Search Results (326)

Cardiorenal–metabolic (CKM) syndrome has emerged as a unifying condition describing the interplay between metabolic dysfunction, chronic kidney disease, and cardiovascular disease. To address this concept, the American Heart Association, in a 2023 Presidential Advisory, presented an official statement to capture the transition from metabolic risk and subtle cardiorenal dysfunction to overt cardiovascular and renal disease. Although this framework provides a structured representation of disease burden and facilitates risk stratification, emerging evidence suggests that it is primarily focused on the progressive nature, whereas high-risk patients may experience sudden cardiac or renal events. While staging systems provide important tools for risk stratification, they remain primarily descriptive and do not adequately reflect the dynamic and non-linear interactions underlying disease progression. Importantly, patients exhibit substantial heterogeneity in dominant pathophysiological drivers, related to various baseline risk factors and primitive cardio–kidney disorders, that is not fully captured by stage-based classifications. Notably, we propose a phenotype-oriented approach to CKM syndrome based on the recognition that its clinical expression reflects heterogeneous and evolving pathophysiological mechanisms rather than a uniform disease trajectory. According to this strategy, the paradigm of management shifts from an evolutive concept to a more appropriate use of disease modifying agents with cross-organ effects. Sodium–glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1a), and non-steroidal mineralocorticoid receptor antagonists (MRA) have demonstrated the ability to modulate key biological pathways across the cardiovascular, renal, and metabolic axes. Therefore, personalized management that identifies a specific strategy according to CKM phenotypes must be assessed. Full article

The therapeutic landscape for heart failure (HF), particularly in patients with mildly reduced (HFmrEF) and preserved ejection fraction (HFpEF), has historically been characterized by limited effective disease-modifying options. The recent approval of nonsteroidal mineralocorticoid receptor antagonists (nsMRAs), specifically finerenone, represents a major paradigm shift. This review synthesizes contemporary evidence, including the landmark FINEARTS-HF trial, which demonstrated significant reductions in cardiovascular death and heart failure hospitalizations in patients with left ventricular ejection fraction (LVEF) ≥ 40%. These findings contrast with the neutral overall results and subgroup limitations observed with steroidal MRAs such as spironolactone in the TOPCAT trial. Mechanistic distinctions, cardiorenal benefits, and emerging metabolic effects of finerenone are explored alongside its complementary role with sodium–glucose cotransporter-2 (SGLT2) inhibitors. Practical considerations for implementation, including patient selection, dosing, monitoring, and combination therapy strategies, are discussed. Overall, nsMRAs establish a new foundation for the management of HFmrEF and HFpEF and represent a critical advancement in contemporary heart failure therapeutics. Full article

Proteinuria is a strong predictor of graft failure in kidney transplant recipients (KTRs). While non-steroidal mineralocorticoid receptor antagonists (NS-MRAs), particularly finerenone, have demonstrated renoprotective benefits in chronic kidney disease, KTRs were excluded from pivotal trials. Evidence on finerenone’s safety and antiproteinuric effects in this population remains limited. This retrospective observational study evaluated 13 diabetic KTRs with persistent proteinuria despite optimized renin–angiotensin system blockade and sodium–glucose cotransporter 2 inhibitor therapy. Finerenone (10 mg/day) was added to standard care. Clinical and laboratory parameters, including estimated glomerular filtration rate (eGFR), serum electrolytes, total proteinuria, albuminuria, and their creatinine ratios, were assessed at baseline, 3 months, and 6 months. Safety outcomes focused on hyperkalemia and eGFR. Finerenone was discontinued in one patient due to hyperkalemia. In the remaining 12, 24-h proteinuria and urinary protein-to-creatinine ratio declined at 3 months and stabilized by 6 months. Conversely, no statistically significant changes were observed in albuminuria or the albumin-to-creatinine ratio. No clinically relevant changes occurred in eGFR, blood pressure, body weight, or serum electrolytes. This is the first study assessing finerenone in diabetic KTRs. Finerenone was well tolerated, was associated with an early reduction in proteinuria, and showed no adverse effects on graft function. These findings provide novel insights into the safety and potential role of finerenone in kidney transplant recipients. Full article

