Search Results (1,198)

Amphibian malformation syndromes significantly impact both conservation efforts and aquaculture, yet their underlying systemic pathophysiological mechanisms remain poorly characterized. This study comprehensively examines the multi-level pathological processes associated with the “short-leg” malformation syndrome in the black-spotted frog (Pelophylax nigromaculatus) using an integrated methodology, encompassing morphological, histopathological, gut microbiome, and hepatic transcriptomic analyses. Affected frogs demonstrated shortened limbs, impaired motor function, and a distinctive metabolic phenotype, including increased body weight despite a shorter body length, accumulation of visceral fat, and shortened intestines. Gut microbiota analysis identified significant compositional shifts, characterized by a decreased Firmicutes-to-Bacteroidota ratio, expansion of pro-inflammatory Proteobacteria, and reduction in beneficial Actinobacteriota, suggesting microbial niche restructuring that likely promotes metabolic and inflammatory disorders. Hepatic transcriptome profiling revealed 2617 differentially expressed genes, demonstrating a clear molecular dichotomy with concurrent up-regulation of immune-related pathways (e.g., neutrophil extracellular trap formation, complement cascades, and inflammatory signaling) and broad suppression of metabolic pathways (e.g., lipid oxidation, nutrient absorption, and PPAR and renin–angiotensin systems). This integrated analysis illustrates that the malformation syndrome represents a systemic pathophysiological state involving dysfunction of the gut–liver axis, characterized by the coexistence of gut microbiota alterations, hepatic metabolic suppression, and immune activation. These findings provide a framework for understanding amphibian malformations and suggest potential strategies to improve health outcomes in aquaculture. Full article

The mechanisms underlying doxorubicin (DOX) cardiotoxicity include activation of the renin–angiotensin–aldosterone system (RAAS), oxidative stress, mitochondrial dysfunction, calcium overload, and cardiomyocyte apoptosis. Cortisol plays a key role in regulating multiple metabolic, immunological, cardiovascular, and neuroendocrine processes and may additionally influence drug pharmacokinetics by modulating the activity of P-glycoprotein (P-gp). The peptide apelin, through its specific target, angiotensin II protein J receptor (APJ), exerts cardioprotective, antifibrotic, and anti-inflammatory effects. The available data demonstrate that apelin signaling protects against DOX-induced cardiotoxicity, impacts cortisol secretion, and inhibits RAAS. Short-term elevation in cortisol levels, caused by apelin, may reduce inflammation and thus have cardioprotective properties. However, through chronically elevated cortisol levels, apelin may indirectly contribute to peripheral resistance, cardiac remodeling, and myocardial damage, especially when cortisol metabolism by 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) is altered. This narrative review explores the potential molecular and cellular mechanisms shaping the outcome of apelin–cortisol interplay, offering a potential foundation for developing cardioprotective strategies during anticancer therapy. Future studies should be aimed at assessing the complex interactions between cortisol, apelin, and the RAAS regarding DOX-induced cardiotoxicity. Full article

The recently conceptualized Cardiovascular–Kidney–Metabolic (CKM) syndrome represents a pressing global health burden, characterized by a vicious cycle of dysfunction among the cardiac, renal, and metabolic systems. Growing evidence suggests that gut microbiota dysbiosis, specifically, a loss of butyrate-producing bacteria (BPB) and the resulting systemic butyrate deficiency, may be an important but previously overlooked driver of CKM progression. In this review, we synthesize available evidence linking butyrate to the integrated, multi-organ pathophysiology of CKM and propose a conceptual framework we term the gut-butyrate-CKM axis. We discuss the multiple mechanisms by which butyrate and BPB exert protective effects, including targeting key pathophysiological features of CKM, such as insulin resistance (IR), metabolic inflammation, oxidative stress, endothelial dysfunction, renin–angiotensin–aldosterone system (RAAS) overactivation, and gut dysbiosis itself. Through a critical appraisal of human studies, we bring together findings from direct butyrate supplementation, dietary interventions, and microbiota-directed strategies. Based on this, we argue that butyrate serves as a central hub linking gut homeostasis to systemic metabolic and cardiorenal health. By integrating previously fragmented observations into a coherent framework, this review addresses a conceptual gap in our understanding of CKM pathogenesis and points to actionable, microbiota-targeted therapeutic strategies that could help break the disease cycle. Given the current lack of integrated management options for CKM, our work offers insights for future translational research and clinical practice, highlighting butyrate-centered approaches as a potential paradigm shift in CKM care. Full article

