European Journal of Clinical Investigation最新文献

Background

Parvovirus B19 (PVB19) has emerged as a relevant etiologic agent of paediatric myocarditis, particularly during recent epidemiological surges in Europe and the United States. Despite increasing recognition, current knowledge remains fragmented, and standardised diagnostic and therapeutic strategies are lacking.

Methods

We conducted a systematic review of the literature up to May 2025, including 40 studies encompassing 53 individual case reports, 107 patients from registry-based cohorts, and 4 tissue-based investigations.

Results

Clinical presentation was frequently fulminant, with cardiogenic shock, severe left ventricular dysfunction, and need for mechanical circulatory support in up to 47% of cases. Mortality rates ranged from 10% to 30%, with heart transplantation rates varying between 5% and 42% across cohorts. Diagnosis relied primarily on blood polymerase chain reaction (PCR), while serology showed limited diagnostic utility. Histological confirmation via endomyocardial biopsy (EMB) was variably applied across studies, and myocardial viral load quantification was reported in only one study. Case series and cohort studies confirmed early age of onset (median 16–24 months), respiratory or gastrointestinal prodromes, and poor outcomes in fulminant presentations. Tissue-based studies revealed high myocardial PVB19 loads in acute myocarditis, particularly in infants, but also demonstrated viral persistence in asymptomatic individuals, complicating causal inference. Immunomodulatory therapy was administered in up to 58% of cases, although its clinical impact remains uncertain due to heterogeneity in treatment protocols. No antiviral treatments have been evaluated to date.

Conclusion

These findings highlight the need for standardised diagnostic criteria incorporating PCR, serology, imaging, and, where appropriate, EMB and viral load assessment. Given recent epidemiologic surges and high morbidity, prospective multicentre studies and surveillance efforts are urgently required to refine clinical algorithms and improve outcomes in paediatric PVB19 myocarditis.

Background

Despite universal coverage, inequities persist in acute coronary syndrome (ACS) care. This study examines how educational levels impact the quality and outcomes of health care.

Methods

A cohort of ACS patients hospitalized in five Swiss university hospitals was categorized into four educational levels (EL) with EL1 defined as lower than vocational school and EL4 as a university degree. The use of medical therapies, achievement of preventive targets and risk of clinical events were evaluated across ELs at baseline (N = 6040), 1-year (N = 5756) and 5-years (N = 2253) and presented with adjusted marginal odds ratios (mOR), average marginal effect (AME) and hazard ratios (HRs).

Results

Among 6040 patients, the mean age was 63 years, and 81% were male. Participants with lower EL had a greater burden of cardiovascular risk factors at baseline. Compared with EL4 participants EL1 participants had lower adherence to cardiac rehabilitation (mOR = .6 [95% CI .5–.8], AME = −10%) and were less likely to be followed by a cardiologist (mOR .6 [95% CI .5–.8], AME = −6%). Use of medical therapies did neither differ across EL at discharge nor during follow-up. At 1 year, smoking cessation (mOR = .7 [95% CI .5–.9], AME = −10%) and weight reduction ≥5% among overweight or obese participants (mOR = .7 [95% CI .5–.9], AME = −6%) were less frequent in individuals with EL1 compared with EL4. At long term, achievement of LDL-C <1.8 mmol/L (<70 mg/dL) (mOR = .6 [95% CI .4–.9], AME = −9%) was less frequent in individuals with EL1 compared with EL4. Lower EL was associated with an increased risk of major acute coronary event (MACE) at short- (aHR = 1.4 [95% CI 1.0–2.0] for EL1 vs. EL4) and long term (aHR = 1.3 [95% CI 1.0–1.6] for EL1 vs. EL4) and all-cause death at long term (aHR = 1.6 [95% CI 1.1–2.2] for EL1 vs. EL4).

Conclusion

In Switzerland, disparities in ACS care and outcomes remain across EL, emphasising the need for tailored interventions to reduce inequities.

Background

Cardiovascular disease (CVD) remains the leading cause of mortality worldwide. The human myocardium has a limited regenerative capacity, prompting the development of innovative strategies to restore cardiac function. Stem cells (SCs) and bioartificial tissues (BATs) have emerged as promising tools in regenerative cardiology for myocardial repair and functional recovery.

Methods

This review analyzes current preclinical and clinical research focused on SC- and BAT-based therapies for CR. Literature was identified through comprehensive database searches. Studies evaluating cardiomyocyte differentiation, integration into host tissue, vascularisation and electromechanical properties were selected. Emphasis was placed on therapeutic potential, safety and translational challenges.

Results

SCs, including embryonic and mesenchymal stem cells, demonstrated potential to differentiate into cardiomyocyte-like cells and contribute to myocardial restoration. When combined with biomaterial scaffolds or decellularized matrices, SCs showed improved survival, structural support, and functional integration. BATs, such as engineered heart tissue, replicated native myocardial architecture and supported synchronized contraction. Despite these advances, concerns persist regarding immunogenicity, arrhythmias, and long-term efficacy. Technical hurdles in large-scale production and personalised application remain unresolved.

