Search Results (177)

Background/Objectives: Hypertension represents a leading contributor to cardiovascular disorders and premature mortality. Given the pervasive nature of adverse effects associated with current angiotensin-converting enzyme inhibitors (ACEIs), there is a significant interest in identifying novel bioactive lead compounds from natural sources. This study identifies, for the first time, three novel angiotensin-converting enzyme (ACE) inhibitory peptides released from Bungarus multicinctus (BM) via simulated gastrointestinal digestion (SGD). Methods: Active fractions were enriched by ultrafiltration and subjected to stability assessment. The peptide sequences were then determined using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) and bioinformatics tools, followed by chemical synthesis. Finally, the inhibitory mechanism was investigated using kinetic analysis and molecular docking. Results: The intestinal digest exhibited potent ACE inhibition, with the <5 kDa fraction achieving 79% inhibition at 1 mg/mL and demonstrating favorable stability under varying temperatures, pH, and ionic strengths. Molecular docking revealed strong binding (affinity < −9.9 kcal/mol) of the peptides PPSPPRW, WGFTKF, and PSLFPPRL to key ACE residues—Tyr523, His513, and Arg522—via hydrogen and hydrophobic interactions. Enzyme kinetics characterized PPSPPRW and WGFTKF as competitive inhibitors, and PSLFPPRL as mixed type. The peptides demonstrated acceptable cell viability at lower concentrations, establishing a preliminary safety window for therapeutic application. Conclusions: These findings establish BM as a valuable source of stable, bioactive ACE-inhibitory peptides (ACEIPs) acting as promising lead compounds for antihypertensive therapies. 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

The role of hepatic stellate cells (HSCs) in the development of liver fibrosis and portal hypertension has already been largely clarified. Activation of HSCs might lead to self-increased proliferation and enhanced contractile activity, causing their transdifferentiation into myofibroblasts (activated HSCs), which drive the release of proinflammatory mediators, collagen, proteoglycans, and other extracellular matrix components, responsible for liver fibrosis and portal hypertension development. A possible mechanism for the pathophysiological role of HSCs in liver fibrosis might be autophagy, which breaks down the lipid droplets in quiescent HSCs, releasing fatty acids and providing the energy required for their activation into myofibroblasts. An ever-growing body of scientific evidence indicates that renin–angiotensin system (RAS) blockade can inhibit the evolution of fibrosis in patients with chronic liver diseases, and especially metabolic dysfunction-associated steatotic liver disease (MASLD), although the use of both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) has not yet been officially identified as a potential fibrosis treatment. More recently, researchers have shown that overexpression of ACE2, induced by ACE inhibitor (ACEI) activity and leading to the degradation of angiotensin (ANG) II into ANG 1-7, inhibition of autophagy and consequent HSC activation, might prevent liver fibrosis development. This review aims to summarize recent pre-clinical studies and to identify a common thread underlying the latest scientific evidence in this field. Full article

Diabetes mellitus (DM) continues to be a global world health problem. Despite medical advances, both DM and chronic kidney disease (CKD) remain global health issues with high mortality and limited options to prevent end-stage renal failure. Current therapies encompass five classes of drugs: (1) angiotensin-converting-enzyme inhibitors (ACEI) or angiotensin II receptor blockers (AIIRB); (2) sodium-glucose-transporter 2 (SGLT2) inhibitors; (3) glucagon-like peptide-1 receptor agonists (GLP-1 RA); and (4) an antagonist of type 1 endothelin receptor (ET1R) with proven efficacy to reduce albuminuria and proteinuria. (5) The mineralocorticoid receptor antagonist (MRA) finerenone has been tested in RCTs as a kidney protective agent. In our review, we summarize many of the principal trials that have generated evidence in this regard. Many novel agents—many of them proven not only for DM management but also for the treatment of obesity with or without DM or heart failure (HF)—are now in development and may be added to the five classical pillars: other non-steroidal MRA (balcinrenone); aldosterone synthase inhibitors (baxdrostat and vicadrostat); other GLP-1 RA (tirzepatide, survodutide, retatrutide, and cagrilintide); ET1 R antagonists, (zibotentan); and soluble guanylate cyclase activators (avenciguat). These new agents aim to slow disease progression further and reduce cardiovascular risk. Future strategies rely on integrated, patient-centered approaches and personalized therapy to curb renal disease and its related complications. Full article