Background: While vaccines are designed to elicit targeted immune responses, in some cases, the immunogenic molecules employed can inherently interact with broader host cellular pathways as a secondary consequence. This phenomenon can be exemplified by COVID-19 vaccines. COVID-19 vaccines, including mRNA platforms, use the SARS-CoV-2 spike protein as an immunogen to induce the production of neutralizing antibodies. The spike protein binds the ACE2 (angiotensin-converting enzyme 2) receptor on human cells, mediating viral entry and infection. ACE2 is widely expressed across multiple tissues and is a key component of the renin–angiotensin–aldosterone system (RAAS) that acts as a homeostatic regulator of systemic and local blood flow, blood pressure, cardiac function, fluid balance and immunity. Some studies have proposed the interaction between the spike protein and ACE2 as a possible contributing factor to rare adverse effects observed following COVID-19 vaccination, including myocarditis, pericarditis, thrombosis, and reported alterations in blood pressure, though these mechanisms remain to be fully elucidated. Objectives: As a proof-of-concept approach in vaccine antigen development, we engineered SARS-CoV-2 spike mutants with impaired binding to the host receptor ACE2. Methods: By rational design, we produced and validated in vitro and in vivo spike point mutants that do not effectively bind ACE2. Results: The engineered spike mutants do not effectively bind the human entry receptor ACE2 while retaining the immunogenic properties equal to or better than the wild type spike and thus generate a protective response in animals when used as a vaccination agent. Conclusions: By establishing a straightforward molecular strategy for rational vaccine design, this work demonstrates the feasibility of limiting specific antigen–host receptor interactions while maintaining immunogenicity. This approach may be applicable to future vaccination strategies where antigen interaction with host cells could potentially interfere with physiological pathways. Full article

Progression to fibrosis is a major complication of chronic kidney disease (CKD) in obesity, type 2 diabetes, hypertension, and metabolic syndrome, yet effective antifibrotic therapies remain limited. Here, we review how disordered renal energy metabolism—ectopic lipid accumulation, impaired fatty acid oxidation (FAO), and a compensatory shift toward glycolysis—drives tubulointerstitial fibrosis in fatty kidney disease. Lipid overload in tubular, glomerular, and vascular cells arises from increased uptake via scavenger and lipoprotein receptors, enhanced lipogenesis, and reduced lipid catabolism and clearance. Spatial lipidomic studies further reveal nephron-segment-specific lipid signatures and obesity-associated oxidized phospholipids linked to glomerular inflammation. Lipotoxicity, mitochondrial damage, and associated innate-immune signaling, ferroptosis, cellular senescence, and adipose-derived mediators (including leptin, adiponectin, and a locally active renin–angiotensin system) converge on myofibroblast activation from pericytes, fibroblasts, and other resident cells. We discuss established and emerging therapies targeting this metabolic axis—peroxisome proliferator-activated receptor-α (PPARα) modulators, sodium–glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and the mineralocorticoid receptor antagonist finerenone—and propose that restoring metabolic flexibility, by rescuing FAO while limiting maladaptive glycolysis, offers a promising disease-modifying strategy for fatty kidney disease. Full article

