Search Results (155)

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome with increasing prevalence and substantial morbidity and mortality. Recent advances in pharmacotherapy have transformed its management. This review summarizes current evidence supporting the use of sodium–glucose cotransporter 2 inhibitors, non-steroidal mineralocorticoid receptor antagonists, and glucagon-like peptide-1 receptor agonists, alongside selected use of angiotensin receptor–neprilysin inhibitors. Emphasis is placed on early initiation of disease-modifying therapies, phenotypic tailoring, and comorbidity-targeted strategies, especially in obese and diabetic patients. Together, these approaches define a new era of guideline-directed, personalized care for patients with HFpEF. Full article

Background/Objectives: Guidelines recommend patients with heart failure with reduced ejection fraction (HFrEF) receive four-pillar heart failure (4P-HF) therapy, which significantly reduces cardiac morbidity and mortality. However, implementing these guidelines effectively into clinical practice remains challenging. Methods: Patients with HFrEF on submaximal 4P-HF therapy were identified from a large, multicentre Cardiology network database using a natural language processing tool, supported by manual file review. A nurse-led, remotely delivered, medication uptitration program aimed to optimise therapy in this real-world cohort. Results: The final cohort included 2004 patients with a mean age of 72.7 ± 11.6 years. Utilisation of 4P-HF increased from 11.1% at baseline to 49.8% post intervention, and each individual medication class increased significantly post intervention (all p < 0.001). The largest increase was observed with the use of sodium–glucose cotransporter 2 inhibitors, which rose from 17.3% to 73.9%, followed by mineralocorticoid receptor antagonists (51.6% to 65.7%), beta-blockers (88.4% to 97.0%), and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor blocker–neprilysin inhibitors (89.8% to 96.4%). In patients on submaximal therapy, barriers were documented in all cases. Following medication optimisation, left ventricular ejection function (LVEF) improved significantly (38.5% ± 10.8% vs. 42.5% ± 11.7, p < 0.001). Conclusions: This nurse-led, remotely delivered, medication optimisation program significantly improved the adoption of 4P-HF therapy and LVEF in patients with HFrEF. The program demonstrates a practical, scalable solution for the optimisation of HFrEF therapy across a large healthcare network. Full article

Insulin-degrading enzyme (IDE) plays a critical role in regulating insulin levels in various tissues, including the brain, liver, and kidneys. In type 2 diabetes mellitus (T2DM), key features include insulin resistance, elevated insulin levels in the blood, and hyperglycemia. In this context, the function of IDE becomes particularly important; however, in T2DM, IDE’s function can be impaired. Notably, individuals with T2DM have a higher risk of developing Alzheimer’s disease (AD), suggesting that impaired IDE function may contribute to both diabetes and neurodegeneration. IDE has been studied for its ability to degrade Amyloid-β peptides, the primary constituents of amyloid plaques in AD. However, its role in Aβ clearance in vivo remains debated due to limited enzymatic efficacy under physiological conditions and differences in subcellular localization between IDE and its putative substrate. Other proteases, such as neprilysin, appear to play a more prominent role in preventing plaque formation. Additionally, the long-standing hypothesis that insulin competes with Aβ for IDE activity has been questioned, as brain insulin levels are too low to inhibit Aβ degradation significantly. Genetic variants in the IDE gene have been associated with increased AD risk, although the mechanisms by which they alter enzyme function are not yet fully understood. A deeper understanding of IDE’s role in the context of both metabolic and neurodegenerative diseases may provide valuable insights for the development of new therapeutic strategies. Full article

