European Journal of Clinical Investigation最新文献

Background

Studies implicating dysfunctional mitochondrial respiration in metabolic tissues in the development of insulin resistance in obesity have only included adults. Peripheral blood mononuclear cells (PBMCs) and platelets have been found to reflect systemic mitochondrial fitness and bioenergetic health. We sought to identify bioenergetic differences in PBMCs and platelets from children with obesity and insulin resistance and determine associations with whole-body metabolism and/or biomarkers of metabolic health and inflammation.

Methods

We stratified prepubertal children (ages 5–10 years) into three groups: normal weight insulin sensitive (N-IS; n = 20), overweight/obese insulin sensitive (O-IS; n = 28) and overweight/obese insulin resistant (O-IR; n = 17). We measured oxygen consumption rate and proton efflux rate in PBMCs and platelets. We estimated whole-body resting metabolic rate by bioimpedance and dietary fatty acid oxidation by oral deuterated palmitate and quantifying recovery of D₂O in urine. We used ANOVA for comparisons among groups and Spearman correlations for associations between circulating cell bioenergetics and whole-body metabolism and biomarkers.

Results

O-IS and O-IR PBMCs exhibited increased maximal mitochondrial respiration and spare respiratory capacity compared to N-IS. Bioenergetics shifted towards glycolysis in O-IS PBMCs as compared to both N-IS and O-IR PBMCs. In platelets, glycolysis and ATP production rates were decreased in O-IR compared to O-IS children. PBMC respiration positively correlated with BMIz, HOMA-IR and fasting glucose and insulin, but negatively correlated with inflammatory cytokines. Dietary fatty acid oxidation was higher in O-IS compared to N-IS children and positively correlated with PBMC spare respiratory capacity. Resting metabolic rate correlated positively with several parameters of PBMC mitochondrial respiration.

Conclusions

PBMCs from young children with overweight/obesity exhibit adaptations to the metabolic stressors associated with insulin resistance, and PBMC metabolism correlates well with whole-body metabolism.

Background

The increasing prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), represents a significant public health concern, as it is closely linked to rising obesity rates and metabolic syndrome, affecting approximately 30% of the global population. In addition, MASLD, along with its more severe form, metabolic dysfunction-associated steatohepatitis (MASH), increases the risk of cardio-metabolic diseases and hepatocellular carcinoma. In recent years, multiple G-protein-coupled receptors (GPCRs) have been identified as potential therapeutic targets for these disorders. Additionally, autoimmunity is believed to potentially play a role in the development of mechanisms contributing to the pathogenesis of MASLD/MASH. This narrative review examines the diverse autoantibodies associated with the disease, with a particular emphasis on antibodies targeting apolipoprotein A-1 (AAA-1) and their relationship with anti-GPCRs antibodies.

Results

Several autoantibodies have been identified in up to 30% of individuals with MASLD/MASH, both with and without concomitant autoimmune diseases. Among the anti-GPCR autoantibodies identified in MASLD to date are those targeting the angiotensin II type 1 receptor and the endothelin-1 type A receptor. While the contribution of this class of autoantibodies to MASLD/NASH remains unclear, AAA-1 appears to be pathogenic, acting as pro-steatotic and pro-inflammatory mediators. Additionally, current data suggest shared functional responses between anti-GPCR antibodies and AAA1 in cell-based assays used to detect anti-GPCR presence.

Conclusion

A better understanding of the role of humoral autoimmunity and the interactions among its various components in the metabolic dysfunction underlying MASLD/MASH has the potential to open new perspectives for early detection and therapeutic interventions.

Background

Sex and gender are fundamental determinants of health, influencing disease risk, diagnosis, treatment, and outcomes across medical disciplines. While sex refers to biological characteristics, gender encompasses sociocultural dimensions, including behaviours and identities.

Results

The field of gender medicine has evolved significantly from its roots in the women's health movement of the 1960s and 1970s, which initially sought to address reproductive rights and the systematic exclusion of women from clinical research. Over time, the focus has expanded to recognize sex- and gender-based differences in all populations, including men and gender-diverse individuals. Despite progress, persistent challenges remain. Many clinical guidelines inadequately incorporate sex and gender considerations, and women continue to be underrepresented in clinical trials, resulting in suboptimal efficacy and a higher incidence of adverse effects in women. Recent initiatives, including government-funded research programs, specialized gender medicine professorships and regulatory measures promoting equitable clinical trial participation, represent positive steps forward. However, a systematic, interdisciplinary approach is required to fully integrate gender-sensitive medicine into research, education and clinical practice. This narrative review explores the historical development of gender medicine, current advancements and remaining challenges. We highlight the need for improved research methodologies, policy changes and targeted interventions to ensure equitable healthcare. A structured action plan emphasizing regulatory support, education, industry involvement and public awareness is essential to accelerate the field's integration.

Conclusion

Recognising and addressing sex- and gender-sensitive health differences will lead to more personalised and effective medical care, ultimately improving health outcomes for all individuals.

