European Journal of Clinical Investigation最新文献

Besides the well-known role of hormonal factors in mineral and bone metabolism, the sympathetic nervous system participates in this regulation by inhibiting bone formation and promoting bone resorption, primarily via β-adrenergic receptors expressed on osteoblasts. Conversely, the parasympathetic system, through cholinergic signalling, inhibits osteoclast activity, promoting bone formation and maintaining skeletal homeostasis. This review presents the role of the autonomic nervous system, with particular focus on the potential role of β-blockers, especially β1-selective blockers, in modulating bone health in people with normal kidney function and those with CKD. While early studies with non-selective β-blockers like propranolol showed mixed results, recent findings in postmenopausal women suggested that β1-selective β-blockers could enhance bone density by modulating sympathetic activity. Trial emulation using large databases and eventually randomized controlled trials are needed to test the hypothesis that β-blockade can favourably impact bone disease in patients with kidney failure.

Background: Atrial fibrillation (AF) and low body weight (BW, <60 kg) are common in patients with heart failure (HF). However, the safety and effectiveness of direct oral anticoagulants (DOACs) in this group remain unclear. This study compares the efficacy and safety of apixaban versus vitamin K antagonists (VKAs) in patients with nonvalvular AF, low BW and HF.

Methods: We analysed 155,152 patients with HF and AF, weighing ≤100 kg and treated with oral anticoagulants (apixaban 86,493; VKA 68,659), from the TriNetX Global Research Network. Outcomes included ischaemic stroke/systemic embolism (SEE), clinically relevant bleedings, intracranial haemorrhage (ICH), all-cause death and net clinical benefit (composite of stroke/SEE, bleedings and all-cause death) across three BW categories: 60-100 kg (reference), 50-60 kg (low BW) and ≤50 kg (very low BW). Propensity score matching was used to balance the treatment groups.

Results: Patients with low BW had a higher risk of adverse events compared to those with reference BW, regardless of treatment. Apixaban consistently reduced the risk of ischaemic stroke/SEE and bleeding (including ICH) across all BW ranges (all p-interaction >.10), and improved net clinical benefit compared to VKA (reference BW: HR .82 [95% CI: .80-.84]; low BW: HR .79 [95% CI: .74-.85]; very low BW: HR .86 [95% CI: .78-.95], p-interaction = .366). However, a significant BW-treatment interaction was observed for all-cause mortality, indicating reduced relative effectiveness of apixaban vs. VKA as BW decreases.

Conclusion: In this large real-world analysis, treatment with apixaban was associated with a superior effectiveness and safety profile compared to VKA in patients with AF, HF and low BW. These results remained consistent, albeit slightly attenuated, in patients with very low BW. These findings provide preliminary evidence supporting the use of apixaban in this high-risk population.

Background: Heart failure (HF) remains a major cause of morbidity and mortality worldwide. Therefore, there is a need to identify robust biomarkers to improve early diagnosis, stratify disease severity and predict outcomes. Biomarkers such as galectin-3 (Gal-3), TIMP-1, BNP, NT-proBNP, CysC, CA125, ST2 and MMP9 have shown the potential to reflect the pathophysiology of HF. Despite their clinical potential, their integration into routine practice is still limited. The use of bioinformatics may help uncover critical associations between these biomarkers and the progression of HF, providing opportunities for personalized disease management.

Methods: Following PRISMA guidelines, a systematic review of clinical studies was performed using databases with time constraints. The major proteins associated with HF were identified and their diagnostic and prognostic roles were analysed.

Results: The study emphasizes that galectin-3 (Gal-3) and TIMP-1 serve as key indicators of fibrosis and inflammation, while BNP and NT-proBNP are reliable markers of cardiac stress. Cystatin C (CysC) reflects renal dysfunction, and CA125 correlates strongly with venous congestion. In addition, ST2 and MMP9 provide valuable insights into inflammation and tissue remodelling processes. These biomarkers are consistently elevated in patients with HF, emphasizing their critical role in detecting the systemic and cardiac manifestations of the disease.

Conclusion: Our results emphasize the importance of including biomarkers such as Gal-3, TIMP-1, BNP, NT-proBNP, CysC, CA125, ST2 and MMP9 in the diagnosis and treatment of HF. Their upregulation reflects the complex pathophysiological processes of HF and supports their use in the clinical setting to improve diagnostic accuracy, prognostic precision and personalized therapeutic strategies.

Background: Hospitalisation offers an opportunity for medication review and correction, yet it has received little attention. We aimed to evaluate oral anticoagulant (OAC) use in patients with atrial fibrillation at hospital admission and discharge and determine whether hospitalisation improves care.

Methods: We conducted an observational study at the Royal Hobart Hospital, Australia, in patients with atrial fibrillation. The appropriateness of stroke-prevention therapy at admission and discharge was evaluated using Australian guidelines. Factors associated with correcting inappropriate OAC therapy were identified using multiple logistic regression.