Background: Hyperkalemia (HK) is a common complication of renin-angiotensin-aldosterone system inhibitor (RAASi) therapy, and the risk is often increased by concomitant use of a mineralocorticoid receptor antagonist (MRA). The effect of SGLT2i co-prescription on this risk in routine clinical practice remains incompletely understood. Methods: This is a secondary analysis of a published retrospective cohort of 905 adult RAASi users attending outpatient clinics at King Abdulaziz Medical City, Jeddah, Saudi Arabia (IRB: NRJ22J/279/11), followed for a median of 28 months. Patients were classified as RAASi alone (n = 723) or RAASi plus MRA (n = 182). Beta-blockers and digoxin were excluded from the exposure definition. Effect modification by SGLT2i was assessed using logistic regression with a multiplicative interaction term. Results: MRA addition was associated with significantly higher rates of any HK (48.4% vs. 28.9%; RR 1.67, 95% CI 1.38–2.02, p < 0.001) and moderate-to-severe HK (13.7% vs. 6.9%; RR 1.99, 95% CI 1.26–3.12, p = 0.003). Overall, RAASi discontinuation rates were similar between groups. SGLT2i co-prescription significantly modified the association between MRA use and HK-driven RAASi discontinuation (interaction p = 0.004): among patients without SGLT2i, MRA addition was associated with a more than 5-fold increase in HK-driven discontinuation (21.1% vs. 4.1%; RR 5.11, p = 0.001), whereas no significant excess risk was observed among SGLT2i users (1.8% vs. 4.2%; RR 0.44, 95% CI 0.12–1.57, p = 0.190), although this subgroup estimate was imprecise. CKD (aOR 2.16, 95% CI 1.56–2.99) and age ≥ 75 years (aOR 1.64, 95% CI 1.04–2.58) were the strongest independent predictors of HK. Conclusions: MRA addition to RAASi substantially increases HK burden, and SGLT2i co-prescription appears to protect against HK-driven RAASi discontinuation in combined RAASi–MRA-treated patients. In patients with established indications for SGLT2i, co-prescription may confer the additional benefit of preserving RAASi continuity in the setting of MRA combination therapy. Full article

Background: The 2022 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines suggest the use of Renin–angiotensin–aldosterone system inhibitors (RAASIs) in chronic Kidney Disease (CKD) stages IV–V, in contrast to the 2012 KDIGO guidelines, which discouraged it. This study aims to assess the impact of RAASIs on kalemia and mortality in a large sample of dialysis patients, where longitudinal data remain scarce, comparing traditional statistical methods with machine learning (ML) algorithms. Methods: This observational longitudinal analysis included 4764 hemodialysis (HD) patients from the Sicilian Registry of Nephrology, Dialysis and Transplantation, with a total of 56,964 longitudinal measurements. We evaluated the impact of RAASIs on serum potassium levels and all-cause mortality in the dialysis setting, comparing traditional statistics and ML. Linear Mixed Models (LMM) and Cox models with mixed effects were used for longitudinal and survival analyses. These were compared with ML approaches, including Random Forest (RF) for potassium variability and Lasso-regularized models for mortality, using four-fold cross-validation. Results: The study included 4764 patients, of whom 1207 (25%) were treated with RAASis. The mean age was 66 ± 15 years, 62% were male, 33% were diabetic, and a history of arterial hypertension was reported in 74% of patients. Hyperkalaemia at baseline was present in 1848 patients. The longitudinal model showed a statistically significant increase in kalemia [adjβ = 0.10 mmol/L, 95%CI 0.05/0.15, p < 0.001], but it was clinically negligible. Indeed, RF did not detect RAASIS as a relevant variable. Association between RAASIs and mortality was not detected either with Cox or ML models. Furthermore, the RF model outperformed traditional LMMs in explaining total potassium variability (56% vs. 43%). Conclusions: RAASI therapy in HD patients is associated with a minimal, non-clinically significant increase in serum potassium and does not impact all-cause mortality. The integration of ML reinforces the robustness of these findings, supporting the safety of RAASIs in the dialysis setting. Full article

