bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multi-omics integration analysis identifies pathogenic candidate genes of congenital heart defects with vascular malformation
Authors: Ding X W , Huang J X , Chen Y H , Li Z Y , Wu Y Z , Qian Z L , Feng W Q , Li Y R , Zhao L D , Zhao P J , Lu Y N , Yu Y 
Published: October 2024

Abstract

Background
Congenital heart defects (CHD) with vascular malformation harbors numerous genetic and epigenetic aberrations of DNA copy numbers and methylation. Proteomic deregulation by the aberrations plays key driver roles in heterogeneous progression of CHD. However, it still remains largely unknown about integrative analysis of genetic, epigenetic regulation and proteome in CHD.

Purpose
We employed a multi-omics approach to explore pathogenic candidate genes in CHD with vascular malformation.

Methods
Previously, we gathered WES data for 216 CHD patients with vascular malformation and 100 healthy controls. Meanwhile, we carried out DNA methylation analysis from 11 patients and 5 controls. Here, we profile proteomics of vascular tissues from 11 patients and 5 controls. Integration analysis of DNA copy-number-correlated (CNVcor) genes, methylation-correlated (METcor) genes and differentially proteins reveal the innovative and crucial pathogenetic genes. We then detected spatiotemporal expression patterns of candidate genes in zebrafish embryos using in situ hybridization and qPCR, and verified the roles in vascular development by morpholino-mediated gene knockdown.

Results
90 differentially expressed proteins (DEPs) were obtained using proteomics and were mainly related to cell adhesion and migration, angiogenesis, amino acid metabolism, and HIF-1 signaling pathway through GO and KEGG pathway enrichment analysis. 15 hub proteins were identified by WGCNA analysis (Fig 1). Additionally, we found that the frequencies of the aberrancies of the CNVcor genes were significantly correlated with the METcor genes (Fig 2 C). We obtained 1924 differentially CNVcor genes and 952 differentially METcor genes. Then, we computed the Pearson’s correlation coefficients of all three-omics by pairwise comparison and found that the distribution of correlations was bimodal (Fig 2 D). Meanwhile, 28 overlapped genes were observed among three-omics. We screened out 11 candidate genes (TIMP1, BGN, LTBP1, AKR1C3, LOXL3, MAOA, MAOB, GNA12, IFI30, CNTNAP1, IGF2BP1) according to the node degree of PPI network analysis between 28 genes and known vascular development related genes. We further figured out LOXL3, MAOA, CNTNAP1 and IGF2BP1 are the novel important genes for vascular malformation, of which CNTNAP1 is the joint gene of three-omics. Through expression patterns and gene knockdown in zebrafish embryos, we revealed that LOXL3, MAOA, CNTNAP1 and IGF2BP1 affect vascular development (Fig 2 E-G).

Conclusions
We identify novel key candidate genes (LOXL3, MAOA, CNTNAP1 and IGF2BP1) potentially related to CHD with vascular malformation and elucidate the possible molecular pathogenesis of CHD. Our multi-omics integrative analysis provides new insights on the multi-layered etiology of CHD, which might be helpful in developing clinical diagnosis and precaution for CHD.Figure 1Figure 2
Pregnancy in women with congenital heart disease : new insights into neonatal risk predictioc
Authors: Rahnama N , Ben Jemaa N , Colson A , Pasquet A , Houard De Castro L , Debieve F , Pierard S 
Published: October 2024

Abstract

Background
Advances in managing adult congenital heart disease (ACHD) have led to an increased number of women with CHD reaching childbearing age. This demographic shift underscores the need for improved understanding and prediction of complications during pregnancy in this specific ACHD population. Despite progress in maternal cardiac risk assessment, the prediction of neonatal outcomes for ACHD pregnancies remains underdeveloped. Therefore, the aims of this study are (1) to assess neonatal outcomes in a CHD women population, (2) to identify their predictive factors and (3) to propose a new risk score for predicting neonatal complications.

Methods
This registry study included all women born between 1975 and 1996 diagnosed with ACHD who underwent at least one cardiology consultation for ACHD in Cliniques Universitaires Saint-Luc. A multivariate analysis was performed to identify predictors of neonatal complications and these were incorporated into a new risk index. Its validity was assessed using bootstrap method. This score was then compared with scores adapted from the ZAHARA and CARPREG studies for offspring events prediction.