Background/Objectives: Contextual memory associated with methamphetamine (METH) use contributes to relapse and persistence of addiction. Angiotensin II type 1 receptor (AT1R) signaling has been implicated in drug reinforcement. LCZ696, a clinically used combination of sacubitril (a neprilysin inhibitor) and valsartan (an AT1R antagonist), may interfere with METH-associated memory through the modulation of dopaminergic pathways. Methods: Male C57BL/6J mice were tested in a conditioned place preference (CPP) paradigm to assess the effects of LCZ696, sacubitril (AHU377), and valsartan on METH-induced memory expression and reinstatement. Synaptic plasticity in the nucleus accumbens (NAc) was examined by assessing the levels of synaptophysin (Syp) and postsynaptic density protein 95 (Psd95), as well as dendritic spine density. Dopaminergic signaling in the ventral tegmental area (VTA) was evaluated via ELISA, Western blotting, and chromatin immunoprecipitation (ChIP), targeting cAMP response element-binding protein (Creb) binding to the tyrosine hydroxylase (Th) promoter. To further assess the role of Th, an adeno-associated virus (AAV9) carrying a CRISPR-Cas9-based sgRNA targeting Th (AAV9-Th-sgRNA) was microinjected into the VTA. Results: LCZ696 and valsartan significantly reduced METH-induced CPP and reinstatement. LCZ696 reversed METH-induced synaptic and dopaminergic alterations and suppressed Creb-mediated Th transcription. Th knockdown attenuated both CPP acquisition and relapse. Conclusions: LCZ696 disrupts METH-associated contextual memory by modulating dopaminergic signaling and Creb-dependent Th expression, supporting its potential as a treatment for METH use disorder. Full article

Chicken feathers constitute a major by-product from the poultry industry, with a potential environmental impact and significant difficulties in their management. This study aimed to develop a sustainable method to hydrolyse chicken feathers and evaluate the effects of microwave (MW) irradiation pre-treatment in the generation of bioactive hydrolysates by simple or sequential hydrolysis with Alcalase. The hydrolysate with MW irradiation pre-treatment and Alcalase (2%, 2 h) (MWA) showed the highest overall antioxidant activity and neprilysin-inhibitory activity (55%), whereas samples without MW irradiation pre-treatment exerted the highest inhibitory activity of dipeptidyl peptidase IV (DPP IV) and angiotensin-converting enzyme (ACE-I), with values close to 50 and 70%, respectively. Mass spectrometry in tandem of bioactive hydrolysates was performed, and an in silico approach was used to characterise the obtained sequences. These results confirmed that MW irradiation pre-treatment improved Alcalase hydrolysis, leading to the generation of bioactive peptides with potential multifunctional properties, including antioxidant, antidiabetic, and antihypertensive activities. Moreover, this study highlights the potential of combining MW irradiation and enzymatic hydrolysis as a sustainable strategy for the revalorisation of chicken feathers. Full article

Introduction: Cardiac involvement in patients with systemic sclerosis (SSc) can present variably from being asymptomatic to manifesting with heart failure, conduction abnormalities, pulmonary hypertension, and pericardial effusion. Symptomatic cardiac involvement portends a poor prognosis and worse overall survival. Sacubitril/valsartan (SV), an angiotensin receptor neprilysin inhibitor, has been shown to significantly reduce hospitalization rates and morbidity in patients with heart failure with reduced ejection fraction (HFrEF). This study aimed to investigate the effects of SV treatment in patients with SSc and heart failure. Methods: A retrospective analysis of patients with SSc was conducted using an electronic data capture tool. Patients with SSc treated with SV between January 2015 and August 2023 were identified. Comprehensive clinical phenotyping and longitudinal data analysis were performed to characterize the sub-type of patients and evaluate clinical outcomes, including hospitalizations and mortality, laboratory markers, and echocardiographic findings. Results: Twenty-four patients with SSc were treated with SV for a mean duration of 20.6 months. HFrEF was the primary indication for SV use in 91% of patients, primarily due to non-ischemic cardiomyopathy (87.5%). There was a significant reduction in systolic blood pressure from 128 mmHg to 114 mmHg (p < 0.001) and NT-proBNP levels from 15,130 pg/mL to 5082 pg/mL (p = 0.046). In the 19 patients with baseline and follow-up echocardiograms, there was a significant improvement in LVEF from 40.3% to 47.7% (p = 0.014). Hypotension was a common side effect leading to discontinuation of SV (n = 4, 16.7%). Serum creatinine had trends of improvement (1.9 mg/dL to 1.3 mg/d), though it did not reach statistical significance (p = 0.057). Conclusions: This study showed that SV effectively improved cardiac symptoms and function in patients with SSc presenting with HFrEF. Further prospective studies are needed to confirm these findings and explore the role of SV in the treatment of other manifestations of SSc. Full article

