European Journal of Clinical Investigation最新文献

Background

Early diagnosis is pivotal for guiding the intensity of clinical monitoring, optimizing therapeutic strategies and preventing organ damage in inflammatory and autoimmune rheumatic diseases (IARDs). This review summarizes current evidence on early diagnostic and therapeutic approaches of some IARDs, including rheumatoid arthritis (RA), systemic sclerosis (SSc) and detection of large-vessel vasculitis (LVV) in polymyalgia rheumatica (PMR), representing distinct pathophysiological mechanisms of joint synovitis, tissue fibrosis and vasculitis, respectively.

Methods

A comprehensive narrative literature review was conducted focusing on early recognition strategies, searching PubMed and Scopus databases with emphasis on studies from the past 5 years and recent EULAR/ACR conference abstracts (2023–2025).

Results

In RA, clinically suspect arthralgia with seropositivity for rheumatoid factor and anti-citrullinated peptide antibodies significantly increases progression risk to definite RA. Musculoskeletal ultrasound detects subclinical synovitis in 44%–51% of high-risk individuals, while MRI identifies bone marrow edema predicting erosive progression. Abatacept significantly reduces RA development in seropositive individuals at high risk of RA.

In SSc, Raynaud's phenomenon combined with SSc-specific autoantibodies and abnormal nailfold capillaroscopy predicts progression to definite disease, with 79.5% developing SSc within 4.6 years. LeRoy's criteria, validated by Koenig, enables early identification, though evidence for disease-modifying interventions in preclinical stages remains limited.

For PMR, imaging reveals subclinical LVV in 16%–23% of patients without cranial symptoms. Subclinical LVV associates with higher relapse rates in retrospective studies, though optimal management approaches require prospective validation.

Conclusions

Advances in early IARD recognition through refined clinical criteria, enhanced biomarkers and imaging enable risk stratification and personalized management. While intervention strategies show promise, particularly in RA, optimal patient selection and treatment protocols require further research.

Background

Dysmenorrhea, a common gynaecological complaint, is often underdiagnosed, particularly in adolescents. The Developmental Origins of Health and Disease hypothesis suggests that maternal cardiometabolic conditions during pregnancy may influence offspring reproductive health. We investigated whether cardiometabolic risk (CCMR) is associated with dysmenorrhea risk in offspring and whether early-puberty BMI and menarcheal age mediate these associations.

Methods

Data was from the Amsterdam Born Children and their Development cohort. A total of 982 mother-daughter pairs were included. Maternal CCMR included pre-pregnancy body mass index (BMI), blood pressure, glucose, triglycerides and Apolipoprotein A1. Dysmenorrhea was defined as menstrual abdominal/back pain requiring analgesics. Inverse probability weighted multivariable logistic regression examined associations between maternal CCMR or its components and dysmenorrhea in offspring. Multiple imputation was used to handle missing data in the sensitivity analysis. Serial multiple mediation analysis tested the mediating role of offspring's BMI and menarcheal age.

Results

Dysmenorrhea was reported in 49.2% of daughters. In the model adjusted for maternal age, socioeconomic status, smoking, alcohol use, anxiety and depressive symptoms, CCMR was not significantly associated with dysmenorrhea (OR: 1.03, 95% CI: .72–1.48). However, higher maternal pre-pregnancy BMI was associated with increased dysmenorrhea risk in offspring (OR: 1.20, 95% CI: 1.02–1.42). A partial mediation via BMI and menarcheal age was observed (indirect effect: 1.01, 95% CI: 1.00–1.03).

Conclusion

No evidence was found of maternal CCMR and dysmenorrhea in offspring. However, higher maternal pre-pregnancy BMI increased dysmenorrhea risk, partly mediated by heavier BMI and earlier pubertal timing in offspring. These findings align with the hypothesis of a possible intrauterine origin of menstrual disorders and highlight the importance of early life factors in dysmenorrhea research.

Background

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become a leading cause of chronic liver disease worldwide, driven by the increasing prevalence of obesity and insulin resistance (IR). IR, a central feature of the metabolic syndrome, promotes hepatic lipid accumulation, inflammation and mitochondrial dysfunction, fostering the transition from steatosis to advanced liver injury and hepatocellular carcinoma (HCC). This review summarizes current evidence on the molecular mechanisms linking MASLD, IR and HCC, highlighting the role of insulin resistance in liver carcinogenesis and disease progression.

Methods

A comprehensive literature search was conducted to identify experimental, clinical and epidemiological studies addressing the interplay between MASLD, IR and HCC. Key molecular pathways and risk profiles were synthesised and compared across etiologies.

Results

IR contributes to hepatic lipid deposition, oxidative stress and chronic inflammation through activation of PI3K/Akt and mTOR signalling. The coexistence of MASLD and IR enhances pro-inflammatory and pro-fibrotic pathways, accelerating the evolution to HCC. Patients with MASLD-associated HCC exhibit distinct metabolic and molecular characteristics compared with those with viral or alcohol-related HCC. Novel biomarkers and advanced imaging modalities show promise for identifying high-risk individuals at earlier disease stages.