Background

Chronic kidney disease (CKD) significantly impacts patient well-being, with declining glomerular filtration rate (eGFR) often leading to worsening quality of life (QoL). However, the directionality of the eGFR–QoL relationship remains unclear due to limitations of prior cross-sectional and longitudinal studies.

Methods

This study applied cross-lagged analysis to investigate the reciprocal relationship between eGFR and QoL (measured using SF-36 Physical and Mental Component Scores [PCS and MCS]) over 36 months in 422 CKD patients recruited from nephrology units in Southern Italy. Generalized Method of Moments (GMM) models tested two hypotheses: (1) PCS as a determinant of MCS, or vice versa; and (2) eGFR as a determinant of MCS/PCS, or vice versa.

Results

Cross-lagged analysis confirmed that lower eGFR significantly predicted declines in both PCS and MCS in subsequent visits (p < .05). At the same time, the reverse relationship (QoL affecting eGFR) was not statistically significant. Multivariable models, adjusting for potential confounders including demographic factors, comorbidities, and socioeconomic status, confirmed these findings.

Conclusion

Kidney function decline leads to worsening QoL, whereas deterioration in QoL does not impact eGFR decline. These findings support prioritising interventions that slow the progression of CKD as a means to preserve quality of life. This study highlights the utility of cross-lagged analysis in nephrology research and underscores the importance of early chronic kidney disease (CKD) management to maintain patient well-being.

Background

Clinical associations and prognosis of patients with symptom-controlled AF (scAF) remain poorly understood.

Methods

We analysed data from the Asian-Pacific Heart Rhythm Society and EURObservational Research Programme registries. Based on the European Heart Rhythm Association (EHRA) score, patients were classified as scAF (EHRA I or II) or symptomatic AF (EHRA III or IV). Clinical characteristics were examined by logistic regression, and prognosis was assessed by Cox models. The primary outcome was composed of all-cause death and major cardiovascular events. Interaction analyses were performed to investigate ethnic differences.

Results

Among 13,577 AF patients (mean age 69.0 ± 11.6 years; 38.7% female), 11,470 (84.5%) had scAF. Asians were more likely to be scAF, characterised by younger age and lower cardiovascular burden compared to Europeans. Diabetes mellitus was significantly associated with scAF only in Asians (adjusted odd ratio [aOR] 1.43, 95% confidence interval [CI] 1.03–2.04, p_interaction = 0.021). The associations with hypertension (aOR 1.29, 95% CI 0.98–1.70, p_interaction = 0.004) and prior ischemic stroke (aOR 1.75, 95% CI 0.96–3.58, p_interaction = 0.045) were more evident in Asians.

Patients with scAF showed a notable association with increased likelihood of using vitamin K antagonists (aOR 1.19, 95% CI 1.07–1.33), which was more prominent in Asians. In both Asians and Europeans, scAF was associated with reduced rhythm control management. Compared to non-scAF, European patients with scAF had a reduced risk of the composite outcome, but the association was non-significant in Asians (p_interaction = 0.594).

Conclusion

Asians and Europeans with scAF demonstrate clinically relevant differences in terms of overall prevalence, related risk factors, and clinical management.

Background

Atrial fibrillation (AF), the most prevalent cardiac arrhythmia, is associated with a significantly increased risk of mortality and morbidity from stroke, thromboembolism and dementia. Recent advances in stroke prevention strategies necessitate an updated approach to management.

Results

Published evidence shows that the Atrial Fibrillation Better Care (ABC) pathway significantly improves stroke prevention outcomes in AF patients, reducing mortality, stroke incidence and bleeding events. Characterisation of AF using the 4S-AF framework helped guide personalised treatment selection and was associated with improved clinical outcomes. For patients unsuitable for anticoagulation, left atrial appendage occlusion has been identified as a viable alternative. Digital health technologies demonstrate increasing utility in early AF detection to enable timely stroke prevention interventions. There is evidence for the dynamic nature of stroke (and bleeding) risk, as well as arrhythmia burden and AF progression over time, in addition to changes in ABC pathway adherence.

Conclusions

Effective stroke prevention in AF requires a comprehensive holistic approach incorporating appropriate risk stratification, guideline-adherent anticoagulation and management of underlying cardiovascular conditions and other comorbidities. The ABC pathway, supported by characterisation using the 4S-AF framework, provides a structured approach to optimise outcomes. Regular reassessment of risk, along with careful selection of anticoagulation strategies, remains crucial. Integration of digital health technologies and structured care pathways shows promise in improving patient outcomes.

Background

The role of the gastric microbiome in the pathophysiology of gastritis beyond Helicobacter pylori (HP) infection is poorly understood and has remained unexplored in patients with obesity. The aim of this study was to analyse gastric mucosa-associated microbiota in patients with obesity and nonatrophic chronic gastritis in the absence of HP infection or history of HP eradication.

