Search Results (181)

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

Antibodies directed against β-amyloid (Aβ) have been developed for the treatment of Alzheimer’s disease (AD). However, the in vivo central efficacy is reduced by the poor penetration of antibodies across the blood–brain barrier (BBB). In addition, these antibodies have been associated with adverse effects like amyloid-related imaging abnormalities. Thus, the development of new antibody-based therapies for AD with improved transport across the BBB may improve efficacy and reduce adverse effects. Antibodies targeting the BBB transferrin receptor (TfR) are able to cross the BBB through receptor-mediated transcytosis, producing a global distribution throughout the brain. Along the same line, bispecific antibodies directed to both the BBB TfR and Aβ showed enhanced brain uptake and pharmacological effects with diminished adverse side effects in experimental animal models of AD and in clinical trials. A generation of brain-penetrating fusion proteins targeting the BBB-TfR has been shown to represent novel treatments for AD, and this includes erythropoietin, tumor necrosis factor alpha inhibitors, neprilysin, somatostatin, oligonucleotides, and an antibody activating TREM2. The aim of this article is to review the progress made in the delivery of antibody-derived biologicals to the brain for AD, targeting the BBB-TfR. Full article

Obesity is a chronic, highly prevalent disease affecting nearly one-third of the global population and represents a major independent risk factor for heart failure (HF), particularly heart failure with preserved ejection fraction (HFpEF). Excess adiposity—especially visceral and epicardial adipose tissue (EAT)—acts as an active endocrine and immune organ, promoting chronic low-grade inflammation, oxidative stress, endothelial dysfunction, and adverse myocardial remodeling. Expanded EAT exerts both paracrine inflammatory effects and mechanical constraint on the myocardium, contributing to diastolic dysfunction, microvascular impairment, atrial arrhythmogenesis, and elevated filling pressures despite preserved systolic function. Evidence demonstrates a dose–response relationship between increasing body mass index and incident HF. Clinically, obesity-related HFpEF is characterized by concentric left ventricular hypertrophy, impaired relaxation, increased plasma volume, reduced exercise tolerance, and relatively low natriuretic peptide levels, complicating diagnosis. HF management includes traditional treatment with diuretics, renin-angiotensin system inhibitors, β-blockers, mineralocorticoid receptor antagonists, and angiotensin receptor-neprilysin inhibitors. These agents widely remain foundational as they primarily target hemodynamic and neurohormonal pathways in HF. In contrast, sodium–glucose cotransporter 2 inhibitors consistently reduce HF hospitalizations across the ejection fraction spectrum, while glucagon-like peptide-1 receptor agonists and dual incretin therapies (e.g., tirzepatide) promote substantial weight loss, improve symptoms, and demonstrate promising anti-remodeling effects in obesity-related HFpEF. Recognizing obesity-driven HF as a distinct cardiometabolic entity supports an integrated therapeutic strategy combining structured weight reduction with guideline-directed HF polypharmacotherapy to address both hemodynamic burden and upstream adiposity-related mechanisms. Full article

Heart failure (HF) is a systemic syndrome in which cardiac dysfunction is closely linked to multiorgan involvement, including the gastrointestinal tract. Increasing evidence highlights the relevance of the gut–heart axis in HF pathophysiology, whereby intestinal hypoperfusion, congestion, and barrier dysfunction promote gut microbiota dysbiosis, systemic inflammation, and adverse cardiovascular outcomes. In parallel, the advent of novel HF therapies, particularly sodium–glucose cotransporter 2 inhibitors (SGLT2i) and the angiotensin receptor–neprilysin inhibitor sacubitril/valsartan, has markedly improved clinical outcomes across HF phenotypes. Beyond their established cardiovascular benefits, these therapies may exert pleiotropic effects that extend to the intestinal environment and the gut microbiota. Through integrated actions on hemodynamics, neurohormonal activation, metabolic pathways, and inflammatory processes, recent data suggest that novel HF drugs may indirectly influence the gut-microbial composition and function. Conversely, the gut microbiota may modulate drug efficacy and result in interindividual variability in therapeutic responses, suggesting a bidirectional interaction between pharmacological treatment and the gut ecosystem. This narrative review summarizes current evidence of gut microbiota alterations in HF and critically examines emerging data on interactions between the gut microbiota and novel HF therapies, focusing on SGLT2 inhibitors and sacubitril/valsartan. Understanding this crosstalk may support the development of microbiota-informed, personalized therapeutic strategies in heart failure. Full article