Myxomatous mitral valve disease (MMVD) is the most common acquired cardiac disease in small-breed dogs and shows particularly high prevalence and early onset in Cavalier King Charles Spaniels (CKCS). Although MMVD is considered a complex, polygenic disease, the clinical relevance of individual genetic variants remains incompletely understood. The angiotensin-converting enzyme (ACE) gene variant rs850683722 has previously been associated with altered ACE activity and differences in renin–angiotensin–aldosterone system-related responses in dogs with MMVD. The aim of this study was to determine the prevalence of rs850683722 in a Polish population of CKCS dogs and to assess whether this variant is associated with the clinical course of MMVD. A total of 105 CKCS dogs were included in the study. All dogs underwent standardized cardiovascular evaluation, including echocardiography, electrocardiography, and systolic blood pressure measurement. MMVD diagnosis and staging were performed according to current ACVIM consensus criteria. Genotyping of the rs850683722 variant was performed using Sanger sequencing for 95 dogs, while next-generation sequencing data was obtained for 10 dogs. Genotype distribution, allele frequencies, conformity with the Hardy–Weinberg equilibrium (HWE), sex-related differences, and associations between genotype and age at progression to selected MMVD stages or the primary clinical endpoint were assessed statistically. The most frequent genotype was AA, detected in fifty-nine dogs, followed by GG in thirty-seven dogs and AG in nine dogs. When dogs carrying at least one A allele were considered variant-positive, the overall prevalence of the variant-positive genotype was 64.8%. The calculated allele frequencies were 0.605 for the A allele and 0.395 for the G allele. The observed genotype distribution deviated markedly from the Hardy–Weinberg equilibrium, mainly because of a pronounced deficit of heterozygous dogs. No significant association was detected between genotype and sex. Genotype was also not significantly associated with age at progression to stage B2 or stage C. A statistically significant difference in age of death was demonstrated by genotype, but this difference was not reflected in the survival analysis. The rs850683722 variant was highly prevalent in the studied Polish CKCS population, with a frequency comparable to previously reported data for this breed. Despite its documented biological association with ACE activity and RAAS-related responses, the variant was not significantly associated with the clinical progression of MMVD in this cohort. These findings suggest that rs850683722 alone seems unlikely to be a reliable marker for predicting the severity or rate of MMVD progression in Polish CKCS dogs. Further studies including larger cohorts, longer follow-up, pedigree information, and the direct assessment of RAAS activity may help clarify whether this variant has stage-dependent or treatment-related clinical relevance. Full article

Diabetic kidney disease (DKD) represents the single most common etiology of chronic kidney disease and end stage kidney disease globally, a burden that continues to expand in direct proportion to the worldwide growth of the diabetes epidemic. The pathogenesis of DKD is multifactorial, involving metabolic, hemodynamic, inflammatory, and fibrotic pathways. Among these, aldosterone has emerged as a key mediator of kidney injury, extending beyond its traditional role in sodium balance and blood pressure regulation. Through activation of both MR-dependent transcriptional processes and MR-independent signaling cascades, aldosterone drives a coordinated pattern of renal injury encompassing oxidative stress generation, endothelial dysfunction, podocyte damage, inflammatory cell recruitment, and progressive interstitial fibrosis. Current therapies targeting the renin–angiotensin–aldosterone system (RAAS), including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists, have significantly improved outcomes in DKD. Despite these advances, a considerable degree of residual cardiovascular and renal risk persists, attributable in part to the incomplete attenuation of aldosterone activity and the well-characterized phenomenon of aldosterone escape under sustained RAAS blockade. Aldosterone synthase inhibitors (ASIs) represent a mechanistically distinct therapeutic approach that targets aldosterone overproduction at its enzymatic source, potentially addressing both MR-dependent and independent pathways. Early clinical trials evaluating the efficacy of ASIs have demonstrated promising effects on blood pressure and albuminuria. This review summarizes the role of aldosterone in DKD pathogenesis, evaluates current therapeutic approaches, and discusses emerging evidence supporting ASIs as a potential addition to the evolving treatment landscape. Full article