Heart failure (HF) is a major socioeconomic problem worldwide, associated with high morbidity and mortality due to several underlying diseases. HF is driven by several closely linked mechanisms whose effects are mutually reinforcing. Some of the signalling pathways involved in the progression of HF may initially be compensatory, such as the renin–angiotensin–aldosterone system (RAAS), whose hyperactivation plays a central role in the progression of HF by promoting fluid retention, inflammation, oxidative stress (OS), and myocardial dysfunction. Fluid retention is also promoted by the action of neprilysin, which contrasts natriuresis and vasodilation. Among the compensatory and subsequently maladaptive systems, chronic hyperactivation of the sympathetic nervous system (SNS) exacerbates maladaptive remodelling and drives the progression of HF. At the molecular level, mitochondrial dysfunction and inflammatory substances are involved in the development of a state of systemic oxidative stress and inflammation. The aim of the following manuscript was to revise the pathophysiology and role of OS in HF, focusing on the current knowledge of the molecular pathways involved. Full article

Cardiovascular diseases and cancer are the two primary causes of mortality worldwide. Although traditionally regarded as distinct pathologies, they share numerous pathophysiological mechanisms and risk factors, including chronic inflammation, insulin resistance, obesity, and metabolic dysregulation. Notably, several cancers have been identified as closely linked to cardiovascular diseases, including lung, breast, prostate, and colorectal cancers, as well as hematological malignancies, such as leukemia and lymphoma. Additionally, renal and pancreatic cancers exhibit a significant association with cardiovascular complications, partly due to shared risk factors and the cardiotoxic effects of cancer therapies. Addressing the overlapping risk factors through lifestyle modifications—such as regular physical activity, a balanced diet, and cessation of smoking and alcohol—has proven effective in reducing both CV and oncological morbidity and mortality. Furthermore, even in patients with established cancer, structured interventions targeting physical activity, nutritional optimization, and smoking cessation have been associated with improved outcomes. Beyond lifestyle modifications, pharmacological strategies play a crucial role in the prevention of both diseases. Several cardiovascular medications, including statins, aspirin, beta-blockers, and metformin, exhibit pleiotropic effects that extend beyond their primary indications, demonstrating potential anti-neoplastic properties in preclinical and observational studies. Recently, novel therapeutic agents have garnered attention for their possible cardioprotective and metabolic benefits. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is), initially developed for managing type 2 diabetes, have shown CV and renal protective effects, alongside emerging evidence of their role in modulating cancer-related metabolic pathways. Inclisiran, a small interfering RNA targeting PCSK9, effectively lowers LDL cholesterol and may contribute to reducing CV risk, with potential implications for tumor biology. Additionally, sacubitril/valsartan, an angiotensin receptor–neprilysin inhibitor, has revolutionized heart failure management by improving hemodynamic parameters and exerting anti-inflammatory effects that may have broader implications for chronic disease prevention. Given the intricate interplay between CVD and cancer, further research is essential to clarify the exact mechanisms linking these conditions and assessing the potential of CV therapies in cancer prevention. This review aims to examine shared risk factors, consider the role of pharmacological and lifestyle interventions, and emphasize crucial epidemiological and mechanistic insights into the intersection of CV and oncological health. Full article