Background: Renal arteriovenous malformations (rAVMs) are rare vascular anomalies that may lead to hematuria, anemia, or acute kidney injury (AKI). Although endovascular embolization is the treatment of choice, post-procedural complications such as new-onset proteinuria may occur and require long-term management. Case Presentation: A 56-year-old man with recurrent gross hematuria and elevated serum creatinine (128 μmol/L) was diagnosed with a right rAVM and underwent successful selective embolization. Despite recovery of renal function, follow-up revealed new-onset proteinuria (2.2 g/24 h). Results: Introduction of an angiotensin-converting enzyme inhibitor (ACEi) resulted in partial improvement of proteinuria, while subsequent addition of a sodium–glucose cotransporter-2 inhibitor (SGLT2i) achieved almost complete resolution of proteinuria (0.33 g/24 h) and stable renal function (serum creatinine 93 μmol/L) after 12 months. Conclusions: This case highlights the occurrence of post-embolization proteinuria and illustrates the synergistic renoprotective effect of combined ACEi and SGLT2i therapy in a non-diabetic patient with vascular kidney disease. 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

Renin–angiotensin system (RAS) inhibitors, including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), have been associated with improved outcomes in metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to assess the differential impact of ACEIs versus ARBs on survival and cardiovascular outcomes in individuals with MASLD. Using data from the UK Biobank, we identified 52,143 participants with exclusive use of either an ACEI or ARB. Individuals with viral, autoimmune, cholestatic, or alcohol-related liver disease were excluded. MASLD was defined as fatty liver index ≥ 60 with ≥1 cardiometabolic risk factor. Inverse probability of treatment weighting (IPTW) was used to adjust for confounders. Outcomes included all-cause mortality, cardiovascular events, hepatic decompensation, and hepatocellular carcinoma (HCC), analyzed using Cox proportional hazards models. Among MASLD participants, ARB use was associated with significantly lower all-cause mortality compared to ACEI use (HR, 0.94; 95% CI, 0.90–1.00; p = 0.031) after IPTW adjustment. Cardiovascular risk was also lower with ARBs (HR, 0.92; 95% CI, 0.89–0.96; p < 0.001), particularly in subgroups with BMI ≥ 25 kg/m², no diabetes, and advanced fibrosis. No differences in hepatic decompensation or HCC incidence were observed. Benefits of ARBs were not significant in participants without steatotic liver disease. ARB use was associated with improved survival and reduced cardiovascular events in individuals with MASLD, whereas ACEIs expressed no comparable benefit. These findings suggest that ARBs might be a more effective RAS inhibitor subclass in MASLD and support their preferential use in patients with steatotic liver disease requiring antihypertensive therapy. Full article

Background: Conventional HF treatment in transthyretin cardiac amyloidosis (ATTR-CA) resulting in restrictive cardiomyopathy is debated due to absent trial evidence in this specific sub-population of heart failure (HF) patients. Current European Society of Cardiology guidelines recommend the use of diuretics and mineralocorticoid receptor antagonists (MRAs). However, beta-blockers (BBs) and angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACEi/ARBs) are often discontinued due to hypotension or bradycardia. This study assesses real-world HF treatment patterns and their impact on survival in a multinational ATTR-CA cohort. Methods: A retrospective analysis of 794 ATTR-CA patients examined baseline BB, ACEi/ARB, and MRA prescriptions. The cohort was divided based on guideline publication dates. Results: Patients were predominantly male (73.2%) with a median age of 78 years. Prescription of diuretics (52.8%) and disease-modifying therapy (44.9%), mostly tafamidis, was common. BBs (43.7%) and ACEi/ARBs (41.2%) were prescribed more often in patients with higher NYHA class, elevated NT-proBNP, and more comorbidities. Blood pressure and heart rate were similar regardless of BB or ACEi/ARB use. BB prescription and combination therapy with BB and ACEi/ARB increased over time. Neither BB nor ACEi/ARB use significantly impacted mortality when analyzed in a multivariate Cox proportional hazard regression. Conclusions: Use of BBs and ACEi/ARBs has increased over time, particularly in advanced-stage ATTR-CA patients, and although these therapies appear to be reasonably tolerated, survival was not significantly altered. Full article

