Hypercholesterolemia, a major risk factor for cardiovascular diseases, arises from elevated blood cholesterol levels and remains a global health concern. The limitations of current therapies underscore the need for alternative drugs from natural sources. Mikania cordata (Asteraceae) is an ethnomedicinally important species that harbors numerous bioactive phytoconstituents. In this study, 91 phytocompounds of this medicinal species were virtually screened targeting the HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase protein. Molecular docking, ADMET (absorption, distribution, metabolism, excretion, and toxicity), and MM/GBSA (molecular mechanics/generalized born surface area) analyses identified epifriedelanol as the best lead candidate among the phytocompounds with strong binding affinity (-8.6 kcal/mol), drug-likeness, and free binding energy (-39.5 kcal/mol), outperforming the standard drug atorvastatin (-7.7 kcal/mol and -21.4 kcal/mol). Analogs of epifriedelanol (EA) were further explored, generating 451 compounds. High-throughput screening of these analogs identified 244 compounds with a docking score higher than atorvastatin (-7.7 kcal/mol). The ADMET evaluation highlighted two analogs, EA2 and EA3, with docking scores of -9.3 kcal/mol and supportive MM/GBSA free energies (-31.9 and -43.7 kcal/mol). Molecular dynamics simulation (500 ns) confirmed the structural stability of epifriedelanol, EA2, and EA3, while essential dynamics and Gibbs free energy landscape analyses indicated a binding behavior comparable to that of atorvastatin. Target class analysis predicted interactions with nuclear receptors. These findings suggest that epifriedelanol and its analogs are promising natural leads against hypercholesterolemia, warranting further in vitro and in vivo validation.

Effective control of cardiovascular risk factors reduces mortality among patients with type 2 diabetes (T2D), but most evidence is based on baseline measurements. This study investigated the associations between changes and cumulative control of cardiovascular risk factors over the follow-up period and mortality.

We analyzed 138,193 participants with T2D aged 35-75 years from the ChinaHEART project. Risk factor control included no current smoking, healthy diet, physical activity, and normal levels of blood pressure, cholesterol, glucose, and BMI. Cumulative control was assessed using time-weighted average (TWA), and Cox models estimated hazard ratios (HRs). Changes in control were evaluated by comparing the number of risk factors controlled at baseline and the second follow-up.

Over a median follow-up period of 5.6 years, 9,698 deaths occurred (4,475 from CVD). Compared with participants with 0-2 risk factors controlled, those with 3 and 6-7 factors controlled had lower risks of all-cause mortality [HRs: 0.77 (95% CI: 0.73-0.81) and 0.43 (0.38-0.48), respectively]. Improved control was associated with reduced mortality [HR: 0.86 (0.77-0.96)] compared to stable low control, whereas degraded control increased mortality risk by 23% compared to stable high control. Participants in the highest quartile of TWA risk factor control had 47% lower mortality [HR: 0.53 (0.47-0.60)] than those in the lowest quartile. Similar associations were observed for CVD mortality.

Sustained and cumulative cardiovascular risk factor control substantially lowers mortality among patients with T2D, underscoring the critical importance of continuous risk factor management.

Multisystemic Smooth Muscle Dysfunction Syndrome (MSMDS) is a rare disorder caused by ACTA2 mutations, including the R179H variant, which alters actin filament stability and dynamics and smooth muscle contractility. While cardiovascular complications dominate its clinical presentation, gastrointestinal (GI) dysfunction significantly impacts quality of life. To investigate the structural, functional, and cellular basis of gut dysmotility in MSMDS, we reviewed clinical data from 24 MSMDS patients and studied the ACTA2 R179H mouse model Patients exhibited severe gut dysmotility, with 75% requiring medication for chronic constipation. ACTA2 mutant mice displayed cecal and colonic dilatation, reduced intestinal length, and disrupted colonic migrating motor complexes (CMMCs). Delayed whole-gut transit and impaired contractile responses to electrical and pharmacological stimulation were observed. Transcriptomic analysis revealed significant actin cytoskeleton-related gene changes in smooth muscle cells, and immune profiling identified increased lymphocytic infiltration. Despite functional abnormalities, there were no obvious changes in the enteric nervous system. These findings establish ACTA2 mice as a robust model for studying GI pathology in MSMDS, elucidating the role of smooth muscle dysfunction in gut dysmotility. This model provides a foundation for developing targeted therapies aimed at restoring intestinal motility by directly addressing actin cytoskeletal disruptions in smooth muscle cells.

Endothelial-mesenchymal transition (EndMT) is a critical process in cerebrovascular diseases, contributing to vascular instability, fibrosis, and inflammation. This review summarizes the molecular mechanisms driving EndMT-including TGF-β, Wnt, Notch pathways, inflammation, oxidative stress, and hemodynamics-and its role in specific conditions such as cerebral cavernous malformations, brain arteriovenous malformations, and moyamoya disease. We also evaluate promising pharmacological strategies, including statins, antihypertensives, antidiabetic drugs, and anti-inflammatory agents, that show efficacy in preclinical models. However, clinical translation remains challenging due to issues of specificity, drug delivery across the blood-brain barrier, and disease heterogeneity. Future directions emphasize biomarker-driven approaches and endothelial-specific therapies to bridge mechanistic insights into clinical applications.