Methods

This was a case–control study conducted at Virgen de la Victoria University Hospital in Malaga, performed in patients with severe obesity (body mass index ≥40 kg/m²) undergoing sleeve gastrectomy, without HP infection and no history of HP eradication. Gastric biopsy specimens were collected at surgery and were analysed by 16S rRNA sequencing. Participants were divided into two groups according to the histological evaluation: nonatrophic chronic gastritis and nongastritis. An exploratory prospective analysis to determine the influence of gastritis on short-term outcomes after surgery was also performed.

Results

Sixty-seven participants (38 in the gastritis and 29 in the nongastritis group) were included. A lower alpha diversity (evenness and Shannon diversity indexes) and beta diversity (weighted Unifrac distance) were shown in the gastritis group. Higher relative abundances in the families Micrococcaceae, Streptococcaceae and Leuconostocaceae and the genera Streptococcus, Weissella and Cryptobacterium were observed in the gastritis group, compared with the nongastritis group. An enrichment in pathways involved in toluene degradation, heterolactic fermentation and secondary metabolites biosynthesis, such as ergothioneine and terpenoids, was found in the gastritis group. Also, higher total cholesterol levels 1 year after the surgery were observed in the gastritis group compared with the nongastritis group, although no within-group differences from baseline to 1 year were detected in this parameter.

Conclusion

Our results suggest a relationship between the gastric microbiome and nonatrophic chronic gastritis in obesity, beyond HP infection.

Background

This study evaluated whether plasma PCSK9 is associated with coronary plaque progression in patients with coronary artery disease (CAD) and assessed its involvement in molecular processes of atherogenesis.

Methods

Plasma PCSK9 was measured in 159 patients with stable CAD submitted to coronary computed tomography angiography (CTA) at baseline and after a follow-up of 6.5 ± 1.1 years. Plaque progression was defined as the annual increase in Total, Fibrous, Fibro-fatty, Necrotic-Core and Dense-Calcium plaque volumes (PV). Pathways linked with PCSK9 were studied by RNA-sequencing of whole blood and in vitro studies using endothelial cells (EC).

Results

At multivariable analysis, plasma PCSK9 was associated with an annual increase in Necrotic-Core PV (p = .022) independent of cardiovascular risk factors, molecular markers, and medications, including LDL-C and statins. At RNA-seq analysis, PCSK9 was linked to the expression of genes involved in the innate-immune response. Treating EC with PCSK9 resulted in a significant increase in ICAM-1, VCAM-1, MCP1 and IL6 mRNA expression.

Conclusions

In patients with CAD, plasma PCSK9 is associated with progression of Necrotic Core-PV. The link with inflammatory pathways suggested for PCSK9 a potential role for the occurrence of prognostically adverse plaque phenotypes beyond LDL-C regulation.

Background

Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice and the pulmonary vein (PV) is the most important AF trigger. Neuregulin 1β (NRG1β), which is elevated in patients with paroxysmal AF, may activate signalling pathways that mediate cellular adaptations and subsequent stress in the myocardium. The objectives of this study were to study the effects of NRG1β on the PVs and explore the underlying mechanisms.

Methods

A conventional microelectrode, a whole-cell patch clamp, Western blotting and immunofluorescent confocal microscopy were used to investigate electrical activity, calcium (Ca²⁺) regulation, protein expression, ionic currents, reactive oxygen species and cytosolic sodium ([Na⁺]_i) in isolated rabbit PV tissue and single cardiomyocytes with or without NRG1β (10 nM) incubation for 4 h.

Results

NRG1β-treated PVs had faster beating rates and a higher incidence of triggered activity than control PVs. The increased PV spontaneous beating rate induced by NRG1β could be mitigated by ranolazine (a late Na⁺ current inhibitor, 10 μM), KN93 (1 μM) and AIP (1 μΜ) (CaMKII inhibitors) and AKTi (AKT-1/2 inhibitor, 10 μM). NRG1β-treated PV cardiomyocytes demonstrated larger late Na⁺ and Na⁺-Ca²⁺ exchanger current than control PV cardiomyocytes. AIP decreased late Na⁺ current in NRG1β-treated PV cardiomyocytes. Furthermore, NRG1β-treated PV cardiomyocytes had smaller intracellular Ca²⁺ transients and reduced sarcoplasmic reticulum Ca²⁺ contents, but higher levels of [Na⁺]_i, oxidative stress and RyR-dependent SR Ca²⁺ leak than control PV cardiomyocytes. The increased RyR-dependent SR Ca²⁺ leak by NRG1β could be alleviated by KN93. Additionally, NRG1β–treated PV cardiomyocytes exhibited upregulated AKT, pAKT, ERK, pERK, CaMKII and pCaMKII, while SERCA2a and PLB were downregulated. AKTi can downregulate oxi-CaMKII and CaMKII in NRG1β–treated PV cardiomyocytes.

Conclusion

By modulating electrophysiological characteristics, Ca²⁺ homeostasis, and enhancing oxidative stress through AKT/CaMKII signalling, NRG1β increased PV arrhythmogenesis with increasing RyR-dependent SR Ca²⁺ leak of PV cardiomyocytes.