Background: Contemporary guidelines recommend rapid initiation of four classes of guideline-directed medical therapy (GDMT) for heart failure (HF) with reduced ejection fraction (HFrEF); however, real-world persistence, adherence, and dose optimization remain suboptimal. Methods: We analysed a predefined subregistry within the prospective Cardiology Research Dubrava (CaRD) registry, a real-world HF registry at a tertiary centre that includes patients across the ejection-fraction spectrum in whom contemporary HF therapy, including sodium-glucose cotransporter 2 inhibitors (SGLT2i), is introduced or optimised in routine practice. For this analysis, we included patients with newly diagnosed HFrEF (left ventricular ejection fraction (LVEF) ≤ 40%) who were discharged on all four GDMT classes; 167 of 179 patients with newly diagnosed HFrEF during the study period had an available 6-month medication assessment and comprised the final analytic cohort. The four GDMT pillars (beta-blocker; angiotensin-converting enzyme inhibitor (ACEi), angiotensin receptor blocker (ARB), or angiotensin receptor-neprilysin inhibitor (ARNI); mineralocorticoid receptor antagonist (MRA); and SGLT2i) were initiated within 4 days when clinically feasible. Medication adherence and target-dose attainment were assessed at 6, 12, and 24 months using a structured self-report questionnaire. Major adverse events (MAE) and all-cause mortality were recorded over 24 months. Patients were classified as adherent if they reported regular intake (≥80% of prescribed doses) of all four drug classes at 6 months; otherwise, they were classified as nonadherent. Results: Among the 167 analysed patients (median age 64 years, 74% men, median LVEF 30%), regular adherence at 6, 12, and 24 months was 65%, 55%, and 59% for beta-blockers; 66%, 50%, and 49% for ACEi/ARB/ARNI; 62%, 52%, and 49% for MRAs; and 84%, 57%, and 68% for SGLT2i. Target doses were achieved in 25–33% for beta-blockers, 42–50% for ACEi/ARB/ARNI, and 73–78% for MRAs. At 24 months, 56 survivors (37%) were adherent to all four drug classes. Over 24 months, all-cause mortality was 9.0% and MAE 18.6%, occurring less frequently in adherent vs. nonadherent patients (mortality 0% vs. 13.5%; MAE 8.9% vs. 23.4%). Conclusions: In this real-world, non-randomized HFrEF subregistry, in-hospital initiation of quadruple GDMT was feasible, yet maintaining long-term adherence and achieving target doses remained challenging. These data underscore the gap between guideline recommendations and routine practice and support structured follow-up and protocol-driven titration to optimize implementation. Full article

Background/Objectives: Reduced-ejection-fraction heart failure (HFrEF) constitutes a challenge due to its high morbidity and mortality. The use of sacubitril/valsartan (angiotensin receptor–neprilysin inhibitors [ARNI]) and SGLT2 inhibitors (SGLT2i) represents a change in management approach with a demonstrated association with positive ventricular remodeling and a reduction in cardiovascular events. We describe the clinical and therapeutic course of patients with HFrEF in a specialized unit, comparing two consecutive periods (2011–2016 vs. 2017–2021), with emphasis on the impact of ARNI and SGLT2i upon clinical parameters and the use of devices. Methods: A retrospective, longitudinal observational study was carried out in 1363 outpatients with HFrEF, with at least two years of follow-up. Clinical characteristics, treatments, the evolution of left ventricular ejection fraction (LVEF), mortality, and the use of devices (implantable cardioverter–defibrillator [ICD], cardiac resynchronization therapy [CRT]) were evaluated. Results: A total of 1363 patients were analyzed, showing a significant therapeutic change in the 2017–2021 group with the incorporation of ARNI (40%) and SGLT2i (25%). This cohort achieved better ventricular recovery, with a significantly higher mean LVEF at one year compared to the 2011–2016 group (44.3% vs. 42.1%; p = 0.004). Regarding devices, ICD implantation rate decreased in the recent period (7.2% vs. 11.1%; p = 0.016), while CRT indication increased. Most importantly, all-cause mortality after two years fell from 9.4% to 5.9% (p = 0.023). Multivariate analysis confirmed that this survival improvement was independently associated with the study period (HR 1.57 for the earlier group) and was linked to the protective effect of contemporary pharmacological treatments. Conclusions: The systematic introduction of ARNI and SGLT2i in the treatment of HFrEF was associated with improved ventricular function, reduced need for device implantation, and lower mortality over the middle term in a real-life clinical setting. Full article

Atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) coexist in 40–60% of cases and mutually reinforce each other through adverse electrical, cellular, and functional remodelling. There is considerable overlap in signs and symptoms, and diagnosis may be challenging due to nonspecific clinical presentations and chronic course. AF is clearly linked with worsening morbidity and mortality in HFpEF with higher rates of HF hospitalizations, HF progression, stroke, systemic embolism, and all-cause death. Optimal management of HFpEF-AF patients requires aggressive treatment of comorbidities and risk factor modification. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have demonstrated consistent benefit with respect to HF hospitalizations, symptoms and exercise haemodynamics, and potential to reduce AF burden. Gastric inhibitory polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) agonists, mineralocorticoid receptor antagonists (MRAs), angiotensin receptor-neprilysin inhibitors (ARNIs), and statins may provide benefit in selected phenotypes, though evidence remains heterogeneous. A rhythm control strategy in the early clinical course of HFpEF might be a reasonable strategy to improve symptoms and delay both AF and HFpEF disease progression. Catheter ablation appears to improve exercise haemodynamics and quality of life, and observational data suggest it may reduce mortality and HF hospitalization, though current evidence is inconsistent and not yet definitive. Emerging device-based and molecular therapies could represent promising avenues for future research. Overall, early detection of AF, comprehensive risk-factor modification, and tailored rhythm-control strategies are central to improving outcomes in the HFpEF-AF overlap syndrome. Full article

Overactivation of the renin–angiotensin–aldosterone system (RAAS) promotes haemodynamic overload, inflammation, and fibrosis in the heart and kidneys. Recently, sodium–glucose cotransporter-2 (SGLT2) inhibitors have emerged as a cornerstone therapy in cardiorenal protection. Emerging data indicate that adding SGLT2 inhibitors to angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, or angiotensin receptor–neprilysin inhibitors confers additional cardiorenal protection, yet their mechanistic basis and optimal clinical use in cardiovascular (CV) disease remain unclear. This review will integrate pre-clinical and clinical evidence on dual RAAS/SGLT2 modulation in CV disease, providing mechanistic insight into dual therapy. The review will finally outline priorities for future translational and outcome studies. Clinically, adding SGLT2 inhibitors to RAAS-based therapy reduces heart failure hospitalizations and slows kidney disease progression without new safety liabilities in type 2 diabetes, heart failure, and chronic kidney disease. Mechanistically, SGLT2 inhibition restores tubuloglomerular feedback and constricts the afferent arteriole; RAAS blockade dilates the efferent arteriole, and together, they lower intraglomerular pressure. Both classes also reduce oxidative stress, inflammatory signalling, and pro-fibrotic pathways, with SGLT2 inhibitors in several settings shifting RAAS balance toward the protective ACE2/angiotensin-(1–7)/Mas receptor axis. Key gaps include the scarcity of adequately powered trials designed to test combination therapy versus either component alone, limited evidence on timing and sequencing, incomplete characterization in high-risk groups, and mechanistic insight limited by study design in animal and cell models. Collectively, current data support layering SGLT2 inhibitors onto RAAS-based therapy, while definitive evidence from dedicated clinical trials is awaited. Full article

Heart failure (HF) remains a major challenge in cardiovascular medicine, contributing to high global rates of hospitalization and mortality. Recent research (2022–2025) has emphasized its heterogeneity, highlighting distinct phenotypes—HFpEF, HFmrEF, and HFrEF—driven by mechanisms such as chronic inflammation, myocardial fibrosis, and neurohormonal imbalance. Advances in therapy, particularly with sodium–glucose cotransporter-2 inhibitors (SGLT2i), angiotensin receptor–neprilysin inhibitors (ARNI), and iron supplementation, have reshaped treatment strategies. Moreover, the growing recognition of overlaps between HF and cardiomyopathies such as hypertrophic, Takotsubo, and amyloidosis underscores the need for integrated care. This review summarizes recent findings from leading journals, mapping the evolving understanding of HF pathophysiology and management, and outlining emerging directions for research and clinical practice. Full article

