European Journal of Clinical Investigation最新文献

Background: Obesity is a growing epidemic affecting approximately 40% of the adult population in developed countries with major health consequences and comorbidities, including diabetes mellitus and insulin resistance, metabolically associated fatty liver disease, atherosclerotic cardiovascular and cerebrovascular diseases and chronic kidney disease. Pharmacotherapies targeting significant weight reduction may have beneficial effects on such comorbidities, though such therapeutic options are highly limited. In this narrative review, we aim to evaluate current knowledge regarding dual agonist therapies and potential implications for managing fatty kidney and chronic kidney disease.

Results and conclusion: Glucagon-like peptide-1 agonists and sodium-glucose cotransporter-2 inhibitors are two novel classes of glucose-lowering medications with potential implications and beneficiary effects on renal outcomes, including estimated glomerular filtration rate, albuminuria and chronic kidney disease progression. Recently, dual agonist therapies targeting glucagon-like peptide-1 and glucagon receptors, namely survodutide and cotadutide, have been evaluated in managing metabolically associated fatty liver disease, a well-established example of visceral obesity. Fatty kidney is another novel concept implicated in the pathophysiology of chronic kidney disease among patients with visceral obesity.

Background: 4D-CT has garnered attention as complementary imaging for patients with primary hyperparathyroidism (pHPT). Herein we evaluated a diagnostic strategy using [¹⁸F]Fluorocholine Positron Emission Tomography/Computed Tomography (PET/CT), followed by 4D-CT integrated into PET/4D-CT after negative/inconclusive PET/CT results in a single-center retrospective cohort of 166 pHPT patients who underwent parathyroidectomy after [¹⁸F]Fluorocholine PET/4D-CT.

Methods: PET/CT and 4D-CT images were interpreted by three nuclear medicine physicians and one expert radiologist. Pathological findings were documented, and concordance rates were assessed. PET/CT results were categorized as positive/negative, with positive cases rated on a 3-level certitude scale: low, moderate, high. Inconclusive cases included low/moderate positivity. The added value of PET/4D-CT was assessed for negative/inconclusive cases through joint reading.

Results: PET/CT lesion-based analysis showed almost perfect interobserver concordance (Cohen's kappa >.8). Across the cohort, PET/CT had a sensitivity of 83%, specificity of 97%, PPV of 90% and NPV of 94%. For 4D-CT, these values were sensitivity: 53%, specificity: 84%, PPV: 56% and NPV: 82%. PET/CT was significantly more accurate than 4D-CT. Among 44 patients with negative/inconclusive results, PET/CT had sensitivity: 60%, specificity: 91%, PPV: 71% and NPV: 86%. In the same patients, sensitivity and specificity of the sequential diagnostic algorithm increased to 80% and 97%, showing significantly better global accuracy (92% vs. 83%) than standard PET/CT.

Conclusions: We support a personalized imaging algorithm for pHPT, placing [¹⁸F]Fluorocholine PET/CT at the forefront, followed by 4D-CT integrated into PET/4D-CT in the same imaging session for negative/inconclusive results. When PET/CT results are clearly positive, the additional sensitivity benefit of 4D-CT is minimal.

Objective: Eosinophilic granulomatous polyangiitis (EGPA) is a rare autoimmune disease characterized by multisystemic inflammation, with eosinophils playing a central role in its pathogenesis. Traditional management relies heavily on corticosteroids and immunosuppressants, which are associated with significant side effects. The emergence of biologic agents, such as benralizumab, offers targeted therapeutic options by inhibiting the interleukin-5 receptor α, thereby reducing eosinophilic inflammation.

Methods: This systematic review and meta-analysis comprehensively evaluate the efficacy and safety of benralizumab in EGPA patients, focusing on its ability to reduce oral corticosteroid (OCS) use, facilitate remission and spare immunosuppressants. We searched MEDLINE, LILACS and ISI Web of Science databases for relevant studies up to July 2024.