Background/Objectives: Cardiac resynchronization therapy (CRT) and angiotensin receptor–neprilysin inhibitors (ARNIs) are cornerstone therapies for patients with heart failure with reduced ejection fraction (HFrEF). However, nearly 30% of patients show no significant response to CRT alone. The potential of ARNI to enhance CRT outcomes—especially in non-responders—is an emerging field of interest. The objective of this review is to systematically evaluate and synthesize the available evidence on the clinical outcomes of combining CRT with ARNI therapy in patients with HFrEF. Methods: We conducted a comprehensive search of PubMed, Scopus, and Google Scholar up to September 2024, using the keywords “CRT and ARNI” and “cardiac resynchronization therapy and sacubitril/valsartan”. We included retrospective and prospective clinical studies, observational studies, and review articles reporting on patients with HFrEF treated with both CRT and ARNI. Studies not in English, animal studies, and those without full-text availability were excluded. Study selection and data extraction were performed in duplicate by independent reviewers, using PRISMA guidelines for transparency. The final selection included 8 studies published in the last four years, summarized by design, population, outcomes, and statistical significance. Results: The reviewed studies suggest that ARNI therapy, when combined with CRT, may contribute to improvements in left ventricle ejection fraction (LVEF), NYHA functional class, and ventricular remodeling, particularly in CRT non-responders. Some studies also report a potential reduction in ventricular arrhythmias and implantable cardioverter-defibrillator (ICD) interventions. However, outcomes varied across subgroups, and the influence of ARNI timing relative to CRT implantation remains inconclusive. Limitations: Heterogeneity in study designs and small sample sizes in some included studies limited the ability to conduct a meta-analysis. This review is not registered. Conclusions: ARNI therapy shows promise in enhancing CRT response in patients with HFrEF, particularly in non-responders. Further large-scale, prospective studies are needed to clarify optimal patient selection and treatment sequencing. Full article

Background: Current guidelines emphasize the importance of initiating or optimizing the four pillars of heart failure with reduced ejection fraction (HFrEF) therapy—beta-blockers (BB), mineralocorticoid receptor antagonists (MRA), angiotensin receptor–neprilysin inhibitors (ARNI), and sodium–glucose cotransporter-2 inhibitors (SGLT2i)—during hospitalization for acute decompensation. This study compares clinical characteristics and outcomes in HFrEF patients hospitalized for decompensated heart failure based on whether they were newly initiated on or were already receiving at least one of these four pillars. Methods: This prospective observational study included 203 HFrEF patients hospitalized for acute decompensation. Patients were divided into two groups: Group A (n = 126), not receiving any of the four pillars prior to admission, and Group B (n = 77), receiving at least one. Clinical and biological parameters were evaluated during hospitalization, with outcomes including changes in weight, blood pressure, heart rate, renal function (serum creatinine), electrolyte levels (sodium, potassium), and 30-day mortality. Statistical analyses included the non-parametric Mann–Whitney test and Chi-squared test. Results: Baseline characteristics (age, gender, LVEF, NT-proBNP) were similar between the two groups. No significant difference was observed in 30-day mortality (Group A: 7.14%, Group B: 5.55%, p = 0.74). Both groups experienced significant improvements in systolic and diastolic blood pressure and heart rate during hospitalization (p < 0.05). While serum creatinine levels remained stable in both groups, creatinine dynamics (Δcreatinine) were significantly different (p = 0.02), with Group B exhibiting a higher increase. The improvement in ejection fraction was more pronounced in Group A (p = 0.057) compared to Group B. Both groups demonstrated significant improvements in NYHA functional class (p < 0.001). In Group B, the use of MRAs and SGLT2 inhibitors significantly increased during hospitalization (p = 0.01 and p < 0.001, respectively). Conclusions: The initiation or optimization of the four pillars of HFrEF therapy during hospitalization for acute decompensation is feasible and well-tolerated. Early intervention leads to improvements in clinical parameters and functional status, supporting guideline recommendations for in-hospital initiation or optimization of HFrEF therapy. Special consideration should be given to renal function when optimizing therapy. Full article