Osteoarthritis (OA) is a debilitating joint disease affecting over 500 million people globally, characterized by cartilage degradation, chronic pain, and failed tissue repair. Neurogenic inflammation, driven by neuropeptides including Substance P (SP) and calcitonin gene-related peptide (CGRP), plays a key role in the pathogenesis of OA. This study explores the therapeutic potential of extracellular vesicles (EVs) derived from infrapatellar fat pad mesenchymal stem/stromal cells (IFP-MSCs) transduced with CGRP antagonist CGRP_8-37 (aCGRP IFP-MSC EVs). These EVs are enriched in anti-inflammatory miRNAs and proteins, and they express neprilysin (CD10), enabling SP degradation. Herein, several LncRNAs were identified, which have been known to interact with miRNAs that affect the knee joint homeostasis. Specifically, 11 LncRNAs (ZFAS1, EMX2OS, HOTAIRM1, RPS6KA2-AS1, DANCR, LINC-ROR, GACAT1, GNAS-AS1, HAR1A, OIP5-AS1, TERC) interact with miRNAs that promote cell proliferation, prevent apoptosis, and preserve homeostasis. In vitro, aCGRP IFP-MSC EVs downregulated pro-inflammatory markers (TNF, TLR4, MAPK8) in dorsal root ganglia and promoted chondrocyte gene expression consistent with anabolism and matrix remodeling. In vivo, intra-articular EV delivery attenuated pain behaviors, preserved the cartilage structure, restored PRG4+ stem/progenitor cell localization, and trended toward reduced SP levels. Histological analysis confirmed improved collagen organization and reduced matrix degradation. These findings suggest that aCGRP IFP-MSC EVs exert multimodal effects on neuroinflammation, cartilage regeneration, and joint homeostasis. This cell-free, gene-enhanced EV therapy offers a promising disease-modifying strategy for the treatment of OA, with the potential to address both structural changes and chronic pain associated with this disease. Full article

In Myanmar, Russell’s viper (Daboia siamensis) bite is a significant public health problem. In this study, we expend upon our previous RNA-sequencing approach to characterize candidate toxin genes encoding D. siamensis toxins. The mRNA was extracted from Myanmar Russell’s viper venom glands. The RNAseq was performed using Illumina next-generation sequencing. Subsequently, candidate toxin transcripts were recognized by the Venomix pipeline. This study focused on 29 unique cDNA sequences representing eight newly identified venom gene families with low-to-moderate expression levels. These transcripts represented 0.088% of the total number of transcripts in the dataset. The translated protein sequences were analyzed for their conserved motifs and domains to predict their functions. They were neprilysins (bioactive peptide inactivators), cystatins (protease inhibitors with anti-metastatic activities), waprin and vipericidin (antimicrobial peptides), veficolin (platelet and complement activation), vespryns and three-finger toxins (elapid toxin homologs causing neurotoxic activity and tissue damage), and endothelial lipases (unknown function). Their functional activities should be further investigated for potential therapeutic applications, for example, in cancer or antibiotic-resistant infections. Full article

Despite substantial progress in medical care, acute myocarditis remains a life-threatening disorder with a sudden onset, often unexpectedly complicating a simple and common upper respiratory tract infection. In most cases, myocarditis is triggered by viral infections (over 80%), with an estimated incidence of 10–106 per 100,000 annually. The clinical course may worsen in cases of mixed etiology, where a primary viral infection is complicated by secondary bacterial pathogens, leading to prolonged inflammation and an increased risk of progression to chronic active myocarditis or dilated cardiomyopathy. We present a case report illustrating the clinical problem of acute myocarditis progression into a chronic active form. A central element of host defense is the inflammasome—an intracellular complex that activates pyroptosis and cytokine release (IL-1β, IL-18). While these processes help combat pathogens, their persistent activation may sustain inflammation and trigger heart failure and cardiac fibrosis, eventually leading to dilated cardiomyopathy. In this review, we summarize the current understanding of inflammasome pathways and their dual clinical role in myocarditis: they are essential for controlling acute infection but may become harmful when overactivated, contributing to chronic myocardial injury. Additionally, we discuss both novel and established therapeutic strategies targeting inflammatory and anti-fibrotic mechanisms, including IL-1 receptor blockers (anakinra, canakinumab), NOD-like receptor protein 3 (NLRP3) inhibitors (colchicine, MCC950, dapansutrile, INF200), NF-κB inhibitors, and angiotensin receptor-neprilysin inhibitors (ARNI), as well as microRNAs. Our aim is to emphasize the clinical importance of early identification of patients at risk of transitioning from acute to chronic inflammation, elucidate the role of inflammasomes, and present emerging therapies that may improve outcomes by balancing effective pathogen clearance with limitation of chronic cardiac damage. Full article

