [ABSTRACT FROM AUTHOR]

Aims: Cardiac resynchronization therapy (CRT) is an established treatment for drug‐refractory heart failure (HF) in patients with left bundle branch block (LBBB). Acute haemodynamic improvement after CRT implantation may enable the intensification of HF medication soon thereafter. Immediate pharmacotherapy intensification (IPI) after CRT implantation achieves a synergetic effect, possibly leading to a better prognosis. This study aimed to explore the incidence, characteristics, and impact of IPI on real‐world outcomes among CRT recipients with a history of hospitalization for acute HF. Methods and results: This multicentre retrospective study enrolled CRT recipients with LBBB morphology, a QRS width ≥120 ms, a left ventricular ejection fraction ≤35%, and New York Heart Association II–IV HF symptoms. All patients had previous HF hospitalizations within the previous year and received guideline‐directed medical therapy before CRT implantation. Patient baseline characteristics, including HF medication, were collected. IPI was defined as the intensification of beta‐blockers, angiotensin‐converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists within 30 days of CRT implantation. The primary endpoint was all‐cause death or first hospitalization for HF; the secondary endpoint was all‐cause death. We enrolled 194 patients (75% male; mean age, 65 ± 13 years; 78% with non‐ischaemic cardiomyopathy). One hundred five (54%) patients received IPI. Patients who received IPI exhibited a significantly shorter QRS duration (159 ± 26 vs. 171 ± 32 ms; P = 0.004), higher estimated glomerular filtration rate (55.2 ± 20.0 vs. 47.8 ± 24.7 mL/min/1.73 m2; P = 0.022), and more dilated cardiomyopathy. During a median follow‐up period of 29 months, 70 (36%) patients reached the primary endpoint and 42 (22%) patients died. Patients with IPI showed significantly better outcomes for the primary and secondary endpoints than patients without IPI. The volumetric responder ratio at 6 months after implantation was not significantly different between patients with and without IPI; however, patients who received IPI had reduced mortality even at 6 months after implantation. In the multivariate analysis, IPI was an independent predictor of the primary endpoint (hazard ratio, 0.51; 95% confidence interval, 0.27–0.97; P = 0.043). Conclusions: Immediate intensification of HF medication was achieved in 54% of CRT recipients and was significantly higher in patients without excessive QRS prolongation, preserved renal function, and dilated cardiomyopathy than others. In patients with LBBB morphology and QRS ≥ 120 ms, IPI was associated with a significantly better prognosis and fewer HF hospitalizations after CRT implantation than others. [ABSTRACT FROM AUTHOR]

Aims: Reducing sodium intake is necessary for patients with chronic heart failure (CHF). Salt substitutes (saltSubs) have become increasingly popular as recommendations by healthcare professionals (HCPs) as well as options for patients and their caregivers. However, their consumption is generally potassium based and remains poorly evaluated in CHF management. Their impact on guideline‐directed medical therapies (GDMTs) also remains unknown. The primary objective of this study was to provide a description and estimate of HCP recommendations and reported use of saltSubs in France. Secondary objectives were to identify if there was an association between these recommendations by HCPs and the use of GDMTs. Methods and results: A nationwide, questionnaire‐based, cross‐sectional, epidemiological study was conducted from September 2020 to July 2021. Data collection included baseline characteristics, the use and recommendations of saltSubs, and the use of GDMTs, which included (i) angiotensin‐converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) or angiotensin receptor–neprilysin inhibitors (ARNis), (ii) mineralocorticoid receptor antagonists (MRAs), and/or (iii) beta‐blockers (BBs). In total, 13% of HCPs advised saltSubs and 17% of patients and 22% of caregivers reported their consumption. CHF patients advised to take saltSubs did not differ in terms of left ventricular ejection fraction (EF) <40%, ischaemic origin, and New York Heart Association III–IV class, but were more recently hospitalized for acute HF (P = 0.004). HCPs who recommended saltSubs to patients were more likely to advise an anti‐diabetic diet (P < 0.001), cholesterol‐lowering diet (P < 0.001), and exercise (P = 0.018). In the overall population, ACEi/ARB/ARNi use was less frequent in case of saltSub recommendations (74% vs. 82%, P = 0.012). The concomitant prescription of none, one, two, or three GDMTs was less favourable in case of saltSub recommendations (P = 0.046). There was no significant difference for the presence of MRA (56% vs. 58%) and/or BB (78% vs. 82%). The under‐prescription of ACEi/ARB/ARNi was found when patients had EF < 40% (P = 0.029) and/or EF ≥ 40% (P = 0.043). In the subgroup with left ventricular EF ≥ 40%, we found a higher thiazide use (P = 0.014) and a less frequent use of low EF GDMTs (P = 0.044) in case of being recommended saltSubs. Conclusions: Beyond the well‐established risk for hyperkalaemia, our preliminary results suggest a potentially negative impact of saltSubs on GDMT use, especially for ACEis/ARBs/ARNis in CHF management. saltSub recommendations and their availability from open sale outlets should be considered to avoid possible misuse or deference from GDMTs in the future. Informed advice to consumers should also be considered from HCPs or pharmacists. [ABSTRACT FROM AUTHOR]