Background/Objectives: Pre-discharge NT-proBNP levels may serve as a helpful tool in the algorithm of assessing the long-term risk of mortality after a hospitalization for symptomatic heart failure (HF). The goals were: (a) to identify a cut-off for NT-proBNP concentrations for predicting the two-year all-cause mortality in our sample of patients, and (b) to identify risk factors associated with NT-proBNP concentrations being higher than this cut-off. Methods: The present prospective study included 96 patients diagnosed with symptomatic HF with left ventricular ejection fraction (LVEF) < 50%, who were followed for up to 2 years post-hospital discharge. Results: Levels of pre-discharge NT-proBNP were found to be predictive of all-cause mortality. We determined that an NT-proBNP cut-off score of 8700 pg/mL may predict with 75.8% sensitivity and 70.1% specificity a 4.6-fold increase in mortality risk over a period of two years in our study sample, 95% CI (2–10.8), p = 0.001. Predictors of NT-proBNP concentrations > 8700 pg/mL included: older age, OR 4.73, 95% CI (1.74–12.85), p = 0.002; lack of angiotensin converting enzyme inhibitor (ACE-I) treatment, OR 0.3, 95% CI (0.12–0.74), p = 0.009; low systolic blood pressure (SBP) at admission, OR 3.4, 95% CI (1.36–8.49), p = 0.009; and low serum hemoglobin at admission, OR 3.2, 95% CI (1.38–7.46), p = 0.007. Conclusions: NT-proBNP may serve as a helpful tool for predicting mortality after an episode of HF decompensation, thus allowing the implementation of appropriate long-term monitoring and treatment. Particular attention should be paid to older patients without ACE-I medication, who had SBP < 120 mmHg at admission, and/or low levels of serum hemoglobin—as these patients are more likely to have pre-discharge NT-proBNP concentrations higher than the cut-off. These findings have implications for the long-term community follow-up of patients with HF. Full article

Background/Objectives: Angiotensin receptor–neprilysin inhibitor (ARNI) has a well-established advantage over angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (ACEI/ARB) therapy in patients (pts) with heart failure with reduced ejection fraction (HFrEF), but in pts after acute myocardial infarction (AMI) with left ventricular (LV) systolic dysfunction, the advantage of ARNI has not been clearly proven. The efficacy of ARNI is compared with that of ACEI/ARB therapy in patients with their first AMI in terms of improvement of post-infarction LV systolic function. Methods: The study was conducted as a retrospective one-center cross-sectional analysis. Overall, 1473 pts (990 M, median age 71 [64; 77]) with AMI (their first AMI, complete coronary revascularization, no prior coronary revascularization or history of HF) hospitalized in 2022–2024 were enrolled in a retrospective cross-sectional analysis. The study population was categorized into pts receiving ARNI and ACEI/ARB. Then, based on the ARNI subgroup, matching that included age, sex, and LV ejection fraction (LVEF) was performed by using the 1:1 nearest neighbor method without returning. Finally, two groups (ARNI vs. ACEI/ARB) of 30 pts were obtained and analyzed at baseline and at a 6-week follow-up. The improvement of post-infarction LV systolic function was obtained in terms of LVEF, ΔLVEF, and relative ΔLVEF values (ΔLVEF/baseline LVEF). Results: The comparison of baseline characteristics revealed borderline lower initial LVEF (30 vs. 36%, p = 0.076) and a higher frequency of SGLT-2 inhibitor use (70% vs. 36.7%, p = 0.01) in the ARNI subgroup. At the 6-week follow-up, in both subgroups, a significant improvement in the median LVEF values was achieved—from a median LVEF value of 30% (27.3; 38) to 37% (30; 43; p = 0.0008) in the ARNI subgroup and from a median LVEF value of 36% (33; 39) to 45% (42; 52; p < 0.0001) in the ACEI/ARB subgroup. The median ΔLVEF in the ACEI/ARB subgroup was higher [10% (6; 12)] than in the ARNI subgroup [6% (2; 10.25), p = 0.018]. Similarly, the median relative ΔLVEF was higher in the ACEI/ARB subgroup [30% (15.4; 40)] than in the ARNI group [17.5% (7; 31.9), p = 0.047]. The vast majority of patients, particularly in the ARNI group (99.7%), were treated with the lowest available dose of the drug. Conclusions: Our current experience in ARNI therapy after AMI is promising; however, it is limited to a small group of patients with severe impairment of LV systolic function. Regardless of the significant improvement in the baseline LVEF observed in patients receiving both ACEI/ARB and ARNI at the 6-week follow-up, the absolute and relative increases in the LVEF were higher in subjects treated with ACEI/ARB. However, the clinical benefits of ARNI therapy may emerge more gradually, and its advantages could become more apparent over a longer follow-up period. The clinical efficacy of early use of ARNI in the setting of AMI needs further evaluation. Full article

