The C statistic, also known as the concordance index (C-index), is widely used in clinical research to assess the discriminative ability of risk prediction models. Its appeal lies in its intuitive interpretation and broad applicability, particularly in fields such as cardiovascular medicine and oncology, where accurate risk stratification is essential. However, despite its popularity, the C statistic has notable limitations that can undermine its utility in both research and clinical practice. Chief among these is its inherent conservativeness: the C statistic is often insensitive to meaningful improvements in model performance when new biomarkers or risk factors are added to an already robust model. This insensitivity stems from its rank-based nature, which focuses solely on the correct ordering of risk predictions rather than the magnitude of improvement. As a result, significant advances in risk estimation may be overlooked, potentially discouraging the adoption of clinically valuable innovations. Furthermore, the C statistic does not account for calibration—the agreement between predicted and observed outcomes—or the clinical consequences of misclassification. Alternative metrics, such as the Mean Absolute Difference (MAD), Brier score and Net Reclassification Improvement (NRI), offer complementary perspectives by capturing aspects of predictive accuracy and clinical relevance that the C statistic may miss. A comprehensive evaluation of risk models should therefore integrate these alternative measures to ensure that predictive tools are both statistically robust and clinically meaningful, ultimately advancing patient care and the practice of precision medicine.
Epicardial adipose tissue (EAT) exhibits brown-like features, including the expression of uncoupling protein 1 (UCP1). EAT interacts dynamically with cardiac cells to modulate local cardiac tissue physiology and metabolic function. No studies have evaluated the impact of UCP1 inhibition on oxidative phosphorylation (OXPHOS) in fresh EAT explants. This study aimed to determine the unique bioenergetic characteristics of fresh EAT explants by comparing it to subcutaneous adipose tissue (SAT). Furthermore, the key impact of UCP1 inhibition on EAT respiration and how this process is influenced by the presence of type 2 diabetes mellitus (DM) or coronary artery disease (CAD), was also evaluated.
EAT and SAT biopsies were collected from 205 (151 male and 51 female) study participants, undergoing cardiac surgery. Participants were stratified according to the presence/absence of DM or CAD. Markers of mitochondrial content and bioenergetics were evaluated.
EAT demonstrated a higher bioenergetic activity compared to SAT, in both nicotinamide adenine dinucleotide (NADH)-linked and fatty acid oxidation (FAO)-linked OXPHOS. Importantly, UCP1 inhibition with guanosine 5′-diphosphate (GDP), flattens the differences between the tissues in the NADH-linked OXPHOS; in contrast these differences were potentiated in the FAO-linked OXPHOS. Minor differences in mitochondrial content and respiration were observed when subjects were stratified according to either DM or CAD.
This study emphasizes the important bioenergetic differences between EAT and SAT, which are crucial in the context of the local cardiomyocyte metabolism, as well as the impact of UCP1 inhibition in EAT. A deeper understanding of the unique characteristics of EAT and its metabolic micro-environment may provide valuable insights into the cardiovascular disease pathologies.
Calcific aortic valve disease (CAVD) is the predominant valvular pathology in older adults, advancing from aortic sclerosis to life-threatening stenosis. Without effective medical therapies, intervention mainly relies on timely valve replacement, although silent myocardial and valvular damage may progress before symptoms arise. Early, non-invasive detection of disease activity is a crucial unmet need.
To review circulating and mechanistic biomarkers reflecting the core pathogenic pathways of CAVD and asses their potential for early detection and patient-specific risk stratification.
Narrative review of literature focusing on traditional protein biomarkers, emerging non-coding RNAs, and extracellular vesicles (EVs) associated with lipid oxidation and inflammation, bone and mineral metabolism, extracellular matrix (ECM) remodelling, endothelial dysfunction and non-coding RNA regulation.
Traditional protein biomarkers—such as lipoprotein(a), osteopontin, fetuin-A, galectin-3 and matrix metalloproteinases—offer insights into the disease and correlate with disease burden but lack sensitivity for detecting early-stage CAVD. Emerging non-coding RNA markers, including long non-coding RNAs (lncRNAs) and microRNAs (like miR-30b and miR-125b), show promise as predictive and diagnostic tools by mediating key molecular pathways involved in calcification and inflammation. EVs, which carry proteins, lipids and nucleic acids across all pathogenic pathways, provide stable and comprehensive signatures that enhance risk stratification compared to conventional markers. Notably, no single biomarker has demonstrated sufficient sensitivity or specificity across all stages of the disease. Combining proteins, RNAs and EV cargo into integrative, multimodal panels—supported by proteomics and transcriptomics—provides the greatest potential for early detection and patient-specific management. However, further validation in prospective cohorts and standardization of assays are necessary before clinical implementation.