Gut microbiome composition influences cardiovascular drug efficacy and safety, yet its integration into heart failure (HF) management remains underexplored. Alterations in intestinal microbial communities have been linked to atherosclerosis, coronary artery disease, heart failure, and hypertension through multiple mechanisms. Dysbiosis disrupts the balance between commensal and pathogenic bacterial species, impairing gut barrier function and activating inflammatory pathways. The altered microbial ecosystem modulates the production of key metabolites—such as trimethylamine-N-oxide (TMAO), short-chain fatty acids (SCFAs), and secondary bile acids (BAs)—that directly impact cardiovascular function. This narrative review synthesizes current evidence on bidirectional interaction between heart failure pharmacotherapy and gut microbiome composition. Commonly used drugs in heart failure management show microbiome-dependent pharmacokinetics. Digoxin undergoes bacterial inactivation by Eggerthella lenta, while angiotensin converting enzyme inhibitors and beta-blockers demonstrate enhanced efficacy with specific Firmicutes populations. Conversely, certain probiotic strains attenuate drug-induced gut barrier injury and restore gut homeostasis. Sodium–glucose cotransporter 2 inhibitors (SGLT2i), mineralocorticoid receptor antagonists, and angiotensin receptor–neprilysin inhibitors exhibit beneficial microbiome-modulating effects beyond their primary cardiovascular actions. These findings underscore the potential for microbiome-informed precision medicine in heart failure. However, significant methodological challenges must be addressed, including lack of standardization in microbiome profiling, small sample sizes, and limited longitudinal data. Future research should focus on identifying specific microbial signatures that predict drug response, developing targeted probiotic interventions, and conducting prospective clinical trials to validate pharmacomicrobiomics approaches in heart failure management. Full article

Fibroblasts and lymphangiogenesis promote renal fibrosis. However, whether fibroblasts promote renal fibrosis via lymphangiogenesis has not yet been fully elucidated. This study set out to clarify whether aldosterone induces fibroblast transdifferentiation into lymphatic endothelial-like cells, thus promoting lymphangiogenesis and renal fibrosis. In vivo, twenty-four male Wistar rats were randomized into Sham, ALD (6-week aldosterone infusion), and ALD + ESA (aldosterone infusion with esaxerenone co-treatment) groups. In vitro, primary rat renal interstitial fibroblasts (RKFs) were used. Immunohistochemistry and Western blot were used to detect lymphatic endothelial and fibroblast marker expression in kidneys from aldosterone-infused rats and RKFs. Their co-expression was determined by flow cytometry and immunofluorescence co-staining. Mineralocorticoid receptor (MR) activation and related signaling pathways were also analyzed by Western blot, immunohistochemistry, and flow cytometry. Additionally, RKF migration and tube formation were examined to investigate the role of aldosterone-induced fibroblast-to-lymphatic endothelial-like transdifferentiation in renal fibrosis. Our data suggest that aldosterone activates the MR and induces the transdifferentiation of fibroblasts into lymphatic endothelial-like cells via the MR/VEGFC/VEGFR-3 pathway, thereby promoting lymphangiogenesis. In addition, the administration of esaxerenone (a mineralocorticoid receptor blocker, MRB) to rats significantly suppresses this transdifferentiation and alleviates fibrosis. Full article

Mineralocorticoid receptor antagonists (MRAs) are the cornerstone of the management of heart failure and chronic kidney disease. A well-known adverse event, hyperkalemia, is associated with fatal arrhythmia and discontinuation of MRA. Our narrative review discusses the personalized treatment of MRAs, focusing on the pharmacological profile and drug–drug interactions to address safety concerns related to hyperkalemia. Clinicians should scrupulously monitor potassium levels, especially during dose titration, and review each patient’s medication list. Cytochrome P450 3A4 (CYP3A4) inhibitors are pharmacokinetic precipitators that interact with most MRAs, except spironolactone, and adversely affect the risk of hyperkalemia, although suggestive evidence is scarce. Potassium-elevating drugs synergistically increase serum potassium levels when co-administered with an MRA (e.g., renin-angiotensin aldosterone inhibitors, co-trimoxazole, non-steroidal anti-inflammatory drugs, calcineurin inhibitors, and β blockers). Additional approaches include correction of metabolic acidosis using sodium bicarbonate, potassium-lowering therapy using loop and thiazide diuretics, and sodium-glucose cotransporter 2 inhibitors. Novel potassium binders enable patients to receive the maximum-tolerated MRA with fewer gastrointestinal side effects. Individualized interventions for hyperkalemia risk are important in treatment using MRA. Full article