Background and Objectives: Transcatheter aortic valve implantation (TAVI) is the standard therapy for patients with severe aortic stenosis at intermediate or high surgical risk. Mitral annular calcification (MAC) is frequently observed in this population and has been linked to adverse cardiovascular outcomes. This study evaluated the association between MAC and TAVI-related complications and mortality, and identified predictors of all-cause mortality and permanent pacemaker implantation (PPI) following TAVI. Materials and Methods: Patients undergoing self-expanding TAVI between January 2010 and June 2020 were retrospectively analyzed. Outcomes included TAVI-related complications, in-hospital and long-term mortality, and predictors of all-cause mortality and PPI. Results: A total of 245 patients (98 men [40%], mean age 76.3 ± 8.3 years) were included. Mean left ventricular ejection fraction was 54.8 ± 11.4%, and aortic valve area was 0.74 ± 0.14 cm². MAC was present in 148 patients (60.4%). Pericardial effusion (26.4% vs. 12.4%, p = 0.013) and acute kidney injury (21.6% vs. 7.2%, p = 0.005) were significantly more frequent in patients with MAC. PPI was required in 42 patients (17.8%). In-hospital mortality occurred in 14 patients (5.7%), and all-cause mortality was observed in 89 patients (36.3%) during a median follow-up of 23.1 months (IQR, 11.6–44.3). MAC extension into the left ventricular outflow tract was the only independent predictor of PPI (OR: 3.32, p = 0.002). Independent predictors of all-cause mortality included use of renin–angiotensin–aldosterone system blockers (HR: 0.54, p = 0.012), hemoglobin level (HR: 0.79, p = 0.006), severe MAC (HR: 1.94, p = 0.024), and post-TAVI atrial fibrillation (HR: 2.39, p = 0.002). Conclusions: MAC is common in TAVI patients and is associated with increased procedural complications, including higher rates of pericardial effusion and acute kidney injury. Greater MAC severity independently predicts higher all-cause mortality. In addition, MAC extension into the left ventricular outflow tract is an independent predictor of PPI following self-expanding TAVI, emphasizing the importance of comprehensive pre-procedural imaging. Full article

Background: Endothelial dysfunction and renal injury are emerging as a common feature of long COVID, especially in those with hypertension. It is not yet well characterised whether SARS-CoV-2 infection exacerbates podocyte dysfunction, fibrotic signalling and renal hemodynamic remodelling, over and above the effects of hypertension alone and there are no reliable early biomarkers in this population. Methods: We conducted a comparative cross-sectional study with prospective 6-month treatment response follow-up in 120 adult patients (aged 30–60 years) with essential hypertension (Stage I, II or III; n = 40 per stage), at Bukhara Regional Multidisciplinary Hospital. Each stage subgroup was further divided into post-COVID (3–6 months after recovery; n = 20) and non-COVID (n = 20) strata. Patients with diabetes, known chronic kidney disease, previous myocardial infarction or stroke and other major comorbidities were excluded. Serum cystatin-C, creatinine, aldosterone, TGF-β1 and VEGF-A; urinary nephrin and microalbumin; cystatin-C-derived eGFR (CKD-EPI) and oral protein-loaded renal functional reserve (RFR); and renal Doppler indices (Vps, Ved, RI, PI) of the main, segmental and interlobar arteries were assessed before and after 6 months of guideline-based renin–angiotensin–aldosterone system (RAAS) blockade (enalapril 5–10 mg or azilsartan 40–80 mg, ±eplerenone). Comparisons were made by Student’s t-test—associations by Pearson correlation. Results: At baseline, post-COVID hypertensive patients exhibited consistently higher endothelial–podocyte injury markers than non-COVID counterparts. Urinary nephrin was elevated across all stages (Stage I: 126.5 ± 9.1 vs. 91.9 ± 8.3 pg/mL, p < 0.01; Stage III: 203.3 ± 11.2 vs. 164.5 ± 9.7 pg/mL, p < 0.05), as were VEGF-A (Stage III: 286.1 ± 16.4 vs. 223.2 ± 12.6 pg/mL, p < 0.01) and TGF-β1 (Stage III: 186.4 ± 10.1 pg/mL, 1.3-fold higher; p < 0.01). The detection of microalbuminuria was 100% in Stage III post-COVID patients and 85% in non-COVID controls. The post-COVID groups had selective loss of renal functional reserve (7.8 ± 1.1% in Stage III compared to 12.5 ± 1.6% in non-COVID controls, p < 0.001). Nephrinuria correlated strongly with RFR (r = −0.824, p < 0.001), eGFR (r = −0.797, p < 0.001) and aldosterone (r = 0.613, p < 0.001). Six months of RAAS blockade reduced nephrinuria, microalbuminuria and TGF-β1 in both arms but the magnitude of biomarker reduction appeared smaller in the post-COVID group, particularly in Stage III. Conclusions: Long COVID appears to be associated with persistent endothelial dysfunction and podocyte injury in hypertensive patients. These results indicate that nephrinuria, VEGF-A, TGF-β1 and renal functional reserve are potential exploratory markers of endothelial and renal abnormalities in hypertensive patients following COVID-19. Before clinical utility can be determined, larger studies with multivariable modelling, diagnostic-performance analyses and correction for multiple testing are needed. The differences in biomarker response between groups observed in this study need to be confirmed in larger prospective studies with multivariable modelling and formal interaction analyses. Full article