Conclusions

Although substantial progress has been made in understanding the MASLD–IR–HCC axis, critical gaps remain regarding genetic, environmental and metabolic determinants. A multidisciplinary approach integrating metabolic, molecular and oncologic research is essential for improving early detection, risk stratification and the development of targeted therapies against metabolic liver cancer.

Background

Preeclampsia is a disorder with complex pathophysiology, which underscores the need to study various biomarkers for its early prediction, accurate diagnosis, better understanding of underlying mechanisms and potential links to other diseases. A growing body of research has explored the potential of established and emerging cardiovascular biomarkers in the context of preeclampsia. The overlap in risk factors between preeclampsia and cardiovascular disease, along with findings from numerous epidemiological studies, suggests that cardiovascular biomarkers may play a key role in predicting preeclampsia, assessing its severity and determining the long-term risk of cardiovascular disease.

Aim

To explore the role of cardiovascular biomarkers in the prediction, diagnosis and management of preeclampsia, while investigating their ability to improve insights into disease mechanisms and their connection to long-term cardiovascular risk.

Methods and Discussion

This review summarizes findings from existing research on cardiovascular biomarkers in preeclampsia, including studies examining their predictive and diagnostic capabilities, their role in elucidating disease pathophysiology, and their relevance for long-term cardiovascular risk assessment. Furthermore, it highlights emerging cardiovascular biomarkers, outlining their technical limitations and the need for further studies to clarify their utility in routine clinical practice.

Conclusion

Cardiovascular biomarkers are becoming essential for diagnosing, monitoring and predicting outcomes in preeclampsia, enabling early detection and treatment. While some are already in clinical use, emerging biomarkers show promise for more precise and individualized care. Advancing research in this area offers significant potential to improve maternal and fetal outcomes.

Background

Lipoprotein(a) [Lp(a)] is a primarily genetically determined, causal and independent risk factor for atherosclerotic cardiovascular disease (ASCVD). Lp(a) levels are stable, unaffected by lifestyle, and best measured using isoform-insensitive, molar-based assays. Current guidelines from the European Atherosclerosis Society and U.S. National Lipid Association recommend a one-time Lp(a) measurement in all adults. Cascade testing is advised in affected families.

Results

Elevated Lp(a) levels are associated with increased risk of coronary artery disease, myocardial infarction incidence and recurrence, and aortic stenosis onset and progression. In cerebrovascular disease, high Lp(a) is linked to large artery ischemic stroke incidence and recurrence, as well as poor functional outcomes. Associations with venous thromboembolism are limited to prothrombotic states and extreme Lp(a) concentrations. Elevated levels (≥50 mg/dL or ≥125 nmol/L) should prompt intensified risk factor modification.

Conclusion

There are no currently approved lipid-lowering therapies that substantially reduce Lp(a) levels. Novel agents to lower Lp(a) include antisense oligonucleotides, small interfering ribonucleic acid and small molecules, all of which have shown promising results in phase 2 trials. Ongoing phase 3 trials will evaluate the causal relationship between Lp(a) and ASCVD, and whether lowering Lp(a) reduces cardiovascular outcomes.

Background

Lipoprotein(a) [Lp(a)] is a primarily genetically determined, low-density lipoprotein-like particle that plays an important role in atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve disease (CAVD). Despite optimal control of traditional lipid levels, elevated lipoprotein(a) [Lp(a)] remains a significant contributor to residual cardiovascular risk, affecting up to 20% of the global population.

Methods

We performed a literature search of PubMed/Medline and Google Scholar until July 2025 to provide a comprehensive overview of the genetics, structure, metabolism, and molecular mechanisms underlying Lp(a)'s pathogenicity.

Results

Structurally, Lp(a) consists of an LDL-like core covalently bound to apolipoprotein(a) [apo(a)], a polymorphic glycoprotein characterized by kringle IV type 2 (KIV-2) repeat variability. This copy number variation is the primary determinant of apo(a) isoform size and plasma Lp(a) levels. Small isoforms are produced more efficiently, resulting in higher concentrations. Lp(a) is synthesized in hepatocytes, and its plasma levels are predominantly governed by production rather than clearance. It carries a high burden of oxidized phospholipids (OxPLs), which confer pro-inflammatory and pro-atherogenic properties. Lp(a) promotes arterial inflammation, endothelial dysfunction, monocyte activation and impaired fibrinolysis via competition with plasminogen. It also plays a direct pathogenic role in valvular calcification by delivering OxPLs and autotaxin to valve interstitial cells, triggering osteogenic signaling cascades.

Conclusion

While environmental factors such as inflammation and hormonal status can transiently modulate levels, genetic variation overwhelmingly dictates lifelong Lp(a) burden. As novel agents targeting Lp(a) enter late-stage clinical trials, mechanistic insights into Lp(a) biology will be essential to risk stratification and future clinical management.