Results: Among 902 patients, 47.1% (n = 425) were receiving inappropriate OAC therapy at admission. The most common errors included lack of OAC therapy (58.6%, n = 249) and underdosing of direct-acting OACs (15.5%, n = 66). OAC therapy appropriateness at discharge was assessed for 844 patients; 73.8% were receiving appropriate therapy (versus 53.8% at admission (p < .001)). Specifically, 49.0% (n = 191) of the admission therapy errors were corrected. Correction was more likely in patients admitted to the stroke (adjusted odds ratio [aOR]: 16.93, 95% CI: 1.31-218.48) or cardiology wards (aOR: 4.10, 95% CI: 1.94-8.64), and if bleeding occurred during hospitalisation (aOR: 4.01, 95% CI: 1.07-14.99). Conversely, receiving rivaroxaban at admission (aOR: .23, 95% CI: .11-.51) and having a medium or high bleeding risk (ORBIT score ≥3) (aOR: .46, 95% CI: .25-.84) decreased the likelihood of correction.

Conclusion: Hospitalisation improved OAC therapy appropriateness; however, 51.0% of patients admitted with inappropriate therapy continued without correction. An intervention that enhances the hospital care team correcting inappropriate OAC therapy is warranted.

Background: Antibody-drug conjugates are novel effective therapies for metastatic breast cancer. Nevertheless, their toxicity profile can significantly affect patients' quality of life over time.

Methods: This is a systematic review and meta-analysis of randomized controlled trials of antibody-drug conjugates currently approved for the treatment of metastatic breast cancer [trastuzumab-emtansine (T-DM1), trastuzumab deruxtecan (T-DXd) and sacituzumab-govitecan (SG)] versus standard therapy to evaluate the risk of adverse events, discontinuation rate due to toxicity, impact on quality of life according to EORTC QLQ-C30 scale and subdomains. Relative risks (RR) and hazard ratios (HR) with 95% CIs were calculated using random effects models.

Results: Nine trials with a total of 5753 patients were included. The most common adverse events of any grade for T-DM1 included thrombocytopenia (RR 7.14, 95% CI 4.13-12.36) and increased alanine-transaminase (ALT) (RR 2.04, 95% CI 1.43-2.91), for T-DXd were nausea (RR 2.39, 95% CI 1.90-3.00) and anemia (RR 1.55, 95% CI 1.27-1.90), while for SG were neutropenia (RR 1.30, 95% CI 1.14-1.49), diarrhea (RR 3.62, 95% CI 2.97-4.42) and nausea (RR1.90, 95% CI 1.65-2.19). Severe adverse events such as interstitial lung disease and left ventricular dysfunction were peculiar of T-DXd. Antibody-drug conjugates significantly delayed clinical deterioration of global health status by EORTC QLQ-C30 (HR .71, 95% CI .59-.86), physical, emotional and social functioning, pain and fatigue symptoms.

Conclusions: This meta-analysis offers consolidated data on adverse events associated with antibody-drug conjugates and their effects on patients' quality of life, emphasizing differences based on the specific agent. These findings underscore the critical need for effective strategies to prevent, diagnose and manage these toxicities.

This systematic review and meta-analysis evaluated the impact of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on hepatocellular carcinoma (HCC) and liver decompensation in patients with type 2 diabetes. Analysing over 641,377 patients, GLP-1RA use was associated with a significant 58% reduction in HCC risk, particularly in patients with cirrhotis. While a trend towards reduced liver decompensation risk was observed, it was not statistically significant. These findings suggest a potential role for GLP-1RAs in HCC risk stratification and prevention strategies.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely related to type 2 diabetes mellitus (T2DM) through a common root in insulin resistance. The more severe stage, metabolic dysfunction-associated steatohepatitis (MASH), increases the risk for cardiovascular complications, liver cirrhosis and hepatocellular carcinoma. Several trials investigating established antidiabetic-drugs in patients with T2DM and MASLD have yielded promising results. Therefore, we aimed to systematically review the effect of T2DM-drug treatment on MALSD parameters.

Methods: Medical databases were searched until January 2025 for controlled trials in patients with T2DM and MASLD/MASH. Studies that evaluated the effect of T2DM-medication on the severity of MASLD/MASH in T2DM patients were included. The quality of the studies was assessed by three independent reviewers using a set of Cochrane risk-of-bias tools.

Results: Of 1748 references, 117 studies fulfilled the inclusion-criteria and were assessed for eligibility in full-text. Fifty-two articles were included. Data included a total of 64.708 patients and study populations ranged from 9 to 50.742. Heterogeneity in study-design and analysis hampered the comparability of the results. Most evidence was present for GLP-1 receptor agonists, SGLT2-inhibitors and PPAR-γ-agonists for regression of liver fibrosis and MASH.

Conclusion: Studies on the value of T2DM-drug treatment in the improvement of MASLD vary significantly in study design, size and quality. GLP-1 receptor agonists, PPAR-γ-agonists, SGLT2-inhibitors may all be preferred pharmacological interventions for patients with MASLD/MASH and T2DM. Newer agents like dual GLP-1/GIP or triple GLP-1/GIP/Glucagon agonists will likely play an important role in the treatment of MASLD/MASH in the near future.