Background/Objectives: Familial hyperaldosteronism type IV (FH-IV) is an extremely rare, clinically heterogeneous condition representing the least characterized familial subtype of primary aldosteronism (PA) caused by germline gain-of-function CACNA1H mutations. Despite growing molecular insights, optimal diagnostic and therapeutic strategies remain poorly defined. This systematic review aims to synthesize available evidence regarding the clinical, biochemical, and genetic characteristics of FH-IV, and to evaluate the efficacy of current pharmacological and surgical treatments. Methods: A systematic review was conducted in accordance with PRISMA guidelines and preregistered in PROSPERO (CRD420261324945). A comprehensive search of MEDLINE, Embase, and Web of Science identified studies reporting genetically confirmed FH-IV patients. Data concerning clinical phenotypes, diagnostic evaluations, treatment outcomes, and genetic backgrounds were extracted and analyzed. Results: The primary cohort included 31 fully characterized symptomatic patients, alongside 8 mutation-positive relatives (4 asymptomatic carriers and 4 symptomatic individuals). The genetic landscape was remarkably heterogeneous, encompassing 17 distinct CACNA1H mutations. Clinically, diagnosis was frequently delayed, often complicated by atypical normokalaemic presentations and misleading adrenal imaging. Surgical treatment was generally ineffective, frequently resulting in persistent or recurrent hypertension and biochemical dysregulation. Pharmacologically, patients often required multiple antihypertensive drugs, most frequently a combination of mineralocorticoid receptor antagonists (MRAs) and calcium channel blockers (CCBs). Conclusions: FH-IV is best conceptualized as a systemic adrenal channelopathy. While standard screening parameters are usually elevated, atypical biochemical profiles and misleading structural imaging can complicate the diagnostic process. Optimal management relies on multigene Next-Generation Sequencing (NGS) panels for definitive diagnosis and cascade screening of relatives. Finally, while the combination of MRAs and CCBs is commonly used in PA, it represents a valuable therapy for FH-IV, with dual L-/T-type CCBs emerging as a potential disease-specific option. Full article

Chronic kidney disease (CKD) is a major global health burden associated with substantially increased risks of morbidity and mortality. Cardiovascular disease remains the leading cause of death across all stages of CKD. Over the past few decades, several pharmacologic therapies—including renin–angiotensin system inhibitors, sodium–glucose cotransporter-2 inhibitors, mineralocorticoid receptor antagonists, glucagon-like peptide-1 receptor agonists, and lipid-lowering agents—have demonstrated substantial cardio-nephroprotective benefits and are recommended in international guidelines. However, real-world implementation of these therapies remains incomplete, and emerging evidence highlights important sex-based disparities in prescribing patterns. Although CKD is more prevalent in women worldwide, women with CKD are consistently less likely than men to receive guideline-directed cardioprotective and nephroprotective medications. This treatment gap spans both traditional therapies, such as angiotensin-converting enzyme inhibitors and statins, and newer agents with proven outcome benefits. Women are less likely to initiate treatment, less likely to receive high-intensity or target doses, and less likely to achieve recommended blood pressure and lipid goals. Importantly, the presence of CKD attenuates the usual female survival advantage, and the relative excess cardiovascular risk associated with CKD may be particularly pronounced in women. The under-prescription of cardio-renal therapies in women with CKD reflects a complex interplay of factors. These include older age at presentation, higher reported rates of adverse drug reactions, concerns regarding tolerability and safety in advanced kidney disease, therapeutic inertia, underestimation of cardiovascular risk, and persistent underrepresentation of women in clinical trials. Biological differences in pharmacokinetics and pharmacodynamics, as well as structural and system-level barriers, further contribute to inequities in care. Addressing these disparities requires improved risk recognition, sex-informed prescribing practices, enhanced representation of women in clinical research, and implementation strategies that incorporate sex-disaggregated performance metrics. Reducing treatment gaps is essential to improving cardiovascular and renal outcomes and to achieving equitable, precision-based care for women with CKD. Full article