Background/Objectives: Glucocorticoids, including dexamethasone (DEX), are known to demonstrate anti-inflammatory activity, suppress steroidogenesis, and mitigate the adverse effects of chemotherapy. They are therefore widely employed for managing solid malignancies. Emerging evidence indicates that DEX modulates both systemic and local renin–angiotensin system (RAS) activity, including genomic signaling via the glucocorticoid receptor (GR). Methods: DEX-dependent transcriptional responses for the angiotensin receptor genes (AGTR1, AGTR2, MAS1, and LNPEP) were evaluated in ovarian (SKOV3, KURAMOCHI) and prostate (DU-145, PC3) cancer cell lines. The cells were cultured under different serum conditions to determine the influence of nutrient availability on tumor progression. Results: DEX demonstrated distinct mechanisms of action between the ovarian and prostate cancer models. It was found to promote cancer cell survival through tissue-specific modulation of metabolic activity, clonogenic capacity, cell cycle distribution, and apoptotic responses. These effects were accompanied by condition-dependent alterations in angiotensin receptor gene expression. Hence, DEX may mediate the remodeling of local RAS signaling, which may be significant in overall survival and disease-free survival. The findings also indicate a previously-unreported NR3C1–LNPEP correlation, which was consistently observed across in vitro systems and patient datasets, in both ovarian- and prostate-derived cancer models. Conclusions: DEX appears to exert context-dependent regulation of RAS-associated gene networks in ovarian and prostate cancer, suggesting a role in tumor adaptive responses and potentially in therapeutic contexts. Full article

Cardiovascular diseases (CVDs) remain the leading global cause of morbidity and mortality, imposing an increasing clinical and socioeconomic burden. Despite significant therapeutic advances, optimal control of risk factors and long-term outcomes remain challenging, particularly in patients with complex comorbidities. This narrative review provides a comprehensive and up-to-date synthesis of pharmacological options across major cardiovascular domains, with a specific focus on hypertension, heart failure, arrhythmias, and hypertrophic cardiomyopathy, conditions in which hemodynamic, neurohormonal, and electrophysiological pathways play central roles. We summarize mechanisms of action, clinical evidence, safety profiles, and guideline-based indications of established therapies, highlighting their relevance to vascular tone regulation, neurohormonal modulation, endothelial signaling, and myocardial function, the mechanistic axes that intersect with pathways implicated in pulmonary vascular disease (PVD). In addition, we discuss emerging therapeutic targets and innovative agents such as renin-angiotensin-aldosterone system silencers, endothelin pathway modulators, SGLT2 inhibitors, soluble guanylate cyclase stimulators, myosin inhibitors, and other mechanism-based approaches. Current challenges and unmet clinical needs are examined in the context of translational relevance for PVD and the broader goal of advancing individualized pharmacotherapy. Continued therapeutic innovation targeting shared vascular, metabolic, and neurohormonal pathways holds promise for improving outcomes across both systemic and pulmonary vascular diseases. Full article