Cardiovascular diseases (CVDs) remain the leading global cause of death, partly due to vascular dysfunction. Dietary supplements, including omega-3 fatty acids, are suggested to support vascular health, but their therapeutic effectiveness and optimal dosing are still uncertain.

This systematic review and meta-analysis study assessed the efficacy and dose-response effects of omega-3 fatty acids on vascular health biomarkers in individuals with CVDs.

A comprehensive search of PubMed, Scopus, Web of Science, and the Cochrane Library was conducted through May 2025.

Eligible randomized controlled trials (RCTs) with a minimum intervention duration of four weeks.

Two reviewers independently extracted data and assessed study quality. Data were synthesized as weighted mean differences (WMDs) with 95% confidence intervals (CIs). Risk of bias was assessed using the Cochrane tool, and the certainty of the evidence (CoE) was appraised using the GRADE framework.

The pulse wave velocity (PWV), augmentation index (AIx), and flow-mediated dilation (FMD).

Twenty RCTs involving 1,208 participants were included, with 80% judged at low risk of bias. Omega-3 supplementation (0.3-4.7 g/day) showed no significant effect on PWV, including in subgroups with hypertension or established CVDs. In contrast, omega-3s improved AIx. FMD elevations were greater for eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) than for alpha-linolenic acid. These findings were consistent across sensitivity analyses and supported by dose-response relationships, indicating that achieving approximately 1,650 mg EPA and 750 mg DHA may be important for optimizing vascular outcomes. The CoE ranged from moderate to low.

Omega-3 fatty acids may enhance endothelial function and reduce arterial wave reflection. Future trials with refined methods are needed to maximize clinical benefit.

Systematic review registered with PROSPERO, registration number CRD420251065121.

The clinical presentation of critically ill patients with coronavirus disease 2019 (COVID-19) has evolved significantly with the emergence of the Omicron variant. Current intensive care unit (ICU) admissions involve patients with diverse comorbidities and immune statuses, highlighting the need to redefine homogeneous phenotypic subgroups within this population. This study aimed to characterize distinct clinical phenotypes among critically ill patients with COVID-19 and acute respiratory failure.

This multicenter prospective substudy of the SEVARVIR cohort included adult patients from 39 French ICUs between December 2021 and October 2024 with acute respiratory failure and infected with the Omicron variant. Clustering analysis was conducted using Kohonen's self-organizing maps (SOMs) and validated with ClinTrajan, two unsupervised clustering methods, to identify homogeneous patient phenotypes.

During the study period, 777 patients with Omicron infection were included, and 7 distinct clinical clusters were identified. Clusters 1 and 2 included patients with metabolic and cardiovascular comorbidities. Cluster 3 featured younger, mildly ill patients with isolated chronic respiratory failure, while cluster 4 comprised older male patients with isolated respiratory failure. Cluster 5 included patients with isolated hematologic malignancies, cluster 6 patients with multiorgan failure, and cluster 7 organ transplant recipients, with high severity scores and impaired renal function. ICU management varied substantially across clusters. Patients in clusters 5 and 7 had the highest requirements for organ support, with frequent use of invasive mechanical ventilation, vasopressors (cluster 6), and renal replacement therapy (cluster 7). Dexamethasone and tocilizumab were most commonly prescribed in cluster 4 (91.3% and 30.2%, respectively). Mortality at day 28 varied significantly across clusters, ranging from 13.1% in cluster 3 to 41.1% in cluster 6.

This clustering analysis highlights, for the first time, the clinical heterogeneity of critically ill patients infected with Omicron, identifying seven distinct clusters with varying clinical presentations, management strategies and outcomes. These findings underscore the relevance of a phenotype-driven approach to support personalized treatment strategies and guide future clinical trials.

Clinicaltrials.gov, NCT05162508. A Graphical Abstract is available for this article.

Following a surge in myocarditis in Germany since August 2023, many with parvovirus B19 (B19V) detection, concerns arose about causes and countermeasures.

The authors aimed to verify the association among B19V, myocarditis increase, and severity.

Data from the pediatric multicenter registry (MYKKE) from 27 centers were analyzed. B19V myocarditis cases were defined by polymerase chain reaction (PCR) positivity in blood or myocardium with clinical or histopathologic myocarditis evidence. Comprehensive clinical, histopathologic, and epidemiologic analyses were conducted. Past patients were hospitalized from 2013 to July 2023, current from August 2023 to November 2024. Registry data were compared with surveillance and consultant laboratory data. Specimens of current cases underwent metagenomic analysis and B19V sequencing.