Results
Analysis of 491 pregnancies revealed 31.4% of neonatal complications. Four significant predictors of adverse neonatal outcomes were identified: cardiac treatment during pregnancy (OR 14.9, 95%CI [4.6-64.3]), hypertensive disorders of pregnancy (OR 10.4, 95%CI [3.4-39.5]), smoking during pregnancy (OR 10.3, 95% CI [3.0-44.9]), and pre-pregnancy BMI &lt; 18.5 kg/m² (OR 6.2, 95% CI [2.6-16.5]). The risk model demonstrated an AUC of 0.70 (95% CI [0.65-0.75), which remained stable after bootstrap validation. This model significantly outperformed the scores adapted from ZAHARA and CARPREG data. Based on the regression coefficients, a risk score was subsequently developed comprising 5 risk categories.

Conclusion
One third of ACHD pregnancies are complicated by poor neonatal outcome. These complications are determined by 4 independent factors relating to the cardiac and non-cardiac status of the patients, which have been incorporated into a risk score. Our study is one of the first to propose a predictive risk score of neonatal outcomes in ACHD pregancies, and paves the way for other validation and confirmation studies.Offspring scores: performance comparisonNew risk score for neonatal outcome
Mortality and survival rate in a scottish cohort of adults with congenital heart disease
Authors: Metwaly S , Astengo F , Lennie V 
Published: October 2024

Abstract

Background
Adult patients with congenital heart disease (ACHD) experience higher rates of morbidity and reduced long-term survival in comparison to the general population. The care of this cohort of patients requires specialist expertise which is mainly delivered at tertiary centers.

Aims
We aim to report the clinical characteristics, mortality rates and causes of death in a contemporary cohort of ACHD patients followed up in a North- East Scottish Health Board.

Methods
We prospectively followed up ACHD patients aged ≥17 years (n=645) under review at the Regional NHS ACHD Clinic in a North- East Scottish Health Board between the years 2020 and 2023. We recorded the number and the causes of death as documented on our electronic records and on correspondence with primary care physicians. Survival analysis was performed according to the 2020 ESC Guidelines classification of congenital heart disease complexity (Table 4) classes using Kaplan-Meier method with log-rank (Mantel-Cox) test done in IBM SPSS v.24.

Results
Our ACHD cohort (n=645, 54% females and 46% males) included patients of all three ESC complexity classes (30% mild, 60% moderate and 10% severe). Between 2020 and 2023, 18 patients (2.8%) died, with a total incidence of 0.93 deaths/100 patient years. Median age of death was 59 years (IQR 45–71), and the majority of deceased patients were males (56%). There were 2 deaths in the mild complexity group, 11 deaths in the moderate complexity group and 5 deaths in the severe complexity group (See Table 1). This was found to correspond to an incidence of 0.34, 0.95 and 2.64 deaths/100 patient years respectively. The leading causes of death were heart failure (28%) and malignancy (22%).
Using Kaplan-Meier survival analysis we found that the survival distributions for the mild, moderate and severe ACHD complexity groups were statistically significantly different by log-rank test (χ2(2) = 11.47, p &lt; .005) (See Figure 1). Patients with moderate ACHD complexity had a median survival age 67 years (95% CI 58.1-75.9), patients with severe ACHD had median survival age 57 years (95% CI 44.7-69.2). Median survival could not be calculated for the mild group due to lack of data points.

Conclusion
The ACHD patient group is characterised for a variety of pathophysiology and clinical presentations. They require lifelong medical input and in spite of the local and national expertise, the mortality and morbidity rates are still high. Heart failure was the leading cause of death in this cohort which is similar to previous reported data. Mortality rates were proportional to the complexity of the underlying ACHD diagnosis. The survival rate of patients in the severe complexity group was ten years less than the moderate complex group. ACHD patients in the moderate and severe complexity groups have significantly reduced life expectancy and require access and clinical expertise from National ACHD Specialty Centers.
Long-term outcome after Mustard procedure at young age: longitudinal follow-up of 40 to 48 years after surgery
Authors: Unluturk S , Kauling R M , Cuypers J A A , Van Den Bosch A E , Bogers A J J , Kardys I , Roos-Hesselink J W 
Published: October 2024

Abstract

Objectives
To evaluate the long-term clinical outcome and quality of life up to 48 years of patients with Transposition of the Great Arteries (TGA) after Mustard procedure at young age. Primary outcome was defined as a composite endpoint of death, re-intervention, clinically relevant heart failure or arrhythmia, ischemic stroke and endocarditis.