Background: Guideline-directed medical therapy (GDMT) is recommended after acute myocardial infarction (AMI), particularly in patients with left ventricular systolic dysfunction, yet real-world implementation remains suboptimal. Whether greater early GDMT intensity is associated with post-infarction ventricular remodeling has not been fully established. We aimed to quantify the guideline-to-practice gap and evaluate the association between GDMT intensity, cardiac remodeling, and clinical outcomes after AMI. Methods: In this single-center retrospective cohort study, 186 consecutive patients hospitalized for AMI who underwent successful percutaneous coronary intervention and had baseline plus follow-up transthoracic echocardiography were included. GDMT intensity was defined as the number of prescribed foundational therapy classes at discharge (renin–angiotensin system inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and sodium–glucose cotransporter 2 inhibitors; range 0–4). The primary endpoint was change in left ventricular end-diastolic diameter (ΔLVEDD). Secondary endpoints included changes in left ventricular ejection fraction, left ventricular end-diastolic volume, left ventricular mass, and heart failure rehospitalization. Multivariable models adjusted for relevant clinical covariates were applied. Results: Only 18.8% of the overall cohort and 26.2% of patients with baseline left ventricular ejection fraction ≤ 40% received all four GDMT pillars. A graded association was observed between higher GDMT intensity and more favorable remodeling. In adjusted analyses, each additional GDMT pillar was associated with a greater reduction in LVEDD (β = 0.120 cm, p = 0.004). In the prespecified reduced-ejection-fraction subgroup, the association was stronger (β = 0.204 cm, p < 0.001). Higher GDMT intensity was also associated with lower odds of heart failure rehospitalization (odds ratio 0.384, 95% CI 0.195–0.754; p = 0.006). Conclusions: In this real-world post-AMI cohort, broader implementation of foundational GDMT at discharge was associated with more favorable early ventricular reverse remodeling and lower odds of heart failure rehospitalization. These findings highlight a persistent implementation gap and support prospective studies evaluating rapid comprehensive GDMT initiation after AMI. Full article

The American Heart Association (AHA) recently formalized cardiovascular–kidney–metabolic (CKM) syndrome to characterize the systemic interplay among cardiovascular failure, chronic kidney disease (CKD), and metabolic disturbances. Despite evolving clinical management, identifying a unifying cellular driver of this multi-organ deterioration remains a critical priority. This review explores the hypothesis that mitochondrial dysfunction serves as the fundamental pathological nexus of CKM syndrome, driving the progression from early-stage metabolic risk to end-stage organ failure. We synthesize evidence demonstrating how nutrient overload and lipotoxicity precipitate a vicious cycle of bioenergetic failure. In the cardiovascular system, ATP deficiency and impaired mitophagy lead to the structural remodeling observed in both heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). In the kidney, the high mitochondrial density of proximal tubules renders them uniquely susceptible to oxidative stress and mitochondrial DNA (mtDNA) leakage, which subsequently triggers systemic inflammation. Furthermore, we analyze how established therapies—including sodium–glucose co-transporter 2 (SGLT2) inhibitors, Glucagon-like peptide-1 (GLP-1) receptor agonists, and non-steroidal mineralocorticoid receptor antagonists (MRAs)—exert organ-protective effects via mitochondrial mechanisms, promoting metabolic efficiency, reducing reactive oxygen species generation, stabilizing mitochondrial integrity, and promoting mitochondrial quality control processes. Finally, we review emerging mitochondrial-targeted strategies, such as mitoquinol, elamipretide and NAD+ boosters, which aim to restore the SIRT1-PGC-1 α signaling axis. Mitochondria function as the central engines of the CKM axis. A shift toward a mitocentric clinical model may enable earlier intervention and more precise targeting of the mechanisms driving organ crosstalk. Future success depends on multidisciplinary collaboration and the validation of mitochondrial biomarkers to advance precision medicine in CKM syndrome. Full article