Since 2013, 922 myocarditis patients including 126 (13.6%) with B19V myocarditis were enrolled. With 57 of 126 (45.2%) current cases, B19V myocarditis increased, compared with other myocarditis causes. Most current cases were patients who were <2 years of age (64.9%), 56.1% were female. The ratio of B19V myocarditis to incidence did not increase compared with the earlier period. Current cases presented with more reduced ejection fraction (29.0% vs 34.5%; P = 0.007), linked to severe cardiac T-cell infiltration and high numbers of B19V copies. Increased severity was associated with younger age. Phylogenetic analysis identified B19V genotype 1A, without sequence variants indicating increased virulence.

The increase in pediatric myocarditis since August 2023 was associated with B19V, more likely explained by disproportionately young current cases and young children's vulnerability than a virulent strain. Raising clinicians' awareness and proactive, interdisciplinary approaches are essential for improving prevention of B19V infection, management of myocarditis, and treatment strategies in this vulnerable cohort. (Myocarditis Registry for Children and Adolescents [MYKKE]; NCT02590341).

The cardiac myosin inhibitor aficamten was significantly more effective than metoprolol at improving exercise tolerance in MAPLE-HCM (Metoprolol vs Aficamten in Patients with LVOT Obstruction on Exercise Capacity in HCM), a head-to-head, international, double-blind, randomized trial in patients with obstructive hypertrophic cardiomyopathy (oHCM). Given the primary treatment goal to improve patients' health status, defining the incremental benefits of aficamten over metoprolol on patients' symptoms, function, and quality of life is needed.

In this study, the authors sought to compare patient-reported health status benefits of aficamten with metoprolol.

Adults with symptomatic oHCM (Kansas City Cardiomyopathy Questionnaire [KCCQ] Clinical Summary Score [CSS] ≤90; left ventricular outflow tract obstruction ≥30 mm Hg at rest or ≥50 mm Hg with Valsalva) were randomly assigned to 24 weeks of aficamten or metoprolol as monotherapy. Changes in KCCQ Overall Summary Score (OSS) and Seattle Angina Questionnaire Summary Score (SAQ-SS), collected serially throughout the trial, were compared between treatment groups at 24 weeks using linear regression, adjusted for randomization strata and baseline scores. Individual participant experiences were described by comparing categories of clinically meaningful within-participant change: ≤-5 (worse), >-5 to <+5 (no change), +5 to <+10 (small improvement), +10 to <+15 (moderate improvement), +15 to <+20 (large improvement), and ≥+20 points (very large improvement).

Among 175 randomized patients, baseline health status scores were similar between treatment groups (n = 88 aficamten; n = 87 metoprolol). Aficamten, compared with metoprolol, resulted in a greater 24-week KCCQ-OSS improvement (adjusted between-group difference: +7.8 points; 95% CI: 3.3-12.3; P < 0.001), primarily driven by a greater proportion of aficamten-treated (38.6%) vs metoprolol-treated (18.4%) patients experiencing a very large (≥20 points) KCCQ-OSS improvement (number needed to treat = 4.9; 95% CI: 3.0-13.9), and a smaller proportion experiencing worsening health status (≤-5-point change: 6.8% vs 18.4%; number needed to harm = 8.6; 95% CI: 4.7-53.3). Nonsignificant SAQ-SS improvements with aficamten vs metoprolol (+4.6 points; 95% CI -0.3 to 9.5 points; P = 0.063) were driven by significantly larger improvements in the SAQ Physical Limitation scale (+10.1 points; 95% CI: 3.9-16.2 points; P = 0.001).

Aficamten improved the health status of patients with symptomatic oHCM significantly more than did metoprolol, highlighting its potential as an effective initial therapeutic option. (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Metoprolol Succinate in Adults With Symptomatic oHCM (MAPLE-HCM; NCT05767346).

Therapeutic drug failure poses a significant global health burden, particularly in developing regions with high environmental toxicant exposure. While traditionally attributed to factors such as substandard drugs, genetic polymorphisms, and non-compliance, emerging evidence implicates heavy metals as under-recognized modulators of drug efficacy. This systematic review assessed how heavy metals potentially interfere with the pharmacokinetics and pharmacodynamics of drugs. Following PRISMA guidelines, peer-reviewed articles published between 1999 and 2024 were retrieved from PubMed, ScienceDirect, Web of Science, Scopus and Google Scholar. Studies investigating in vivo, in vitro or clinical evidence of heavy metal interference with therapeutic drug action were eligible. Out of 139 studies identified, 20 studies met the inclusion criteria. Cadmium, lead and mercury were the most implicated metals. Approximately 60% of studies demonstrated that oxidative stress could induce loss of therapeutic drug efficacy, while 40% showed enzyme inhibition (notably CYP3A4 and CYP2C9) or transporter impairment. Experimental models linked these effects to anti-hypertensives, antidiabetics, and drugs used in the management of metabolic disorders. Environmental heavy metal exposures may hinder therapeutic responses through oxidative and metabolic disruption. Integrating environmental exposure assessment into global pharmacovigilance and clinical pharmacology could enhance drug response predictability and treatment success.