Methods
Single center, longitudinal cohort study evaluating consecutive patients with TGA who underwent Mustard procedure before the age of 15 between 1973 and 1980 at our medical center, the Netherlands. Survival of all eligible patients was obtained. All eligible patients were invited for in hospital evaluation and underwent extensive cardiac and psychological evaluation every 10 years. The latest evaluation took place in 2021 and 2022.

Results
The original study cohort consisted of 91 consecutive patients. Cumulative survival at 48 years (95% complete) was 62% and significantly decreased compared to the general Dutch population (p&lt;0.001). Cumulative survival at 48 years in hospital survivors was 66%. Mortality rate was 0.19 per 100 patient-years. Thirty-four patients (77%) of the eligible 44 survivors (71% male, median age at study 46 years) were included in the present study. Median follow-up since initial surgical correction was 46 (range 40-48) years. Event-free survival at 48 years was 14%. Overall, 34 patients underwent re-intervention of which 3 in the last 10 years (predominantly Baffle revision). In total, 29 patients had supraventricular tachycardia and 11 patients had ventricular tachycardia of which 8 and 4 respectively occurred in the last 10 years. Alltogether, 22 patients had symptomatic heart failure of which 9 occurred in the last 10 years. Cardiac magnetic resonance imaging (n=11) showed a median systemic right ventricular ejection fraction (sRVEF) of 35% [32-40%]. In 73% of the patients, sRVEF fraction was below 40%. Echocardiography showed a diminished sRVEF in all patients. VO2max was reduced in 95% of all patients. Self-perceived quality of life (SF-36) generally was comparable to the general Dutch population with the exception of domain general health (p&lt;0.001).

Conclusion
Late mortality, and especially morbidity of hospital survivors after Mustard procedure was substantial, with an event free survival of only 14% at 48 years. Re-intervention and symptomatic arrhythmia were often reported. The function of the systemic right ventricle was diminished and VO2max was also reduced. The burden of heart failure increased drastically in the last decade. Therefore, intensive follow-up of these patients is warranted.
Late pseudo-aneurysms after coarctation repair with extra-anatomic ascending-descending aortic bypass surgery
Authors: Bonassin Tempesta F , Santos Lopes B , Greutmann M 
Published: October 2024

Abstract

Background
Extra-anatomic ascending-descending aortic bypass operations are an alternative to difficult aortic arch reconstruction in patients with complex aortic coarctation. Reported short-term results are favorable, however, data on long-term outcomes are sparse. The aim of our study was to report long-term outcomes in affected adult patients.

Methods
We identified all adults with extra-anatomic ascending-descending aortic bypass surgeries followed at our center. Outcomes were assessed by chart review with a specific focus on formation of late pseudo-aneurysms and requirement for redo surgery.

Results
We identified a total of 12 adults (67% males) with previous ascending-descending aortic bypass surgery. These patients account for 12/171 (7%) of adults with aortic coarctation followed at our center. 10/12 patients (83%) had undergone coarctation repair by different repair techniques before ascending-descending aortic bypass surgeries. Median age at ascending-descending aortic bypass surgery was 17 years (range: 7-42 years). Prosthetic conduit sizes ranged from 12-22mm. In long-term follow-up, 11/12 patients (92%) required antihypertensive medication (median 2 antihypertensive drugs, 50% ≥ 3 drugs). A total of 5/12 patients (42%) required redo-surgery for formation of pseudo-aneurysms (figure 1) at graft anastomoses (4 proximal anastomosis at ascending aorta, 1 distal anastomosis to descending aorta) at a median age of 47.6 years (28.2-65.0 years) and a median of 22.1 years (range: 14.7-24.6 years) after the initial extra-anatomic ascending-descending aortic bypass operation (figure 2). Two of these patients required redo-operations / interventions for recurrent pseudo-aneurysms at 26 and 33 months after the redo-operations.