Background/Objectives: Heart transplantation (HTX) is the definitive treatment for advanced heart failure (AdHF). The angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan (S/V) has been shown to reduce heart failure (HF) hospitalizations and mortality when compared to conventionally administered HF medications (i.e. angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs)). Nevertheless, limited data are available on the hemodynamic (HD) effects of ARNI in patients with AdHF. Therefore, the aim of the present study was to compare echocardiographic, laboratory, and HD parameters relevant to HF before and after switching to ARNI in patients with AdHF awaiting HTX. Methods: A retrospective analysis was conducted utilizing available data on HD parameters, N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, data on kidney function, HF therapy, and comorbidities. The study cohort comprised 13 AdHF patients (3 women, 10 men; mean age 56.4 ± 9 years) of whom 53.8% presented with non-ischemic and 46.2% with ischemic etiology. All patients were awaiting heart transplantation (HTX) and were transitioned to ARNI therapy between 2018 and 2021. Results: After switching to ARNI, we observed significant improvements: in left ventricular ejection fraction (LVEF: 27.27 ± 1.04% vs. 23.65 ± 1.02%, p = 0.03; data are given as mean ± SEM after vs. before ARNI therapy, respectively), cardiac output (CO: 4.90 ± 0.35 L/min vs. 3.83 ± 0.24 L/min, p = 0.013), and stroke volume (SV: 70.9 ± 5.9 mL vs. 55.5 ± 4.12 mL, p = 0.013). Significant reductions in systemic vascular resistance (SVR: 1188 ± 79.8 vs. 1600 ± 100 DS/cm⁵, p = 0.004) and pulmonary vascular resistance (PVR: 232.5 ± 34.8 vs. 278.9 ± 31.7 DS/cm⁵, p = 0.04) were also noted. Central venous pressure (CVP), pulmonary arterial systolic and diastolic pressures (PAPs and PAPd), pulmonary capillary wedge pressure (PCWP), and NT-proBNP levels did not exhibit significant changes upon ARNI administration. Conclusions: Early transition to ARNI therapy offers significant benefits for invasively measured hemodynamic parameters in patients with AdHF, potentially aiding in the stabilization and improvement of this vulnerable patient population. Full article

Background/Objectives: Radiotheranostics of neurotensin subtype 1 receptor (NTS₁R)-expressing tumors, like pancreatic, gastrointestinal, or prostate cancer, has attracted considerable attention in recent years. Still, the fast degradation of neurotensin (NT)-based radioligands, by angiotensin-converting enzyme (ACE), neprilysin (NEP), and other proteases, has considerably compromised their efficacy. The recently introduced [^99mTc]Tc-DT11 (DT11, N₄-Lys(MPBA-PEG4)-Arg-Arg-Pro-Tyr-Ile-Leu-OH; N₄, 6-(carboxy)-1,4,8,11-tetraazaundecane) has displayed promising uptake in NTS₁R-positive tumors in mice and enhanced resistance to both ACE and NEP by virtue of the lateral MPBA-PEG4 (MPBA, 4-(4-methylphenyl)butyric acid; PEG4, 14-amino-3,6,9,12-tetraoxatetradecan-1-oic acid) chain attached to the ε-NH₂ of Lys⁷. We were next interested in investigating whether these qualities could be retained in DT14D, likewise modified at Lys⁷ but carrying the universal chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) via a (βAla)₃ spacer at the α-NH₂ of Lys⁷. This chelator switch enables the labeling of DT14D with a wide range of trivalent radiometals suitable for true theranostic applications, not restricted to the diagnostic imaging of NTS₁R-positive lesions only by single-photon emission computed tomography (SPECT). Methods: DT14D was labeled with Ga-67 (a surrogate for the positron emission tomography radionuclide Ga-68), In-111 (for SPECT), and Lu-177 (applied in radiotherapy). The resulting radioligands were tested in NTS₁R-expressing pancreatic cancer AsPC-1 cells and mice models. Results: [⁶⁷Ga]Ga/[¹¹¹In]In/[¹⁷⁷Lu]Lu-DT14D displayed high affinity for human NTS₁R and internalization in AsPC-1 cells. They remained >70% intact 5 min after entering the mice’s circulation, displaying NTS₁R-specific uptake in AsPC-1 xenografts. Conclusions: Suitably side-chain modified NT analogs show enhanced metabolic stability and hence better prospects for radiotheranostic application in NTS₁R-positive cancer. Full article

