Background: Cardiovascular disease (CVD), including myocardial ischemia, remains the leading cause of mortality. Current therapies for ischemic myocardium rely largely on invasive revascularization strategies, highlighting the need for improved non-invasive diagnostic and therapeutic approaches. Recent studies suggest that extracellular vesicles (EVs) play a critical role in cardiovascular pathophysiology and may offer novel clinical applications. Methods: This review synthesizes current preclinical and clinical literature on EV biology, including their classification, isolation, and characterization methods, and mechanisms of Intercellular communication. Published studies evaluating EVs as biomarkers and non-surgical therapeutics across major cardiovascular conditions were critically analyzed. Results: EVs facilitate intercellular communication by transferring bioactive molecules that influence disease progression and cardiac repair. Accumulating evidence supports their potential utility as biomarkers for disease prediction and severity assessment, as well as cell-free therapeutics in myocardial infarction, cardiomyopathies, atrial fibrillation, and heart failure. However, significant gaps remain, including the lack of validated EV-based biomarkers, inconsistent isolation and characterization methodologies, limited in vivo tracking data, and barriers to clinical translation. Conclusions: EVs represent a promising frontier in non-invasive cardiovascular diagnostics and therapeutics. Addressing current methodological and translational challenges, alongside advances in EV bioengineering, will be essential to realize their full clinical potential in CVD management.

Epidemiological population studies may include cardiac magnetic resonance (CMR)-derived phenotyping and large-scale genotyping, providing unprecedented level of detail to investigate novel gene-lifestyle-disease interactions. The systematic review presents high-level summaries and critically appraises contemporary challenges and biobank opportunities. The authors identified 17 relevant biobanks by searching "CMR," "genome" and "population study" on MEDLINE, EMBASE, and Web of Science 2025. Collectively, studies recruited ∼1 million participants with stored blood samples for extensive genomic analyses, of whom >180,000 have or will undergo CMR. Use of expansive personal data must safeguard participant confidentiality, encourage technological standardization, and champion inclusivity and sustainability. Application of genotypic and imaging-derived phenotypic information will be readily translatable to clinical practice through investigation of, among others, new therapeutic targets and highly sensitive and specific biomarkers. Imaging biobanks are accessible to researchers by application. This systematic review should inspire greater use and cross-collaboration and facilitate powerful discoveries in more heterogeneous population samples.

Atherosclerosis is a chronic lipid-driven inflammatory disease and one of the leading underlying causes of cardiovascular morbidity and mortality in Western society. Macrophages are key players in atherosclerotic development. Although the cellular composition of carotid atherosclerotic lesions has been determined, macrophage population definitions lack granularity and lineage data. Moreover, to date no direct link has been established between cellular content of atherosclerotic lesions and secondary clinical outcome. This study is aimed at characterization of atherosclerotic lesion macrophages and identification of plaque cell types and marker genes that predict the risk of secondary major adverse cardiovascular events in a clinical setting.

Single-cell RNA sequencing on blood and plaques from 46 carotid endarterectomy patients enrolled in the AtheroExpress cohort. Deconvolution was done on bulk transcriptome data from 656 AtheroExpress patients, and findings were validated in 82 patients enrolled in the Carotid Plaque Imaging Project.

Four major archetypes of plaque macrophages were identified: inflammatory macrophages, lipid-associated macrophages (LAMs), tissue-resident-like LAMs, and inflammatory LAMs. Cellular trajectory and fate analyses revealed that these are derived from both classical and non-classical monocytes. Functionally, this study demonstrated the capacity of monocytes to differentiate into inflammatory LAMs via inflammatory- or resident-like LAM and LAM stages. Next, the AtheroExpress bulk RNA-seq cohort was deconvoluted. Macrophages were shown to be the only cell population significantly associated with both symptoms at time of surgery and increased risk of major adverse cardiovascular events during a 3-year follow-up period. Within the macrophage population, mostly LAM and inflammatory LAM foam cell markers such as PLIN2 and TREM1 were associated with an increased risk of major adverse cardiovascular events after 3-year follow-up. These associations were validated in the Carotid Plaque Imaging Project cohort.

Together, these findings provide critical insights into the functional differences and origin of macrophage subpopulations in human atherosclerosis and show their clinical significance and risk prediction value in relation to future cardiovascular events.