Conclusions
Although reported short- and medium-term outcomes after ascending-descending aortic bypass surgery for complex aortic coarctation are favorable, our data suggest a high rate of pseudo-aneurysm formation late (&gt;10 years) after surgery. Our data highlight the need for careful long-term (life-long!) follow-up of these patients at specialized centers.
The impact of exercise training in Fontan procedure patients: a systematic review and meta-analysis
Authors: Katsuyama E , Fukunaga C , Falco Neto W , Vitte S , Tenorio D 
Published: October 2024

Abstract

Background
Patients undergoing the Fontan procedure experience long-term complications related to decreased exercise capacity. Exercise training(ET) has emerged as a non-pharmacological solution for increasing cardiorespiratory fitness. However, the effect and safety of exercise training in patients following the Fontan procedure are still unclear.

Objectives
We aimed to perform a meta-analysis comparing ET versus no exercise intervention for patients following Fontan operation in efficacy and safety outcomes.

Methods
We systematically searched PubMed, Embase, and Cochrane databases on November 23, 2023, for randomized controlled trials (RCTs) comparing ET, including aerobic, endurance, or inspiratory muscle training, versus no exercise intervention in patients following Fontan operation. We computed mean differences (MD) with a 95% confidence interval (CI) for continuous endpoints. The primary endpoint was (1) peak O2 consumption. Our study also included the secondary endpoints of: (2) maximum workload; (3) peak heart rate(HR); and (4) peak saturation of O2. We performed a subgroup analysis between different exercise therapies.

Results
This meta-analysis included five RCTs and 154 patients. Follow-up ranged from 3 to 6 months. Regarding ET, two studies used aerobics, one used endurance, and three used inspiratory muscle therapy as exercise therapy for patients with Fontan operations. Our findings on the maximum workload endpoint were more significant for exercise therapy (MD 20.98W; 95% CI 5.32 to 36.65; p&lt;0.01; Fig. 1A) compared to no intervention group. However, there was no significant difference in peak oxygen (MD 2.03 ml/kg/min; 95% CI -0.29 to 4.35; p=0.095; Fig. 1B), peak HR (MD 1.10 bpm; 95% CI -4.07 to 6.27; p=0.68); and peak saturation of O2 (MD 0.39%; 95% CI -1.93 to 2.72; p=0.74). A subgroup analysis between different ET types (aerobic vs. endurance vs. inspiratory muscle training) showed no significant subgroup interaction(p=0.91; Fig. 1B).

Conclusion
In this meta-analysis, ET is associated with a slight increase in maximum workload in patients following the Fontan procedure. Further multicenter RCTs are warranted to assess the efficacy of comparing different types of ET and their impact on peak oxygen consumption.
Antithrombotic treatment in univentricular heart
Authors: Ozturk A G , Dellborg M , Damlin A , Giang K W , Mandalenakis Z , Sorensson P 
Published: October 2024

Abstract

Background
Univentricular heart (UVH) corrected with Fontan surgery may be associated with an increased risk of thrombosis. Data regarding optimal thrombotic prevention strategy after Fontan surgery in patients with UVH is scarce, and guidelines for antithrombotic treatment are not yet available.

Purpose
The aim was to evaluate the prevalence of antithrombotic treatments and their relation to mortality in patients with Fontan circulation.

Methods
A total of 5,075 patients with UVH were identified using data from the Swedish National Patient Register, the Cause of Death Register, and the National Prescribed Drug Register. Patients with UVH born in Sweden between 1970 and 2017 who underwent Fontan surgery were included. The study population was divided into three groups based on medication: anticoagulation therapy, antiplatelet therapy, and no therapy. Incidence rate (IR) was reported per 1000 person-years and calculated as the total number of deaths divided by total follow-up time. Confidence interval (CIs) for IR was estimated with Poisson regression. Kaplain-Meier was used to estimate the survival probability of 95% for UVH. The Stratified Cox proportional hazards model was used to estimate hazard ratios (HR) with 95% CI.

Results
The total cohort consisted of 864 patients of which 280 individuals (32%) had hypoplastic left heart syndrome (HLHS). The median follow-up time was 14.4 (IQR 3.9;24.9) years, maximum follow-up time was 47 years. Out of all the patients, 36% received no anticoagulation or antiplatelet therapy. Among those who did receive therapy, 75% were treated with antiplatelets. The patients who had no therapy had a higher mortality rate. During long-term follow-up, patients with UVH had higher survival rates when treated with antiplatelets.