Background

Acute kidney injury (AKI) is common and linked to poor outcomes, but early detection remains challenging. Previous research identified urinary trace elements (TE) as early AKI biomarkers in intensive care unit (ICU) or cardiac surgery patients. We aimed to explore whether urinary TE enhance machine learning (ML) models for AKI prediction.

Methods

We constructed ML models using the ICU cohort. We filtered the variables and optimized hyperparameters before predicting Kidney Disease: Improving Global Outcomes stage 2–3 AKI using eight ML classifiers: light gradient boosting machine (LightGBM), random forest (RF), ML logistic regression, support vector machine, multilayer perceptron, eXtreme gradient boosting (XGBoost), Gaussian Naive Bayes and k-nearest neighbors. External validation was performed in the cardiac surgery cohort.

Results

Among 149 ICU patients (median age 56.0 [interquartile range (IQR): 43.5–67.0], 63.1% male), 25 developed stage 2–3 AKI; among 144 cardiac surgery patients (median age 70.0 [IQR: 62.0–76.0], 72.9% male), 12 developed stage 2–3 AKI. Each ML in the internal validation had area under the curve (AUC) above .7, with XGBoost having the highest (.813); LightGBM had the second highest AUC (.799), highest G-mean (.567) and F1-score (.545). In external validation, RF had the highest AUC (.740), XGBoost had the highest G-mean (.289) and F1-score (.286). Age, strontium and boron were consistently ranked among the top five most important features in LightGBM, RF and XGBoost.

Conclusion

ML models primarily based on urinary TE can identify AKI risk in both clinical groups (ICU and cardiac surgery), with LightGBM, RF and XGBoost serving as high-performance models for early prediction of stage 2–3 AKI.

Background

Pulmonary hypertension (PH) is frequently observed in patients with functional mitral regurgitation (FMR) and heart failure with reduced ejection fraction (HFrEF) and adversely impacts prognosis. However, limited data exist on the outcomes of transcatheter edge-to-edge mitral valve repair (M-TEER) in patients with PH, particularly regarding hemodynamic subtypes.

Methods

This multicenter, retrospective analysis included 144 HFrEF patients with moderate-to-severe or severe FMR who underwent M-TEER across four Italian centers. Baseline hemodynamic assessment was performed using right heart catheterization (RHC) in conscious patients. Procedural outcomes and clinical follow-up were evaluated at 1 year. The endpoints studied included death from any cause, heart failure hospitalization and a composite endpoint of both.

Results

Among the 144 patients, 84% had PH (64% combined post- and pre-capillary-PH (Cpc-PH), 20% isolated post-capillary-PH (Ipc-PH)). Procedural success was achieved in 92%, with significant improvements in New York Heart Association (NYHA) functional class (p < .001) and echocardiographic parameters. At 1 year, the composite endpoint occurred in 30% of patients, with higher rates in PH patients compared to no PH group (34% vs. 9%, respectively, p = .039). Among PH patients, Cpc-PH patients demonstrated the worst outcomes (for the composite endpoint at 1 year Cpc-PH 37% vs. Ipc-PH 24% vs. no-PH 9%, p = .031). Multivariate analysis confirmed Cpc-PH as a significant predictor of adverse outcomes at 1 year.

Conclusions

M-TEER is an effective therapeutic option for patients with HFrEF and FMR, providing significant procedural success and clinical improvements. However, patients with PH, particularly those with Cpc-PH, exhibit worse long-term clinical outcomes.

Background

The benefit of statins in multimorbid older adults is controversial. Prior observational studies evaluating statin discontinuation in older adults were retrospective cohorts, did not focus on multimorbidity, or lacked adjustment for geriatric syndromes. We aimed to assess the effect of statin discontinuation on cardiovascular and mortality outcomes using the target trial emulation framework.

Methods

We conducted a prospective cohort study using data from the OPERAM trial in adults aged ≥70 years with ≥3 chronic conditions and ≥5 chronic drugs, comparing statin discontinuation to continuation. The primary composite outcome was cardiovascular events or all-cause mortality at 12 months. We calculated adjusted hazard ratios (HR) using weighted pooled logistic regressions without (model-A) and with adjustment for two geriatric syndromes (falls and weight loss; model-B).

Results

Of 2668 person-trial units (mean age 78.5 years), 2533 (95%) continued and 133 (5%) discontinued statins. Discontinuation was associated with higher composite outcome risk (27% vs. 18%; HR model-A 1.53 [95% CI 1.14–2.06]; model-B 1.49 [1.12–1.99]). This was mainly attributable to increased non-cardiovascular deaths (20% vs. 11%; HR model-A 1.56 [1.08–2.27]; model-B 1.52 [1.06–2.19]); there was no clear evidence for an association with cardiovascular events (7% vs. 8%; HR model-A 1.36 [.86–2.14]; model-B 1.35 [.86–2.12]).

Conclusion

In this first target trial emulation in a multimorbid older population, statin discontinuation was associated with increased risk of the composite of cardiovascular events or all-cause mortality, primarily driven by non-cardiovascular deaths. Geriatric syndromes did not modify these increased risks. Only clinical trials can clarify the safety of statin discontinuation.