Results: Eight studies, including both randomized controlled trials (RCTs) and observational studies, were included in the meta-analysis, involving a total of 396 EGPA patients. The pooled analysis demonstrated a significant reduction in OCS dose, with an overall estimated effect of -8.25 mg/day (95% CI, -9.39 to -7.10). Complete remission was achieved in 56.8% of patients, and immunosuppressants were reduced or discontinued in 28.1% of cases. Adverse events (AEs) were reported in 21.9% of patients, with only one discontinuation due to an AE.

Conclusion: These findings provide robust evidence supporting the use of benralizumab as an effective and well-tolerated treatment option for EGPA, significantly reducing OCS requirements and offering promising remission rates. Future research should focus on larger, multicentre RCTs to confirm these findings and further elucidate the long-term benefits and safety profile of benralizumab in EGPA.

Ischemia/reperfusion injury is attracting continuous interest in science for two reasons: because it affects several clinical conditions and because it has been identified, albeit in broad terms, the molecular entity becoming activated by the reperfusion damage paradoxes. Indeed, calcium, oxygen-dependent oxidative stress and pH would activate conformational changes in the mitochondrial cristae embedded F₁/F_O ATP synthase, allowing the formation of pores in the inner mitochondrial membrane thus increasing its permeability. This is a key determinant for mitochondrial stress, cell death and tissue dysfunction. Targeting each of these factors has never contributed to improved clinical outcome of the patients affected by reperfusion damage; now, the focus on the PTP opening could represent the closest target to solve this pathway made by extensive cell death when the tissues become revascularized. In this review, we summarized last knowledge about the structure, the modulation and the therapeutic targeting of the PTP, focusing on ATP synthase and cardiac ischemia/reperfusion.

Introduction: The use of medications by emergency medical services (EMS) is increasing. Conventional scores are time-consuming and therefore difficult to use in an emergency setting. For early decision-making, an easy-to-use score based on the medications administered by the EMS may have prognostic value. The primary objective of this study was to develop the prehospital drug-derived score (PDDS) for 2-day mortality.

Methods: A prospective, multicenter, ambulance-based cohort study was conducted in adults with undifferentiated acute diseases treated by EMS and transferred to the emergency department. Demographic data, prehospital diagnosis data, prehospital medication and variables for the calculation of the National Early Warning Score 2 (NEWS2), Rapid Emergency Medicine Score (REMS), and Rapid Acute Physiology Score (RAPS) were collected. The PDDS was developed and validated, establishing three levels of risk of 2-day mortality. The predictive capability of each score was determined by the area under the curve of the receiver operating characteristic curve (AUROC) and compared using the Delong's test (p-value).

Results: A total of 6401 patients were included. The PDDS included age and the use of norepinephrine, analgesics, neuromuscular blocking agents, diuretics, antihypertensive agents, tranexamic acid, and bicarbonate. The AUROC of PDDS was .86 (95% CI: .816-.903) versus NEWS2 .866 (95% CI: .822-.911), p = .828; versus REMS .885 (95% CI: .845-.924), p = .311; versus RAPS .886 (95% CI: .846-.926), p = .335, respectively.

Conclusion: The newly developed easy-to-use prehospital drug-derived PDDS score has an excellent predictive value of early mortality. The PDDS score was comparable to the conventional risk scores and therefore might serve as an alternative score in the prehospital emergency setting.

Background: Platelet receptors ACKR3 and CXCR4 play a crucial role in a variety of cardiovascular diseases. Like most chemokine receptors, CXCR4 is a G protein coupled receptor that induces platelet activation. In contrast, the atypical chemokine receptor 3 (ACKR3) lacks the ability to activate heterotrimeric G proteins and its activation leads to platelet inhibition and attenuates thrombus formation. In nucleated cells, heterodimerization of ACKR3 with CXCR4 regulates CXCL12-dependent signalling. The aim of our study was to investigate the formation of ACKR3/CXCR4 heterodimers in platelets and the subsequent consequences for platelet function.