The cardiovascular–kidney–metabolic (CKM) syndrome has emerged as an integrated framework linking obesity, type 2 diabetes, chronic kidney disease (CKD), and heart failure with preserved or mildly reduced ejection fraction through shared mechanisms including inflammation, oxidative stress, endothelial dysfunction, and fibrosis. Persistent mineralocorticoid receptor overactivation plays a central role in this continuum, contributing to progressive cardiac and renal injury despite optimized renin–angiotensin system blockade. Finerenone, a selective non-steroidal mineralocorticoid receptor antagonist, has therefore gained increasing attention as a targeted strategy to reduce residual cardiorenal risk. This narrative review summarizes the mechanistic rationale and clinical evidence supporting finerenone across the CKM spectrum. Experimental data indicate that finerenone attenuates inflammation, fibrosis, myocardial hypertrophy, and adverse remodeling, while proteomic and translational analyses suggest biological complementarity with sodium–glucose cotransporter 2 inhibitors. Clinically, pivotal randomized trials have demonstrated that finerenone reduces kidney disease progression and major cardiovascular events in patients with CKD and type 2 diabetes, while the FINEARTS-HF trial extended these benefits to patients with heart failure with mildly reduced or preserved ejection fraction by reducing worsening heart failure events. Additional subgroup, pooled, and meta-analytic data reinforce the consistency of these effects across a broad range of cardiorenal phenotypes. Taken together, current evidence positions finerenone as an important component of contemporary CKM management, particularly in patients with diabetic CKD and selected heart failure phenotypes. Its principal value lies in targeting residual inflammatory and fibrotic risk beyond conventional hemodynamic and metabolic control. Future progress will depend on earlier phenotype recognition, improved implementation and adherence, and wider adoption of pathway-oriented combination therapy across the cardiorenal continuum. Full article

Background: Despite significant advances in heart failure (HF) management, mortality and readmission rates remain persistently high. Low adherence has been recognised as a contributing factor, although supporting data remain limited. Objective: This study aimed to evaluate the impact of medication adherence on outcome following a HF hospitalisation. Methods: Patients who were discharged after HF hospitalisation were included in the study from a national multicentre HF cohort, and their records were matched with the National Healthcare System database, which includes all health-related claims and clinical events. Adherence to beta blockers, renin-angiotensin system inhibitors, and mineralocorticoid receptor antagonists were measured using the proportion of days covered (PDC). Low adherence was defined by PDC < 80% for at least one of the three HF drug classes. We then analysed the relationship between the PDC and outcome during a two-year follow-up period. Results: A total of 448 patients (median age: 73 years; 67% male; mean ejection fraction: 40%) were included. Of these patients, 152 (34%) were classified as having low adherence. The two-year mortality rate was comparable between the two groups (16.9% vs. 19.1% in adherent and low-adherent groups, respectively, p = 0.6). However, the rates of all-cause and HF rehospitalisations at two years were lower in the adherent group than in the group with low adherence (85.9% vs. 92.8%, p ≤ 0.01; 48.5% vs. 58.2%, p = 0.04, respectively). Conclusions: In patients discharged after acute HF, low adherence to HF drugs is frequent and worsens outcome, particularly the risk of rehospitalisation. Full article

Diabetic kidney disease (DKD) remains a primary driver of end-stage kidney disease and cardiovascular morbidity despite the optimized use of renin–angiotensin system (RAS) inhibitors and sodium-glucose cotransporter-2 (SGLT2) inhibitors. Recent evidence identifies the overactivation of the mineralocorticoid receptor (MR) as a critical, independent pathway leading to persistent renal inflammation and fibrosis. In the diabetic milieu, MR overactivation—driven by both aldosterone and ligand-independent factors such as Rac1 GTPase and oxidative stress—triggers pro-inflammatory and pro-fibrotic gene networks. Unlike traditional steroidal mineralocorticoid receptor antagonists (MRAs), the novel non-steroidal MRA finerenone exhibits a distinct binding mode that more effectively blocks the recruitment of transcriptional co-activators, thereby silencing detrimental downstream signaling in podocytes, fibroblasts, and myeloid cells. Preclinical models have demonstrated that MR blockade significantly reduces albuminuria and preserves podocyte integrity independent of systemic blood pressure. These findings translated into landmark clinical trials; the FIDELIO-DKD and FIGARO-DKD trials established that finerenone significantly reduces the risk of kidney disease progression and cardiovascular events across a broad spectrum of chronic kidney disease stages in type 2 diabetes. Furthermore, recent data from the FINEARTS-HF and CONFIDENCE trials suggest a synergetic benefit when combined with SGLT2 inhibitors, offering more robust cardiorenal protection with a manageable risk of hyperkalemia. This review synthesizes the current understanding of MR pathophysiology and clinical evidence, providing a comprehensive framework for the integration of MRAs into the evolving standard of care for patients with diabetic kidney disease. Full article