Drug development for human disease relies on preclinical model systems such as human cell cultures and animal experiments before therapeutic treatments can ultimately be tested on humans in clinical studies. We here describe the generation of a novel human cell line (HLMVEC/SVTERT289) that we generated by transfection of microvascular endothelial cells from healthy donor lung tissue with the catalytic domain of telomerase and the SV40 large T/small t-antigen. These cells exhibited satisfactory growth characteristics and largely maintained their native characteristics, including morphology, cell surface marker expression, angiogenic potential and the protein composition of secreted extracellular vesicles. In order to test their suitability as a disease model, we simulated mechanical stress induced by cyclic stretch as encountered in ventilator-induced lung injury using the FlexCell^® system and compared their performance to primary lung endothelial cells. In this setting, HLMVEC/SVTERT289 cells exhibited significantly higher neprilysin activity on the cell surface and extracellular vesicles secreted from the cell line exhibited higher Tissue Factor and ACE2 expression but lower ACE expression and ACE activity than vesicles released from the primary cells. This study provides an unprecedented and detailed characterization of the HLMVEC/SVTERT289 cell line, which should help to appraise its suitability in different molecular studies. Full article

Background/Objectives: Inadequate cardiovascular adaptation during pregnancy impairs endothelial function and vascular resistance, contributing to complications such as pre-eclampsia (PE) and gestational hypertension (GH). Neprilysin (NEP), a protease involved in vascular regulation, has been linked to PE, but its role in endothelial function and vascular adaptation remains unclear. This pilot study investigates the associations between soluble neprilysin (sNEP) and markers of vascular and renal function in high-risk pregnancies without PE. Methods: Observed parameters were analyzed in 29 high-risk pregnant women across early, mid-, and late pregnancy. sNEP levels were analyzed alongside body mass index (BMI), endothelial dysfunction (ADMA), arterial stiffness (pulse wave velocity, PWV), retinal microvasculature (central retinal arteriolar and venular equivalents, CRAE and CRVE), and kidney function markers. The impact of gestational hypertension (GH) and prior smoking on sNEP levels was also evaluated. Results: In early and mid-pregnancy, sNEP was inversely associated with BMI. During mid-pregnancy, sNEP showed a positive correlation with CRAE and an inverse correlation with PWV, suggesting reduced arterial stiffness. By late pregnancy, sNEP was positively associated with glomerular filtration rate and inversely correlated with creatinine and protein levels, reflecting improved kidney function. Women with GH exhibited elevated sNEP, while former smokers had lower sNEP levels in early pregnancy. Conclusions: These findings suggest that sNEP plays a role in vascular and renal adaption during pregnancy, offering new perspectives on vascular tone regulation in high-risk pregnancies. Further research is needed to clarify these mechanisms and their clinical relevance. Full article

Introduction: Sacubitril/valsartan is an angiotensin receptor–neprilysin inhibitor (ARNI) drug used to treat patients with heart failure and has shown improvement in outcomes. Different studies reported the use of an ARNI in patients using left ventricular assist devices (LVADs). However, there are limited data on the use of ARNIs in this population. We aimed to assess the efficacy of ARNIs in LVAD patients. Methods: A systematic search was performed in PubMed, Scopus, Web of Science, Embase, and Cochrane from inception to November 2024. We used all relevant words for “ARNI” and “LVAD” to search, and we included studies that assessed ARNIs in patients with LVAD. Efficacy and safety outcomes were extracted from the included studies. R software version 4.4.2 was used for a meta-analysis. Results: Seven studies totaling 249 patients were included. The ARNI was found to be effective in improvements from baseline in the New York Heart Association (NYHA), B-type natriuretic peptide (BNP) (mean = −630.07 pg/mL, 95% CI [−1113.13, −147.01]), diuretic dose (furosemide equivalents) (mean= −76.05 mg/day, 95% CI [−145.11, −6.99]), left ventricular end-diastolic diameter (LVEED) (mean = −7.3 mm, 95% CI [−11.4, −3.1]), and left ventricular ejection fraction (LVEF) (mean =5, 95% CI [3.52, 6.48]). No improvement was found in the creatinine (Cr) level. However, a slight increase in the potassium level was noticed (mean= 0.17 mEq/L, 95% CI [0.02, 0.34]). The overall mortality in patients using the ARNI was 5%, 95% CI [0.00, 20], and discontinuation was found in 25%, 95% CI [0, 100]. Conclusions: The ARNI improved several cardiac structural and hemodynamic parameters in patients on LVAD support. Full article