Biomarker-guided approaches could revolutionize CAVD management by enabling early detection and patient stratification before irreversible valvular damage occurs.
Overweight and obesity are highly prevalent in atrial fibrillation (AF) patients, yet the best anticoagulant strategy for this group is still unclear. We evaluated the risk of all-cause mortality and cardiovascular events (CVEs) in overweight and obese AF patients treated with direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs).
We analysed 10,259 AF patients on anticoagulants from the prospective nationwide START registry. Overweight was defined as BMI 25–29.9 kg/m2 and obesity as BMI ≥30 kg/m2. Mortality risk was assessed with Cox proportional hazards models, and CVEs with Fine–Grey models accounting for competing risks. Additional modelling strategies, subgroup analyses, and propensity score matching were performed to explore data and ensure robustness.
Overall, 6534 (63.7%) patients had BMI >25 kg/m2 (65.7% overweight, 34.3% obese). Over a median follow-up of 17.4 months, 408 deaths and 481 CVEs occurred. DOACs' use was associated with a lower risk of all-cause mortality (HR 0.57, 95% CI 0.46–0.70, p < 0.001) and CVEs (sHR 0.71, 95% CI 0.59–0.86, p < 0.001) versus VKAs. The inverse association of DOACs with mortality was evident in both overweight (HR 0.52, 95% CI 0.39–0.68, p < 0.001) and obese patients (HR 0.69, 95% CI 0.48–0.98, p = 0.040), while the reduction in CVEs reached significance only in the overweight group.
In this nationwide registry, DOACs were associated with lower risks of mortality and CVEs compared with VKAs across BMI groups, though the CVE effect was not evident in obese patients. These findings suggest a potential mortality advantage of DOACs irrespective of BMI, warranting further confirmation.
Venous outflow (VO) is a promising prognostic imaging biomarker in acute ischemic stroke (AIS) patients selected for endovascular treatment (EVT). However, the best score for properly assessing VO profiles on multi-phase CT-Angiography (mCTA) remains to be identified.
A series of consecutive AIS patients undergoing EVT for large vessel occlusion within 24 h from symptom onset were investigated. The following scores were rated: cortical vein score difference in stroke (PRECISE, range 0–8), cortical vein opacification score (COVES, range 0–6), comprehensive venous outflow (CVO, range 0–8) and internal cerebral vein (ICV) asymmetry. Receiver operating characteristic curves and multivariable logistic regression analyses were performed to explore the performance of the different VO scores for prediction of a good outcome (modified Rankin Scale 0–2 at 3 months).
Three hundred and thirty-six subjects (56.2% females, mean age 74.8) were included, of whom 145 (43.1%) had good outcomes. In multivariable logistic analysis, the CVO score (odds ratio = 2.51, 95% CI = 1.49–4.18, p = .001) was the only independent predictor of good functional outcomes. The AUC of the CVO score was .75 (95% CI = .70–.80), with an optimal cut-off of ≥4 (sensitivity 56%, specificity 69%). Patients with favourable CVO profiles had better pial arterial (70.7%, p < .001) and hypoperfusion intensity ratio (HIR) tissue-related collaterals (HIR = .35, p = .005), higher rates of successful recanalization (95.7%, p < .001) and lower symptomatic intracranial haemorrhage occurrence (6%, p = .020) than those with unfavourable CVO profiles.
The CVO score measured on mCTA had the best discriminative performance and was independently associated with functional outcome in AIS patients undergoing EVT within 24 h from onset.
Epilepsy is a common neurological disease that heavily impacts children and adolescents and carries serious physical, cognitive, psychological, social and economic consequences for patients and their caregivers.
Data was obtained via the Global Burden of Disease Study 2021. We reported numbers, rates and percentage changes of prevalence, mortality and disability-adjusted life years (DALYs).
In 2021, there were 18.15 million [95% UI: 14.61–21.85] prevalent cases of epilepsy in children and adolescents worldwide, 8.24 million [5.77–11.13] of which were idiopathic epilepsy and 9.91 million [8.72–11.06] of which were secondary epilepsy. While mortality and DALY rates of idiopathic epilepsy declined between 1990 and 2021, the burden of secondary epilepsy remained substantial and, in some cases, increased—particularly in low-SDI regions. The prevalence rate of secondary epilepsy increased by 16.14% [4.28–29.24], driven by increases in epilepsy attributable to neonatal encephalopathy (82.02%), neonatal jaundice (18.45%) and malaria (77.03%). There were notable geographic variations in the burden of epilepsy, with the burden generally concentrated in Sub-Saharan Africa, Latin America and the Caribbean and Southeast Asia.