Introduction: Protein carbonyl (PC) content, a stable marker of oxidative stress, is increased in chronic obstructive pulmonary disease (COPD) and shows association with cardiovascular events. We investigated prothrombotic effects of increased PC content and its modulation by statin use in COPD.

Materials and methods: We studied 56 patients with stable COPD, who were randomly assigned in an open-label manner to receive simvastatin 40 mg/day (n = 28) or to remain without statin for 3 months (n = 28). Plasma PC levels, along with thrombin generation, fibrin polymerization, clot permeability (K_s), compaction and global fibrinolysis (t50%) were assessed at baseline, at 1 and 3 months.

Results: PC concentration was 4.01 (min 2.20, max 5.43) nM/mg protein and correlated with age (r =.34, p =.0093) and C-reactive protein (CRP) (r =.43, p =.0009). PC was inversely associated with maximum clot absorbance (r = -.27, p =.046) and K_s (r = -.44, p =.0008), but not fibrinolysis or thrombin generation. On statin, PC concentration decreased by 15% after 1 month and by 33% after 3 months compared to baseline, leading to 28.5% lower levels than in controls (p =.0003), with no association with low-density lipoprotein cholesterol or CRP. At 3 months PC showed associations with favourably modified on-treatment K_s (r = -.51, p =.005) and t50% (r =.53, p =.004), but not with lipid profile or inflammation.

Conclusions: This study shows that 3-month simvastatin therapy in COPD patients results in about 30% decrease in PC concentrations, at least in part associated with favourable changes in fibrin clot parameters.

Background: Heart failure (HF) often coexists with cognitive impairment and accelerates cognitive decline. However, the impact of HF medications on cognition has received limited attention. This review evaluates the evidence on the cognitive effects of currently recommended medication classes for HF.

Methods: Systematic review using PubMed and EMBASE following PRISMA guidelines, employing keywords related to HF, cognitive function and guideline-recommended HF medications. Eligible studies were randomized controlled trials (RCT) or cohort studies assessing cognitive function in adult HF patients.

Results: Three cohort studies on ACEi/ARBs (N = 5080; 2 prospective, 1 retrospective) reported no significant impact on cognitive function to higher cognitive scores with ACEi/ARBs. Eight studies on sacubitril/valsartan (ARNI, N = 42,143; all observational studies or post-hoc analyses of RCT) found either no effect on cognitive function or reduced risk of new-onset dementia and improved cognitive outcomes with ARNI. Beta-blockers (N = 40; 1 RCT) lacked significant cognitive effects; empagliflozin (SGLT2i, N = 162; 1 prospective) improved cognitive performance in patients with diabetes and HF with preserved ejection fraction; digoxin (N = 1172; 1 retrospective) was associated with enhanced cognitive function; and statins (N = 112,357; 2 retrospective), which are indicated in HF of ischemic aetiology, were not associated with a significant effect on cognition.

Conclusions: Guideline-recommended HF medication classes appear to have neutral effects on cognitive function, and some may even offer cognitive benefits. However, the limited number and mostly observational nature of studies prevent firm conclusions. Further research is necessary to better understand the cognitive impact of HF medications.

Background and aims: Evidence links body composition and inflammatory markers with type 2 diabetes (T2D). However, the comparative analysis of body composition markers derived from different modalities and inflammatory markers in relation to T2D remains unexplored. This study aims to evaluate and compare the association of body composition and inflammatory markers with T2D.

Methods: We included 4043 participants (2081 female, 51.4%) aged 20-84 enrolled in the population-based Study of Health in Pomerania. Multivariable logistic regression models adjusted for confounding were used to analyse associations of standardized body composition markers derived from classic anthropometry, bioelectrical impedance analysis, magnetic resonance imaging as well as inflammatory markers C-reactive protein, white blood cell count, fibrinogen, ferritin and CRP-to-albumin ratio with prevalent T2D.

Results: Body composition markers were more strongly associated with T2D than inflammatory markers. Waist circumference exhibited the strongest association with T2D (female: odds ratio (OR) = 2.55; 95% confidence interval [CI]: 2.17-3.00; male: OR = 2.20; 95% CI: 1.86-2.60). Similarly, body weight (female: 2.07; 1.78-2.41; male: OR = 1.99; 95% CI = 1.71-2.31), waist-to-height ratio (female: OR = 2.39; 95% CI = 2.05-2.77; male: 2.28; 1.92-2.70) and visceral adipose tissue (female: 3.02; 95% CI = 2.11-4.32; male: 1.50; 1.19-1.89) showed strong associations with T2D. Among inflammatory markers, white blood cell count in male and CRP-to-albumin ratio in female exhibit the strongest association with T2D.

Conclusions: Body composition markers seem to be more tightly associated with prevalent T2D compared to inflammatory markers.