Conclusion
Antithrombotic therapy, in particular antiplatelet therapy, was associated with the highest survival in patients with UVH as compared to no treatment. Our data suggest that antithrombotic treatment, and in particular antiplatelet treatment, could be considered in patients with UVH.Survival with Antithrombotic treatment
Is it useful to washing stored red blood cells in cardiopulmonary bypass priming fluid for neonatal cardiac surgery
Authors: Wang H 
Published: October 2024

Abstract

Background
The small blood volume and immature physiology of neonates necessitate careful consideration of the priming fluid composition during cardiopulmonary bypass (CPB) surgery, as it has a substantial impact on their physiologic stability. This study aimed to investigate the impact of allogeneic stored RBCs processed by an autotransfusion system into the CPB priming fluid for neonatal cardiac surgery.

Methods
This retrospective cohort study investigated the effects of incorporating unwashed (n=56) or washed (n=45) RBCs into the CPB priming fluid for elective neonatal cardiac surgery. We compared perioperative blood parameters, inflammatory mediators, coagulation indicators, vasoactive inotrope score (VIS), other relevant blood parameters and clinical outcomes between the two groups. The regression models were employed to evaluate the independent association between RBCs washing and prognostic outcomes.

Results
The autotransfusion system can effectively improve the quality of stored RBCs. During CPB, washed group exhibited higher peak hematocrit (P &lt; 0.01), peak hemoglobin (P = 0.04), increased oxygen delivery index during rewarming (P &lt; 0.05). The washed group exhibited significantly lower early postoperative lactate levels and VIS scores (P &lt; 0.05). Despite demonstrating fluctuations in inflammatory (IL-6, IL-8, IL-10）and coagulation parameters(DD, FIB, FDP) compared to baseline, the two groups exhibited no significant divergence. Notably, the washed group experienced a lower incidence of hyperlactacidemia and delayed sternal closure at weaning from CPB.

Conclusions
The addition of washed allogeneic stored RBCs to neonatal CPB priming fluid significantly attenuated postoperative lactate elevation and lowered VIS without improving early alterations in the inflammatory and coagulation systems.
Blood biomarkers to detect functional impairment in adult patients with repaired Tetralogy of Fallot
Authors: Alborikan S , Badian S , Althunyyan A T , Pandya B , Bhan A , Cullen S , Prista Monteiro R , Bingcang R , Encarnacion D , Bhattacharyya S , Petersen S , Vonklemperer K , Lloyd G 
Published: October 2024

Abstract

Background
The relationship between plasma brain natriuretic peptide (NT-proBNP) and soluble suppression of tumorigenicity-2 (sST2) with structural adaptions and exercise capacity remains incompletely described in patients with repaired Tetralogy of Fallot (rTOF).

Methods
Peripheral venous blood samples were drawn for 99 patients with repaired TOF, 59 patients with severe pulmonary regurgitation (PR) and 40 patients with no or mild PR. NT-proBNP was measured using enzyme-linked immunosorbent assays (Roche Diagnostics, Indianapolis, IN). Soluble ST2 levels were assessed on Aspect-plus ST2 quantitative rapid test.

Results
The mean value of NT-proBNP was 160±137 pg/ml, and sST2 was 29±13, ng/ml in the entire population. Mean NT-proBNP was significantly higher in patients with severe PR (169±150 vs145±118, pg/ml, p&lt;0.001), while similar sST2 levels were observed in both groups (29±14 vs30±12, ng/ml, p&gt;0.05). NT-proBNP and sST2 levels were higher in patients with transannular patch when compared to other RVOT intervention. Both biomarkers were significantly associated with exercise capacity, but NT-proBNP (r=-.60, p&lt;0.001) was stronger. The optimal cut-off of 90pg/ml for NT-proBNP had a sensitivity of 74% and specificity of 63% for detection of impaired exercise capacity.

Conclusions
Serum levels of sST2 and NT-proBNP are elevated in patients with repaired TOF, with higher values observed in those with severe PR, but also in patients undergoing transannular patch. Incorporating both markers in these patients increased the ability to detect impairment in exercise capacity.