Class B scavenger receptor BI splice variants (SR-BI) and BII (SR-BII) internalize lipoproteins but also bind and internalize bacteria. Their individual roles in sepsis are unknown. We overexpressed human SR-BI or BII in transgenic mice, primarily in the liver, but also in the kidney and in bone marrow-derived macrophages, and then performed cecal ligation and puncture (CLP) surgery. SR-BI and BII transgenic mice had significantly worse survival compared to WT mice. Twenty-four hours after CLP, liver injury markers and histological damage were elevated in both SR-BI and BII transgenic mice, whereas kidney damage was similar. Systemic inflammatory cytokines were markedly increased in SR-BI and BII transgenic mice; parallel increases were seen in liver mRNA expression, but not in the kidney. The highest degree of neutrophil infiltration was observed in the liver of SR-BI. Human SR-BI and BII dramatically decreased bacterial accumulation in the liver. Green fluorescent protein-labeled E. coli were efficiently phagocytosed in hepatic macrophages of SR-BI and BII transgenic mice; phagocytosis was more prominent in SR-BII transgenic mice. Finally, human SR-BI overexpression reduced systemic HDL-C levels, eliminated adrenal cortex lipid droplets, and dampened the systemic increase of corticosterone after CLP. Supplementation with glucocorticoid and mineralocorticoid improved survival in SR-BI but not in SR-BII transgenic mice after CLP. In summary, our findings suggest human SR-BI and BII overexpression contributes to higher mortality after CLP by different mechanisms: excessive inflammatory response due to adrenal insufficiency (SR-BI) or hyperactive phagocytosis (SR-BII) in the liver. Full article

Background: Cardiac involvement represents a major determinant of morbidity and mortality in patients with muscular dystrophies (MDs). Evidence supporting guideline-directed heart failure (HF) therapy in this population remains limited. We aimed to retrospectively assess the effectiveness and tolerability of sodium–glucose co-transporter 2 inhibitors (SGLT2i) in patients with MDs and a previous history of HFrEF, HFpEF and HFmrEF and/or echocardiographic evidence of an LVEF < 50% Methods: In this retrospective, single-center study, we enrolled consecutive patients with MD treated with empagliflozin or dapagliflozin between October 2021 and October 2024. Comprehensive clinical, laboratory, echocardiographic, and functional data were collected at a baseline (V1) and at follow-up (V3) visit to evaluate longitudinal changes. Results: Twenty-four patients (mean age 42 ± 16 years; 92% male) were included, with a median follow-up of 418 ± 104 days. SGLT2i therapy was well tolerated; one patient discontinued treatment due to a urinary tract infection. LVEF significantly improved from 41 ± 5% to 44 ± 6% (p = 0.005). FSS decreased from 36 to 30 (p < 0.001), indicating improved functional capacity. Background HF therapy was intensified over time, with increased prescription of mineralocorticoid receptor antagonists (21% vs. 52%; p = 0.039) and β-blockers (67% vs. 91%). The interval between MD diagnosis and cardiomyopathy onset independently predicted LVEF improvement (β = 0.17; p = 0.012). Conclusions: In patients with MDs and HF, SGLT2i therapy was safe and associated with a modest but significant improvement in LVEF, reduced fatigue, and enhanced prescription of guideline-directed HF therapy. These findings support the potential role of SGLT2i in this high-risk population and warrant confirmation in larger prospective studies. Full article