The renin-angiotensin system (RAS) has evolved from being considered solely a peripheral endocrine system for cardiovascular control to being recognized as a complex molecular network with important functions in the central nervous system (CNS) and peripheral nervous system (PNS). Here we examine the organization, mechanisms of action, and clinical implications of cerebral RAS in physiological conditions and in various neurological pathologies. The cerebral RAS operates autonomously, synthesizing its main components locally due to restrictions imposed by the blood–brain barrier. The key elements of the system are (pro)renin; (pro)renin receptor (PRR); angiotensinogen; angiotensin-converting enzyme types 1 and 2 (ACE1 and ACE2); angiotensin I (AngI), angiotensin II (AngII), angiotensin III (AngIII), angiotensin IV (AngIV), angiotensin A (AngA), and angiotensin 1-7 (Ang(1-7)) peptides; RAS-regulating aminopeptidases; and AT1 (AT1R), AT2 (AT2R), AT4 (AT4R/IRAP), and Mas (MasR) receptors. More recently, alamandine and its MrgD receptor have been included. They are distributed in specific brain regions such as the hypothalamus, hippocampus, cerebral cortex, and brainstem. The system is organized into two opposing axes: the classical axis (renin/ACE1/AngII/AT1R) with vasoconstrictive, proinflammatory, and prooxidative effects, and the alternative axes AngII/AT2R, AngIV/AT4R/IRAP, ACE2/Ang(1-7)/MasR and alamandine/MrgD receptor, with vasodilatory, anti-inflammatory, and neuroprotective properties. This functional duality allows us to understand its role in neurological physiopathology. RAS dysregulation is implicated in multiple neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and neuropsychiatric disorders such as depression and anxiety. In brain aging, an imbalance toward hyperactivation of the renin/ACE1/AngII/AT1R axis is observed, contributing to cognitive impairment and neuroinflammation. Epidemiological studies and clinical trials have shown that pharmacological modulation of the RAS using ACE inhibitors (ACEIs) and AT1R antagonists (ARA-II) not only controls blood pressure but also offers neuroprotective benefits, reducing the incidence of cognitive decline and dementia. These effects are attributed to direct mechanisms on the CNS, including reduction of oxidative stress, decreased neuroinflammation, and improved cerebral blood flow. Full article

Breast cancer is the most prevalent cancer in women. Anthracyclines are commonly used as the first line of treatment, often combined with other agents, including trastuzumab. Despite their efficacy, both drugs pose a risk of cardiotoxicity, which may impair patients’ quality of life (QoL) and hinder treatment persistence. Anthracycline-induced cardiotoxicity is dose-dependent and generally irreversible, whereas trastuzumab is associated with potentially reversible cardiac dysfunction. This review discusses the risk factors and biological mechanisms underlying chemotherapy-induced cardiotoxicity in breast cancer and explores effective strategies for prevention and treatment. It has been demonstrated that several cardioprotective strategies, such as treatments with angiotensin-converting enzyme inhibitors (ACEis), angiotensin receptor blockers (ARBs), beta-blockers, and dexrazoxane, can help lessen cardiotoxic effects. A better understanding of cardioprotective strategies may help optimize cancer treatment without compromising cardiovascular function. Full article

Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are among the most widespread drugs for the prevention of cardiovascular mortality and morbidity. Nevertheless, they are known to cause bradykinin (BK)-mediated angioedema (AE), a paroxysmal, localized, self-limiting, and potentially fatal swelling of the subcutaneous and/or submucosal tissue, due to a temporary increase in vascular permeability. Unlike hereditary angioedema (HAE), which can be mediated similarly by BK, no diagnostic tools, guidelines, or drugs have yet been approved for the diagnosis and treatment of acute non-allergic drug-induced AE. Besides ACEIs and ARBs, inhibitors of dipeptidyl peptidase-IV, neprilysin inhibitors, and tissue plasminogen activators are known to cause AE as an adverse effect. Currently, there are insufficient data on the prevention of AE caused by pharmacological therapies. In addition, the molecular mechanisms underlying BK-mediated AE caused by drugs, which are discussed here, are not fully explained. Specific approved drugs and a structured diagnostic workflow are unmet needs and are required for the management of this kind of AE. The aim of this review is to provide physicians with accurate knowledge of potentially life-threatening drug reactions so that they can be better understood and managed. Full article

The regulation of angiotensin-converting enzyme 2 (ACE2) expression by medications such as ACE inhibitors (ACEis) and angiotensin receptor blockers (ARBs) has raised critical questions regarding their potential benefits and risks during COVID-19. ACE2, a regulator of blood pressure through the renin–angiotensin system (RAS), is the primary receptor for SARS-CoV-2. ACEis and ARBs can modulate ACE2 expression, potentially exacerbating viral load. However, the risks of higher viral load could be mitigated by favorable anti-inflammatory responses associated with ACEi and ARB use, highlighting the complexity of their impact on viral replication and disease outcomes. This study investigates the effects of sustained Losartan monotherapy (ARB) and combination Losartan + Lisinopril (ARB + ACEi) on viral replication, inflammation, lung function, and clinical measures of disease severity in a murine model of severe COVID-19 involving humanized ACE2 transgenic mice infected with SARS-CoV-2 Wuhan strain. Both ARB and ARB + ACEi treatments led to increased ACE2 expression in the lungs and higher viral load post-infection. Despite this, the ARB + ACEi combination improved clinical scores, reduced weight loss and inflammatory cytokine levels, and preserved lung function, though it did not improve survival. Overall, the results of these controlled experiments provide insight into the complex dynamics of ACEi and ARB use in COVID-19; while these drugs induce expression of the ACE2 receptor and increase viral load, they provide compensatory modulation of the inflammatory response that appears to diminish severity of the infection. Full article

Diabetic nephropathy affects approximately 30–40% of individuals with diabetes mellitus (DM) and is a major contributor to end-stage renal disease (ESRD). While angiotensin II receptor blockers (ARBs) have long served as a standard treatment, sodium-glucose cotransporter-2 inhibitors (SGLT2i) have recently gained attention for their renal and cardiovascular benefits. However, comparative real-world data on their long-term renal effectiveness remain limited. We conducted a retrospective, longitudinal study over a 2-year period to compare the impact of ARB monotherapy versus SGLT2i and angiotensin-converting enzyme inhibitor (ACEi) combination therapy on the progression of chronic kidney disease (CKD) in patients with DM. A total of 126 patients were included and grouped based on treatment regimen. Renal biomarkers were analyzed using t-tests and ANOVA (p < 0.01). Albuminuria was qualitatively classified via urinalysis as negative, level 1 (+1), level 2 (+2), or level 3 (+3). The ARB group demonstrated higher estimated glomerular filtration rate (eGFR) and lower serum creatinine (sCr) levels than the combination therapy group, with glycated hemoglobin (HbA1c), potassium (K⁺), and blood pressure remaining within normal limits in both cohorts. Albuminuria remained stable over time, with 60.8% of ARB users and 73.1% of combination therapy users exhibiting persistently or on-average negative results. Despite the expected additive benefits of SGLT2i/ACEi therapy, ARB monotherapy was associated with slightly more favorable renal function markers and a lower incidence of severe albuminuria. These findings suggest a need for further controlled studies to clarify the comparative long-term renal effects of these treatment regimens. Full article