BackgroundAcute coronary syndrome (ACS), a life-threatening cardiovascular emergency, faces challenges in early diagnosis and risk stratification. MicroRNAs (miRNAs) have emerged as key regulators in cardiovascular diseases.ObjectivesTo investigate the diagnostic/predictive significance of miR-1225-5p in ACS and its mechanism of regulating human coronary artery endothelial cells (HCAECs) injury induced by ox-LDL via targeting FAS.MethodsmiR-1225-5p levels in serum were determined by RT-qPCR in 99 ACS patients and controls, with correlation analysis to clinical indicators. HCAECs were used to assess viability, apoptosis, and inflammation/oxidative stress (IL-6, TNF-α, MDA, SOD) via CCK-8, flow cytometry, and ELISA. Target binding between FAS and miR-1225-5p was validated by dual-luciferase reporter and RIP assays, with functional validation experiments.ResultsmiR-1225-5p was significantly downregulated in ACS (P < 0.001), with subtype-specific patterns (UA > NSTEMI > STEMI). ROC analysis showed high diagnostic accuracy (AUC = 0.885 for ACS; 0.790-0.964 for subtypes). miR-1225-5p (HR = 5.409, 95% CI = 1.281-22.837) and Gensini score (HR = 3.524, 95% CI = 1.066-11.646) acted as a predictive factor in ACS, and downregulated miR-1225-5p is linked to MACEs in ACS patients. Overexpression of miR-1225-5p alleviated ox-LDL-induced HCAECs injury (enhanced viability, suppressed apoptosis, reduced inflammation/oxidative stress). FAS acted as a specific target of miR-1225-5p and is negatively associated with miR-1225-5p (r = -0.721). Overexpression of FAS reversed miR-1225-5p-mediated protective effects on HCAECs.ConclusionmiR-1225-5p is a potential diagnostic indicator for ACS and alleviates HCAECs injury by targeting FAS.

Cardiovascular diseases remain a major contributor to the global burden of healthcare, highlighting the importance of accurate and scalable methods for cardiac monitoring. Cardiac biosignals, most notably electrocardiograms (ECG) and photoplethysmograms, are essential for diagnosing, preventing and managing cardiovascular conditions across clinical and home settings. However, their acquisition varies substantially across scenarios and devices, whereas existing analytical models often rely on homogeneous datasets and static bespoke models, limiting their robustness and generalizability in diverse real-world contexts. Here we present a cardiac sensing foundation model (CSFM) that leverages transformer architectures and a generative masked pretraining strategy to learn unified representations from heterogeneous health records. CSFM is pretrained on a multimodal integration of data from various large-scale datasets, comprising cardiac signals from approximately 1.7 million individuals and their corresponding clinical or machine-generated text reports. The embeddings derived from CSFM act as effective, transferable features across diverse cardiac sensing scenarios, supporting a seamless adaptation to the varied input configurations and sensor modalities. Extensive evaluations across diagnostic tasks, demographic recognition, vital sign measurement, clinical outcome prediction and ECG question answering demonstrate that CSFM consistently outperforms traditional one-modal-one-task approaches. Notably, CSFM maintains favourable performance across both 12-lead and single-lead ECGs, as well as in scenarios involving ECG only, photoplethysmogram only or a combination of both. This highlights its potential as a versatile and scalable foundation for comprehensive cardiac monitoring.

Chromodomain-helicase-DNA-binding protein 4 (CHD4) is a critical ATP-dependent chromatin remodeler that plays fundamental roles in transcriptional repression, DNA damage repair, and lineage specification, making it indispensable for cardiovascular development and function. Pathogenic CHD4 mutations are linked to syndromic and nonsyndromic conditions, often presenting with severe cardiac and vascular anomalies. However, most of these mutations are unique and nonrecurrent, complicating variant classification. In this study, we establish a connection between recent advances in CHD4 structure and function and 36 pathogenic CHD4 mutations associated with rare diseases, including Sifrim-Hitz-Weiss syndrome, moyamoya angiopathy, and childhood idiopathic epilepsy with sinus arrhythmia, all of which exhibited cardiomyopathy, congenital heart defects, and/or vascular abnormalities. Among these mutations, 33 were missense variants, one was an in-frame small insertion, one, an in-frame small deletion, and one, a splice-site variant. Variants were classified according to the ACMG guidelines and subsequent refinements, integrating clinical, functional, population, and in silico (REVEL-based PP3/BP4) evidence, and cross-referenced with the ClinVar database to prioritize candidates for further association and functional studies. We classified the missense variants as follows: seven as pathogenic (P), nineteen as likely pathogenic (LP), one as likely benign (LB), and six as variants of uncertain significance (VUS). The splice-site variant was predicted to cause nonsense-mediated decay and reduced CHD4 expression, whereas the structural variants were predicted to exert moderate effects on protein function. LP/P variants associated with congenital heart defects were significantly enriched within the ATPase/helicase domain (p = 0.027), suggesting impairing ATPase motor activity. Nevertheless, several severe heart malformations, including tetralogy of Fallot were linked to pathogenic or LP variants, such as C467Y (plant homeodomain [PHD]), M202I (high-mobility group [HMG]), and Y1345D (C-terminal domain). In contrast, other variants located in the N- and C-terminal regions were more often associated with vascular phenotypes, suggesting domain-specific roles of CHD4 in cardiovascular disease. These findings establish CHD4 as a key regulator of cardiovascular pathophysiology, though a clear genotype-phenotype correlation remains elusive. Further functional validation is essential to elucidate CHD4's molecular mechanisms, aiding in diagnostic and therapeutic developments.