Methods and results: Using a proximity ligation assay (PLA, Duolink®) to screen for CXCR4/ACKR3 heterodimerization inducing compounds, we found that ACKR3 agonism but not conventional platelet agonists or endogen ligands lead to heterodimer formation. To further characterize the formation of ACKR3/CXCR4 heterodimers, we studied the CXCL12-dependent platelet activation via CXCR4. Both, CXCL12-dependent platelet aggregation and collagen-dependent ex vivo thrombus formation were significantly downregulated by ACKR3 agonism. Moreover, platelet intracellular calcium and Akt signalling were increased by CXCL12 and again suppressed by ACKR3-specific agonists. Previously, CXCL12 was shown to decrease platelet cAMP levels via CXCR4. Treatment with a specific ACKR3 agonist counteracted this CXCL12/CXCR4-dependent cAMP decrease.

Conclusion: Our results reveal that the formation of platelet ACKR3/CXCR4 heterodimers is dependent on ACKR3 rather than CXCR4. Furthermore, ACKR3 agonism induced heterodimerization is associated with mitigating CXCL12/CXCR4-dependent platelet activation possibly by modulating CXCR4-dependent G protein signalling. Our results indicate possible ACKR3 agonist functions and reinforce the potential therapeutic applications of ACKR3 agonists.

Background: Maintaining low concentrations of plasma low-density lipoprotein cholesterol (LDLc) over time decreases the number of LDL particles trapped within the artery wall, slows the progression of atherosclerosis and delays the age at which mature atherosclerotic plaques develop. This substantially reduces the lifetime risk of atherosclerotic cardiovascular disease (ASCVD) events. In this context, plaque development and vulnerability result not only from lipid accumulation but also from inflammation.

Results: Changes in the composition of immune cells, including macrophages, dendritic cells, T cells, B cells, mast cells and neutrophils, along with altered cytokine and chemokine release, disrupt the equilibrium between inflammation and anti-inflammatory mechanisms at plaque sites. Considering that it is not a competition between LDLc and inflammation, but instead that they are partners in crime, the present narrative review aims to give an overview of the main inflammatory molecular pathways linked to raised LDLc concentrations and to describe the impact of lipid-lowering approaches on the inflammatory and lipid burden. Although remarkable changes in LDLc are driven by the most recent lipid lowering combinations, the relative reduction in plasma C-reactive protein appears to be independent of the magnitude of LDLc lowering.

Conclusion: Identifying clinical biomarkers of inflammation (e.g. interleukin-6) and possible targets for therapy holds promise for monitoring and reducing the ASCVD burden in suitable patients.

Background: Investigations of very long-term outcomes after percutaneous coronary intervention (PCI) with drug-eluting stents (DES) according to clinical presentation are scarce. Here, we investigated the 10-year clinical outcomes of patients undergoing DES-PCI according to clinical presentation.

Methods: Patient-level data from five randomized trials with 10-year follow-up after DES-PCI were pooled. Patients were dichotomized into acute coronary syndrome (ACS) or chronic coronary syndrome (CCS) groups as per clinical presentation. The primary outcome was all-cause death. Secondary outcomes were cardiovascular death, myocardial infarction (MI), definite stent thrombosis (ST) and repeat revascularization involving the target lesion (TLR), target vessel (TVR) or non-target vessel (nTVR).

Results: Of the 9700 patients included in this analysis, 4557 presented with ACS and 5143 with CCS. Compared with CCS patients, ACS patients had a higher risk of all-cause death and nTVR in the first year, but comparable risk thereafter. In addition, ACS patients had a higher risk of MI [adjusted hazard ratio 1.21, 95% confidence interval (1.04-1.41)] and definite ST [adjusted hazard ratio 1.48, 95% confidence interval (1.14-1.92)], while the risk of TLR and TVR was not significantly different up to 10-year follow-up.

Conclusions: Compared to CCS patients, ACS patients treated with PCI and DES implantation have an increased risk of all-cause death and repeat revascularization of remote vessels up to 1 year, with no significant differences thereafter and up to 10-year follow-up. ACS patients have a consistently higher risk of MI and definite ST. Whether these differences persist with current antithrombotic and secondary prevention therapies requires further investigation.