Background/Objectives: Urgent hospitalization due to acutely decompensated heart failure (ADHF) is an unfavorable event in the trajectory of this disease. Patient condition during decompensation frequently limits opportunities to implement and optimize guideline-directed medical therapy (GDMT). To define the tasks of post-hospital care, it is essential to gain knowledge regarding the extent of GDMT implementation on the day of discharge after ADHF episodes. The purpose of this analisis was to evaluate GDMT changes during hospitalization due to ADHF, with a particular emphasis on patients with reduced ejection fraction. Methods: The analysis was conducted in a group of 262 patients hospitalized due to ADHF and with known left ventricular ejection fraction (LVEF). The HEROES study was a prospective, multi-center, observational study. Results: The mean age in the study group (196 men and 66 women) was 67.6 ± 14.6 years, with a mean LVEF of 33.9 ± 14.8%. Six patients died during hospitalization. In the analysis for the whole group (regardless of ejection fraction [EF]), ARNI (angiotensin receptor-neprilysin inhibitor)/ACEI (angiotensin-converting enzyme inhibitor)/ARB (angiotensin receptor blocker) use increased from 63.3% of the subjects at admission to 81.3% at discharge, beta-blocker use increased from 70.6% to 92.6%, MRA (mineralocorticoid receptor antagonist) use increased from 43.1% to 75.8%, and SGLT2i (sodium-glucose co-transporter 2 inhibitor) use increased from 30.1% to 75.0%. ARNI/ACEI/ARB therapy was optimized in 48.4% of the subjects, with optimization rates of 37.9%, 40.2%, and 44.1% for beta-blockers, MRAs, and SGLT2is, respectively. However, only 38 (22.0%) patients reached the level of treatment corresponding to “SGLT2i and ARNI/ACEI/ARB and betablocker and MRA in doses ≥ 50%”. Conclusions: In patients hospitalized due to ADHF in the HEROES study, the use of GDMT at discharge was significantly higher than at admission. In patients with reduced ejection fraction, GDMTs from all drug classes were prescribed to over 80% of patients. However, an insufficient number of patients attained high doses of GDMT, which emphasizes the need for effective dose up-titration in outpatient settings. Full article

Cardiovascular disorders and the medications used to treat them can affect physiological patterns of behavior. The aim of the present study was to determine whether the dual inhibition of neprilysin and angiotensin II—sacubitril/valsartan (ARNI) can modify anxiety-like behavior in male spontaneously hypertensive rats (SHR). We compared ARNI with two other drugs in the portfolio of heart failure treatment, captopril and ivabradine. Six groups (n = 13) of 12-week-old rats were treated for six weeks: control (Wistar rats), control + ARNI, SHR, SHR + ARNI, SHR + captopril, and SHR + ivabradine. The elevated plus maze test, the open field test, and the light–dark box test were used to determine anxiety-like behavior. SHRs exhibited higher systolic blood pressure (SBP), heart rate (HR), left ventricular weight (LVW), and hydroxyproline concentration (LVHP) but displayed a reduced level of anxiety-like behavior in comparison to controls. ARNI reduced SBP, HR, and LVW but had no significant effect on the level of anxiety in SHR, and similar results were achieved by captopril and ivabradine. Additionally, correlation analysis indicated that anxiety-like behavior in Wistar rats or SHR, either with or without cardiovascular therapy, was independent of SBP, HR, LVW, or LVHP. The level of anxiety-like behavior can, therefore, be considered part of the inherent neurobehavioral traits unrelated to fundamental hemodynamic or structural cardiovascular parameters. Full article

Alzheimer’s disease (AD), the most prevalent form of dementia, poses a critical global health challenge as its incidence rises with aging populations. Despite extensive research into its genetic and molecular underpinnings, effective therapeutic strategies remain limited. Growing evidence suggests that physical exercise may offer neuroprotective benefits, potentially mitigating AD progression through multifactorial mechanisms. This review synthesizes current findings on the interplay between aerobic exercise and AD pathophysiology, with a focus on amyloid-β (Aβ) metabolism, gene expression, and neuroinflammation. We explore how exercise influences Aβ clearance, modulates amyloid precursor protein (APP) processing, and impacts the activity of key enzymes such as secretases and neprilysin. Further, we highlight the gene–exercise crosstalk identified through transcriptomic data, particularly in the entorhinal cortex—an early site of Aβ deposition. Our analysis also discusses how exercise-induced modulation of molecular pathways—including mitochondrial function, oxidative stress responses, and neuroinflammatory cascades—may confer cognitive resilience. By integrating molecular, genetic, and systems biology data, this review underscores the potential of structured physical activity as a non-pharmacological intervention to delay or attenuate AD pathology. These insights support a precision medicine approach, which combines lifestyle interventions with molecular profiling, to improve prevention strategies and therapeutic outcomes in AD. Full article