Hypercholesterolemia is a significant risk factor for severe cardiovascular diseases. Cholestyramine lowers serum low-density lipoprotein cholesterol (LDL-C) levels and is clinically indicated for the treatment of primary hypercholesterolemia, relieve itching symptoms caused by bile acid accumulation in cholestatic diseases (such as primary biliary cirrhosis), as well as to manage bile acid diarrhea resulting from bile acid metabolic disorders. With its widespread clinical application, it is essential to understand its safety in real-world settings.

This study evaluated the clinical safety of cholestyramine by analyzing all adverse event reports since 2004 in the FDA Adverse Event Reporting System (FAERS), where cholestyramine was identified as the primary suspected drug. Bayesian Confidence Propagation Neural Network (BCPNN), the Medicines and Healthcare Products Regulatory Agency (MHRA) composite criteria method, Multi-Item Gamma Poisson Shrinker (MGPS), Proportional Reporting Ratio (PRR), and Reporting Odds Ratio (ROR) were used to analyze adverse events associated with cholestyramine.

The study results confirmed known adverse reactions of cholestyramine, such as constipation, abdominal discomfort, bloating, steatorrhea, bleeding tendencies, night blindness, hyperchloremic acidosis, osteoporosis, rashes, and local irritation caused by deficiencies in vitamins K, A, and D, which are also listed in the drug's package insert. Additionally, adverse reactions not documented in the package insert were identified, including off-label use, administration for unapproved indications, gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), fecal abnormalities (color changes, softening, hardening), blood glucose fluctuations, tooth fracture, and exacerbation of concurrent medical conditions. This study also underscores the importance of early detection of adverse reactions associated with cholestyramine.

By providing insights into both known and potential adverse reactionsin real-world settings, the findings offer enhanced safety information to assist clinicians in prescribing cholestyramine for conditions such as hypercholesterolemia, cholestasis-associated pruritus, and bile acid diarrhea.

Esophageal fistula (EF) is a rare but devastating complication following atrial fibrillation (AF) ablation. Data regarding the impact of age on EF are scarce.

To study the impact of age on the management and prognosis of EF following catheter ablation for AF.

The POTTER-AF study is a worldwide registry on EF following catheter ablation for AF. A total of 553,729 patients underwent AF ablation in 214 centers between 1996 and 2022. Of them, 138 patients experienced EF, and data regarding age, management, and prognosis were available in 113 patients. The population was divided based on the median age.

The median age was 63 years; 54 patients were <63 years old (Group 1), and 59 patients were ≥63 years old (Group 2). The groups were similar regarding procedural characteristics. The older population had a shorter time to symptom onset [15.0 (6.0, 21.0) vs. 21.0 (10.0, 25.3) days; p = 0.031]. Group 2 was less likely to receive a brain CT or MRI for diagnosis (25.9% vs. 45.3%; p = 0.046). The older population was more likely to undergo endoscopic treatment without surgery (27.6% vs. 11.3%; p = 0.035). Conservative and surgical treatments were used in similar proportions. A trend toward higher fatality was noted in the older patients (72.9% vs. 56.6%; p = 0.078).

The older population had a shorter time to symptom onset, was less likely to receive a brain CT or MRI, and more likely to be treated by an endoscopic approach only. The older patient group showed a trend toward a higher fatality.