While efforts to reduce premature mortality of epilepsy have been successful, the burden on children and adolescents living with epilepsy is still significant. A healthcare gap remains for vulnerable populations with increased risk of infectious diseases, perinatal insults, poor sanitation and limited access to healthcare. Global and national action is needed to improve access to specialist care and medication, manage comorbidities, address stigma and discrimination and strengthen primary prevention initiatives.
We present the final report from the Fabry Outcome Survey (FOS) on long-term effectiveness and safety of agalsidase alfa in adults (≥18 years old).
FOS was an international, multicentre, observational registry (NCT03289065), designed to enhance the understanding of Fabry disease and improve clinical management. Primary effectiveness endpoints were annualized change in estimated glomerular filtration rate (eGFR) and left ventricular mass index (LVMI), and time to and age at composite morbidity event (comprising renal, cardiac or stroke events) and death. Safety outcomes were also assessed.
FOS included data for 1864 adults (female/male, n = 907/957) who received agalsidase alfa only for a median (minimum, maximum) of 6.0 (0, 21.6) years, and 1613 untreated adults (female/male, n = 1235/378). At baseline, mean (standard deviation [SD]) eGFR was 94.01 (27.60) mL/min/1.73 m2 in treated adults; annualized changes in eGFR (slope [standard error; SE]) remained relatively stable in females and declined slightly in males (−1.07 [.12] vs. −2.17 [.12] mL/min/1.73 m2). At baseline, mean (SD) LVMI was 58.25 (25.01) g/m2.7 and LVMI (slope [SE]) remained stable (.34 [.16] vs. .38 [.15] g/m2.7/year in females and males, respectively). Time (median [95% confidence interval]) from treatment initiation to first composite event was longer for females than males (83.4 [65.7–98.0] vs. 56.3 [45.6–66.7] months); age (median [minimum, maximum]) at death was also higher for treated females than males (69.9 [32.5, 87.7] vs. 59.1 [26.2, 79.6] years). Agalsidase alfa was generally well tolerated.
This report further supports the long-term effectiveness and safety of agalsidase alfa in adults with Fabry disease.
Lower extremity arterial disease (LEAD) affects over 200 million people globally and is largely driven by chronic vascular inflammation. However, the complex interplay between inflammatory pathways, their prognostic value and potential sex-specific differences remains insufficiently understood.
Literature indicates that elevated inflammatory markers—such as (high-sensitivity) C-reactive protein, fibrinogen, D-dimer, interleukin-6, α-defensins and soluble adhesion molecules as well as newly arising parameters such as neutrophil counts and markers of clonal haematopoiesis—may predict both the onset and progression of LEAD, from declining ankle–brachial indices and impaired walking performance to higher rates of amputation, cardiovascular events and mortality. Moreover, women with LEAD frequently present at older ages with more advanced disease, exhibit distinct lesion patterns and greater functional impairment, and often have higher baseline CRP levels than men, although the strength of association between inflammatory markers and adverse outcomes may be attenuated in women. However, it remains unclear how inflammatory markers can guide (sex) specific patient stratification in LEAD or which markers provide the most clinical utility in general.
Together, these findings underscore the need for comprehensive inflammatory profiling in LEAD risk stratification and highlight the importance of joining sex-specific analyses, new (bio)markers and machine learning to integrate clinical, genomic, proteomic and functional data into future studies to inform patient-tailored prevention and treatment strategies.
Heart failure is an advanced form of cardiovascular disease with a high mortality rate. Management of the condition is possible and blood-based biomarkers could help identify the most vulnerable patients. There is mounting evidence of a link between angiopoietin-like protein 2 (ANGPTL2), a secreted glycoprotein involved in inflammation and tissue remodelling, and heart failure. However, no prospective studies have examined whether ANGPTL2 predicts mortality in heart failure, which this study aims to address.
Mortality was prospectively recorded in a cohort of 303 patients with heart failure over a period of 5 years. Serum ANGPTL2 levels were determined at baseline by means of enzyme-linked immunosorbent assay.
At baseline, elevated ANGPTL2 levels were highly significantly associated with increased concentrations of total, LDL- and HDL-cholesterol and with a lower prevalence of male sex, smoking history, cardiovascular disease and statin use. During the five-year follow-up period, 47% of all patients died. When patients were stratified into tertiles based on ANGPTL2 levels, those in the highest tertile exhibited a significantly increased risk of all-cause mortality compared to those in the lowest tertile (hazard ratio = 1.88 [1.23–2.88]; p = .004). After adjustment for potential confounders, including NT-proBNP, the association remained significant, with an adjusted hazard ratio of 1.91 [1.13–3.23]; p = .015. In addition, the inclusion of ANGPTL2 improved the predictive accuracy of a model based on traditional risk factors, as indicated by a significant 24.3% net reclassification improvement.
Circulating ANGPTL2 is a significant predictor of mortality in patients with heart failure.
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