Conclusions

SC- and BAT-based therapies offer innovative avenues for repairing damaged myocardium. Their application could revolutionise treatment strategies for heart failure and post-infarction remodelling. However, clinical translation requires addressing immune compatibility, arrhythmic risk and manufacturing limitations. Interdisciplinary collaboration and regulatory standardisation are essential for their future clinical adoption.

Background

The high-density lipoprotein (HDL) and the phospholipid transfer protein (PLTP) have been demonstrated to enhance endotoxin elimination and inactivation in animal models of sepsis. This study aimed to confirm such a role in patients presenting with abdominal sepsis undergoing emergent surgery and explore the relationships between HDL, PLTP and the lipopolysaccharide (LPS) burden (mass and activity).

Methods

Patients operated for abdominal sepsis were prospectively included in the study. Blood samples were obtained before surgery, at the end of the operation (H0), 4 h (H4) and 24 h (H24) later. Peritoneal fluid was also sampled. HDL cholesterol, LDL cholesterol, PLTP activity, LPS mass and activity were measured.

Results

Twenty-seven patients were included. At H0, LPS mass was mostly measured in the lipoprotein fractions (46% [23; 58] in HDL and 36% [29; 54] in LDL). Overall, LPS mass and LPS activity did not decrease in the 24 h following admission to the ICU. Both HDLc concentrations and PLTP activity were associated with increased H4-LPS elimination (drop in LPS concentration, −3% [−26;10] vs. 29% [13;52], p < 0.01 and −2% [−15;10] vs. 20% [8:52], p = 0.03, respectively). Increased H4-LPS elimination was associated with reduced inflammation (plasma cytokine concentration) and mortality. High HDL cholesterol was associated with reduced mortality but not with inflammation.

Conclusion

Our data support the role of HDL and PLTP in the elimination of LPS during human peritonitis with sepsis. Increased H4-LPS elimination was associated with reduced inflammation and lower mortality.

ClinicalTrials.gov: NCT04126577.

Background and Aims

Branched-chain amino acids (BCAA) have gained increasing recognition for their role in liver disease. This study investigated plasma BCAA alterations in patients with cirrhosis and liver transplant recipients (LTRs) and examined their associations with all-cause mortality and new-onset type 2 diabetes in LTRs.

Methods

Plasma BCAA concentrations were measured using nuclear magnetic resonance spectroscopy in 129 patients with cirrhosis and 367 LTRs from the TransplantLines cohort study (NCT03272841), and compared with 4834 participants from the population-based PREVEND cohort. Kaplan–Meier survival analysis and Cox regression analysis were performed.

Results

Total BCAA levels were significantly lower in patients with cirrhosis and LTRs than in PREVEND participants (p < .001). While total BCAA levels increased post-transplant, they remained lower than those in PREVEND (p < .001). The highest total BCAA tertile was associated with better survival versus the lowest BCAA tertile in patients with cirrhosis (log-rank p = .002). In Cox regression analysis adjusted for relevant co-variates, higher total BCAA levels were also associated with reduced mortality in patients with cirrhosis (HR .19 [95% CI: .04–.86], p = .031). In LTRs, the highest total BCAA tertile conferred a higher probability of new-onset diabetes (log-rank p = .004) but was not linked to mortality (log-rank p = .65). After adjusting for age, sex, and immunosuppressant use, the highest tertile of total BCAA levels remained independently associated with new-onset diabetes in LTRs (HR 1.42 [95% CI: 1.10–1.82], p = .006).

Conclusions

Total BCAA levels increase after liver transplantation. In patients with cirrhosis, higher total BCAA levels are associated with reduced all-cause mortality. Although this association is not evident in LTRs, higher total BCAA levels are strongly linked to an increased risk of new-onset type 2 diabetes, warranting further investigation.

Background

Previous studies suggest that afamin is associated with steatotic liver diseases (SLD). However, the exact role of afamin in SLD development and fibrogenesis remains unclear. Potential modifying effects of sex and glucose tolerance status have also not been examined. Therefore, we investigated the associations of afamin with steatotic liver diseases and fibrosis defined by non-invasive tests and assessed for possible effect modifications.

Methods

This study included 3080 participants from the population-based KORA F4/FF4 cohort. Cross-sectional and prospective associations (follow-up time 6.5 years) between afamin and NAFLD liver fat score (NAFLD LFS), hepatic steatosis index, fatty liver index and the fibrosis-4 index were assessed using multiple linear regression models. Models were adjusted for age, sex, body mass index, smoking status, alcohol consumption, physical activity, metabolic parameters, medication and subclinical inflammation.

Results

In the cross-sectional analysis, afamin concentrations were positively associated with NAFLD LFS (β = .32; 95% CI .27–.37), hepatic steatosis index (β = .33; 95% CI .26–.39) and fatty liver index (β = 1.78; 95% CI 1.47–2.08) (all p < .001), but not with fibrosis-4 index. In the prospective analysis, higher afamin levels were associated with a higher increase only in NAFLD LFS (p < .001). Cross-sectional and prospective associations between afamin and NAFLD LFS were more pronounced in men than in women (p_interaction < .001 and .022; respectively). Cross-sectional associations between afamin and NAFLD LFS were also stronger in individuals with prediabetes or diabetes compared to those with normal glucose tolerance (p_interaction < .001).