The concept of quadruple therapy as a "one-size-fit-all" approach is effective among all eligible patients with heart failure with reduced ejection fraction, with consistent and significant clinical benefits including reduced mortality across various subgroups. However, with exception of sodium-glucose cotransporter 2 inhibitors, the consistency of benefit with therapies does not extend to patients with heart failure with preserved ejection fraction. The clinical benefits of other promising medical therapies, such as angiotensin receptor–neprilysin inhibitors, mineralocorticoid receptor antagonists, and glucagon-like peptide-1 receptor agonists, have been demonstrated only in certain phenotypes of the highly heterogenous heart failure with preserved ejection fraction population. This variability can confuse frontline practicing cardiologists, potentially leading to the under-implementation of these medications. Therefore, we propose a simple approach: "targeted" combination therapy. This strategy aims to optimize evidence-based medications in heart failure with preserved ejection fraction by tailoring treatments to specific subgroups within the heart failure with preserved ejection fraction population where significant benefits are most evident. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the efficacy and safety of non-steroid mineralocorticoid receptor antagonists (ns-MRAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) in patients with diabetic kidney disease (DKD). Methods: Systematic literature searches were performed using PubMed, Embase and Web of Science encompassing inception until January 20, 2024. Randomized control trials (RCTs) comparing ns-MRAs and SGLT2is in DKD were selected. The efficacy outcomes of interest included kidney-specific composite outcome, cardiovascular (CV)-specific composite outcome, end-stage kidney disease (ESKD), and overall mortality. We also investigated safety outcomes, including acute kidney injury (AKI) and hyperkalemia. Results: A total of 10 randomized clinical trials with 35,786 patients applying various treatments were included. SGLT2is (SUCRA 99.84%) have potential superiority in kidney protection. SGLT2is (RR 1.41, 95%CI 1.26 to 1.57) and ns-MRAs (RR 1.17, 95% CI 1.08 to 1.27) were associated with significantly lower kidney-specific composite outcome than the placebo. Regarding the reduction in CV-specific composite outcome and ESKD, SGLT2is (SUCRA 91.61%; 91.38%) have potential superiority in playing cardiorenal protection. Concerning the CV-specific composite outcome (RR 1.27, 95%CI 1.09 to 1.43) and ESKD (RR 1.43, 95% CI 1.20 to 1.72), SGLT2is significantly reduced the risks compared to placebo. Regarding the reduction in overall mortality, SGLT2is (SUCRA 83.03%) have potential superiority in postponing mortality. Concerning the overall mortality, SGLT2is have comparable effects (RR 1.27, 95%CI 1.09 to 1.43) with placebo to reduce the risk of overall mortality compared to placebo. For AKI reduction, ns-MRAs (SUCRA 63.58%) have potential superiority. SGLT2is have comparable effects (RR 1.24, 95%CI 1.05 to 1.46) with placebo to reduce the risk of AKI. For hyperkalemia reduction, SGLT2is (SUCRA 93.12%) have potential superiority. SGLT2is have comparable effects (RR 1.24, 95%CI 1.05 to 1.46) with placebo to reduce the risk of AKI. Concerning hyperkalemia reduction, nsMRAs (RR 1.24 95% CI 0.39 to 3.72) and SGLT2is (RR 1.01 95%CI 0.40 to 3.02) did not show significant benefit compared to placebo. Conclusion: Concerning the efficacy and safety outcomes, SGLT2is may be recommended as a treatment regimen for maximizing kidney and cardiovascular protection, with a minimal risk of hyperkalemia in DKD. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023458613. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) currently affects approximately 850 million people globally and is continuing to increase in prevalence as well as in importance as a cause of death. The excess mortality related to CKD is mostly caused by an increase in cardiovascular disease. This includes atherosclerotic cardiovascular disease as many promoters of atherosclerosis, such as blood pressure, lipid levels and hypercoagulation, are increased in people with CKD. Diabetes is a leading cause of CKD contributing to the risk of CVD, and obesity is also increasingly prevalent. Management of these risk factors is therefore very important in CKD, and to reduce risk of CKD progression. Heart failure is also more prevalent in CKD and, again, many risk factors are shared. The concept of foundational pillars in the management of heart failure has been adapted to the treatment of CKD, with many organ‐protective interventions, such renin‐angiotensin system blockade, sodium‐glucose cotransporter‐2 inhibition and mineralocorticoid receptor antagonism, reducing the risk for mortality in heart failure with reduced ejection fraction, but also for progression of CKD. Atrial fibrillation is also more common with CKD and affects the management of the former. In this review these non‐renal complications of CKD are discussed, along with how the risk of these complications should be managed. Many new opportunities have demonstrated heart and kidney organ protection, but implementation is a challenge. [ABSTRACT FROM AUTHOR]