Background: Thoracic aortic aneurysm (TAA) remains a high-risk vascular condition despite major advances in imaging surveillance, operative repair, and endovascular therapy. Medical management still relies largely on blood pressure control and global cardiovascular risk reduction. Renin–angiotensin–aldosterone system (RAAS) inhibitors are frequently used in TAA, but contemporary data evaluating survival and cardiovascular outcomes in broad TAA populations are limited. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors) have established cardiometabolic benefits, yet their role in TAA has not been well defined. Methods: We performed a retrospective multicenter cohort study of adults with imaging-confirmed TAA diagnosed between 1 January 2018 and 1 January 2026 using a Mayo Clinic electronic data platform encompassing more than 15 million patient records. Primary exposures were documented use of RAAS inhibitors, GLP-1 RAs, and SGLT2 inhibitors, evaluated individually and in prespecified combination-therapy analyses. Propensity score matching was used to balance demographics, comorbidities, aortic procedural history, and concomitant cardiovascular medications. Primary outcomes were all-cause mortality and major adverse cardiovascular events (MACE) through 60 months. Results: The study included 162,126 patients with TAA. After matching, RAAS inhibitor use was associated with higher 60-month overall survival (88.3% vs. 85.5%; hazard ratio [HR], 0.79; 95% CI, 0.76–0.83; p < 0.001) and MACE-free survival (86.1% vs. 84.2%; HR, 0.87; 95% CI, 0.83–0.91; p < 0.001). GLP-1 RA therapy was associated with higher overall survival (97.5% vs. 92.5%; HR, 0.32; 95% CI, 0.27–0.38; p < 0.001) and MACE-free survival (93.2% vs. 89.3%; HR, 0.62; 95% CI, 0.56–0.70; p < 0.001). SGLT2 inhibitor therapy was similarly associated with higher overall survival (89.8% vs. 81.5%; HR, 0.51; 95% CI, 0.47–0.54; p < 0.001) and MACE-free survival (86.3% vs. 79.1%; HR, 0.62; 95% CI, 0.58–0.66; p < 0.001). Combination therapy with RAAS inhibitors plus either GLP-1 RAs or SGLT2 inhibitors was associated with incremental improvements in overall survival and MACE-free survival compared with GLP-1 RA or SGLT2 inhibitor monotherapy. Conclusions: In this large propensity-matched TAA cohort, RAAS inhibitors, GLP-1 RAs, and SGLT2 inhibitors were each associated with improved survival and fewer major cardiovascular events, with additional benefit observed for RAAS-based combination therapy. These findings support further prospective investigation of integrated cardiometabolic and vascular-targeted therapy in TAA, while underscoring that observational associations should not be interpreted as proof of aneurysm-specific disease modification. Full article

Hypertension is one major risk factor of cardiovascular diseases, and RAS plays vital role during the development of hypertension. To obtain a novel antihypertensive peptide, Coix glutelin was hydrolyzed by trypsin and further separated by Sephadex G10. Based on 751 identified sequences, pharmacophore mapping, molecular docking, and in silico proteolysis were applied to screen and optimize the candidate sequence. Finally, a novel peptide, ENWAAL, was generated with IC₅₀ of 210.57 μM, which acted with ACE in a competitively inhibitory pattern. The in vivo antihypertensive effect was evaluated in SHRs. Significant improvements were observed in hypertension-related characteristics, including blood pressure, cardiac structure and function, and serum angiotensin II (Ang II) level. In the brain, quantitative real-time PCR analysis revealed significant downregulation of angiotensin II type 1 receptor (AT1R) mRNA expression, concomitant with upregulation of angiotensin-converting enzyme 2 (ACE2) and MAS receptor. The protein expression of ACE and AT1R in the ENWAAL group also significantly decreased. This study can provide a candidate antihypertensive drug targeting RAS. Full article