Conclusion

Higher afamin concentrations are positively associated with NAFLD LFS with potential effect modification by sex and glucose tolerance status.

Introduction

Primary heart involvement (pHI) is an overlooked and poorly characterised complication of systemic sclerosis (SSc), associated with the risk of heart failure, arrhythmia and death. Despite consensus definition by the World Scleroderma Foundation/Heart Failure Association (WSF/HFA), diagnostic criteria and risk factors remain poorly elucidated.

Methods

Out of 1922 patients in the Italian national SPRING registry, we excluded those with potentially confounding conditions according to WSF/HFA, and those with incomplete ECG or echocardiographic assessment, resulting in 600 subjects with clearly defined parameters to intercept SSc-pHI. Cross-sectional and longitudinal analyses were performed to identify factors associated with pHI.

Results

ECG and/or echocardiographic signs of SSc-pHI were identified in 25% of patients at enrollment and were associated with older age (OR 1.04; 95% CI 1.02–1.06), diffuse cutaneous SSc (OR 1.85; 95% CI 1.05–3.26) and intestinal symptoms (OR 1.79; 95% CI 1.03–3.08). Diastolic dysfunction (62%) and conduction disturbances (34%) were the most frequent phenotypes, while diffuse hypokinesia with reduced ejection fraction was the least common (3%). During follow-up, new-onset signs of pHI were observed in an additional 25% of patients, particularly in those with skeletal muscle involvement (HR 2.83; 95% CI 1.01–7.73).

Conclusions

pHI is a severe complication potentially affecting one-quarter of patients with SSc. Early detection is crucial, particularly in those with diffuse skin fibrosis, muscular involvement and intestinal manifestations.

Background

Atrial fibrillation (AF) is associated with a prothrombotic state. We investigated whether factor VIIa-antithrombin (FVIIa-AT) complexes, a marker of tissue factor (TF) exposure, are associated with thromboembolic events in AF.

Methods

In 224 nonvalvular AF patients (66% men, median age 69 years, median CHA₂DS₂VASc score 4), 71% on direct oral anticoagulants, we measured FVIIa-AT complexes, along with endogenous thrombin potential (ETP), von Willebrand factor (VWF) and 8-isoprostane, reflecting oxidative stress. During a median follow-up of 53 [interquartile range, IQR 47–57] months, we recorded a composite endpoint: ischemic stroke, systemic thromboembolism or cardiovascular (CV) death.

Results

FVIIa-AT complexes (median 145 [IQR 125–170] pM) were higher in patients with permanent AF (p < .001), vascular disease (p = .02), previous stroke (p < .001) and smoking (p = .006) as compared with patients without these comorbidities. FVIIa-AT correlated with NT-proBNP (r = .15, p = .022) and ETP (r = .25, p < .001). During follow-up, the composite endpoint was recorded in 30 patients (13.4%, 3.0% per year) including 20 with ischemic stroke (8.9%, 2.0% per year, respectively). Patients with the composite endpoint had 29.2% higher baseline FVIIa-AT complexes compared with the remainder. Patients with FVIIa-AT complexes in the top quartile (>170 pM) had an increased risk of the composite endpoint (HR 12.0, 95% CI 5.2–28.0, p < .0001). FVIIa-AT complexes, along with VWF, remained independently associated with the composite endpoint.

Conclusions

This study is the first to show that high plasma FVIIa-AT complexes are independently associated with thromboembolic events or CV death in AF, suggesting the need for more potent anticoagulation to suppress the residual TF-mediated coagulation.

Background

Diabetes of the exocrine pancreas (DEP) is an underdiagnosed form of diabetes, prevalently caused by acute and chronic pancreatitis (CP). The contribution of incretin system dysfunction and the role of glucagon levels in the pathogenesis of DEP remain unclear. The aim of our study is to assess the secretion of glucagon like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP) and glucagon, along with the incretin effect, in individuals with and without CP. By comparing these parameters within the same glucose tolerance class, we seek to elucidate specific hormonal alterations that characterize DEP.

Methods

To pursue this aim, we conducted a cross-sectional study on 32 patients with chronic pancreatitis (wCP) and 60 patients without chronic pancreatitis (w/oCP), who were administered an oral glucose tolerance test, a hyperglycemic clamp and a mixed meal test with measurement of glucose, insulin, C-peptide, GLP-1, GIP and glucagon.

Results

The comparison between individuals wCP and w/oCP showed worse beta-cell function and lower incretin effect for the former, but incretin and glucagon levels were similar. Diabetes prevalence was higher in the group wCP than in the group w/oCP (56% vs. 33%). Thus, to evaluate the differences determined by CP, we found it necessary to stratify individuals according to glucose tolerance class. After stratification, we found that both groups had similar beta-cell function, incretin effect and incretin and glucagon secretion.

Conclusions

Therefore, incretin and glucagon levels and the incretin effect varied according to glucose tolerance, not the presence or absence of CP. Similar defects in incretin secretion and effects are responsible for diabetes development in individuals wCP and w/oCP.