bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human in vitro disease modeling of ATTR cardiac amyloidosis
Authors: Qin J , Dokter I , Qiang Y , Lei Z , Sluijter J P G , Oerlemans M I F , Van Mil A 
Published: November 2023

Abstract

Background
Amyloidosis is a systemic protein-folding disorder characterized by extracellular misfolded fibrillar protein aggregates that are insoluble and resistant to proteolysis, leading to progressive and vital organ damage [1]. Transthyretin amyloidosis (ATTR) is one of the primary amyloidosis types that affect the heart. Based on the TTR gene sequence, ATTR is further classified into wild-type ATTR (ATTRwt) and hereditary ATTR (ATTRv). Advanced stage TTR amyloid infiltration of the myocardium results in progressive thickening and stiffening of the ventricle wall, and symptoms of restrictive cardiomyopathy and congestive heart failure. Due to the lack of specificity of cardiac amyloidosis symptoms, misdiagnosis and delays in diagnosis are common, resulting in worsening symptoms, organ damage, and increased mortality [2]. Despite the development of several disease-modifying agents [3], current experimental cell and animal models do not adequately represent the human situation, thereby limiting disease understanding and therapeutic discovery.

Purpose
This project aims to develop an in vitro ATTR disease model, which is critical to define early disease stages and disease progression, map human disease-specific pathways, and screen for novel drugs or validating cutting-edge therapeutic strategies.

Methods
Recombinant WT-TTR and V122I mutated TTR (V122I) were prepared using E.coli protein production system. TTR purification and acid-mediated TTR-fibril were characterized by SDS-PAGE, Thioflavin T fluorescence measurement, and transmission electron microscope (EM). iPSC-derived cardiomyocytes (iPS-CMs) were differentiated using GiWi protocol as described [4,5]. iPS-CMs or HUVECs were seeded on TTR or TTR-fibril, and we measured beating rate, cell viability (AlamarBlue and LiveDead), and cell/fibril morphology using immunofluorescence.

Results
Purified recombinant WT and V122I TTR was successfully generated (Figure 1A). Fluorescence increase (Thioflavin T) and EM revealed the presence of TTR-fibril (Figure 1B). iPS-CMs seeded on TTR-fibril resulted in a dose- and time-dependent increase in cell death. Confocal microscopy revealed the attachment of TTR-fibril on iPS-CMs, leading to sarcomere disarray, loss of cell-to-cell coupling, resulting in irregular beating (Figure 2A). Additionally, we found drastically affected viability of HUVECs upon TTR-fibril exposure (Figure 2B).

Conclusion
Here, we demonstrate an established method to generate purified TTR and TTR-fibril. TTR-fibril attached to the surface of iPS-CMs decreased cell viability and functionality. Similar reduction in HUVEC viability were observed as well. These findings reflect the cytotoxicity of TTR-fibril in a human in vitro model.TTR and TTR-fibril characterizationCell viability up TTR-fibril exposure
Sex-related disparities in cardiac masses: clinical features and outcomes
Authors: Pizzi C , Di Iuorio O , Angeli F , Bergamaschi L , Cavallo D , Impellizzeri A , Canton L , Amicone S , Bertolini D , Casuso M , Foa A , Rinaldi A , Paolisso P , Galie N , Sansonetti A 
Published: November 2023

Abstract

Background
Cardiac masses (CM) represent a heterogeneous clinical scenario. Sex-related differences of these patients remain to be established. Purpose: To evaluate sex-related disparities in CMs regarding clinical presentation and outcomes.

Material and Methods
Thestudy cohort included 321 consecutive patients with cardiac mass enrolled in our Centre between 2004 and 2022. A definitive diagnosis was achieved by histological examination or, in case of cardiac thrombi, with radiological evidence of thrombus resolution after anticoagulant treatment. All-cause death at follow-up was evaluated. Multivariable regression analysis was performed to assess potential prognostic disparities between men and women.

Results
Out of 321 patients with CM, 172 (54%) were female. Women were more frequently younger (p=0.02) than men. Regarding CM histotypes, females were more frequently affected by benign masses (with cardiac myxoma above all), while metastases were more common in men (p&lt;0.001). At presentation, peripheral embolism occurred predominantly in women (p=0.03). Echocardiographic features such as greater dimension, irregular margin, infiltration, sessile mass and immobility were far more common in men. Despite a better overall survival in women, no sex-related differences were observed in the prognosis of benign or malignant masses. In fact, at multivariate analyses, sex was not independently associated with all-cause death. Conversely, age, smoking habit, malignancy and peripheral embolism resulted independent predictors of mortality.

Conclusion
In a large cohort of heart masses, a significant sex-related difference in histotype prevalence was found: benign CMs affected female patients more frequently, while malignant tumours affected predominantly men. Despite better overall survival in women, sex does not influence prognosis in benign and malignant masses.
Need an endomyocardial biopsy? Call your electrophysiology team
Authors: Fitzpatrick N , Tovmassian L , Calvert P , Ness N , Mc Connon N , Luther V , Rao A , Mahida S , Dobson R , Fairbairn T , Cooper R , Ntouskou M , Ali N , Gosney J , Modi S 
Published: November 2023

Abstract

Introduction
With significant advances in targeted chemotherapeutic options for soft tissue tumours, obtaining a tissue diagnosis is more important than ever. Primary and secondary cardiac tumours are rare [1] and endomyocardial biopsy of these tumours has been sparsely reported [2-9]. Advanced tools in cardiac electrophysiology happen to lend themselves well to cardiac tumour biopsy. Our electrophysiology (EP) guided endomyocardial biopsy (EMB) service includes electrophysiologists, cardio-oncology specialists, cardiac imaging specialists, oncologists, and pathologists. For the last 9 years all targeted endomyocardial biopsies in our tertiary institution have been undertaken by our EP guided EMB service with extensive experience in electroanatomical mapping (EAM), visualisable sheaths and integrated intracardiac echography (ICE). We report the findings.

Methods
We performed a retrospective review of all cases referred to the EP guided endomyocardial biopsy service at our centre and identified those with attempts to biopsy a cardiac mass. We describe the incorporation of advanced electrophysiology techniques utilised by the service. Specifically, the use of intracardiac echocardiography integrated into an electro-anatomical mapping system and bioptome delivery via a visualisable, deflectable sheath. This allows for the real time 3D visualisation of the target mass, surrounding anatomy and position of the bioptome during biopsy.

Results
Of 38 patients who underwent targeted biopsy at our centre, a total of 8 patients (5 female; mean ± SD age 54 ± 21 years) were referred for cardiac tumour biopsy, undergoing a total of 9 procedures (mean ± SD duration 116 ± 21 mins). Table 1 details the patient’s pertinent history and underlying pathology, the tumour site, possible alternative biopsy sites, a summary of techniques and technologies utilised and the eventual diagnosis. In 100% of cases, tissue was sampled from the desired location, though in two patients the histological result was inconclusive due the retrieval of necrotic tissue or fibrotic tissue only. This translated into a definitive histopathological diagnosis in 75% of patients. One patient experienced a transient right bundle branch block during the procedure, in all others the procedures were uncomplicated. Image 1 exemplifies some of the cases with pre-procedure imaging results and intra-procedural views from both ICE and the EAM.

Conclusion
In this study, our approach to utilising the combination of intracardiac echocardiography integrated into an electro-anatomical mapping system and bioptome delivery via a visualisable, deflectable sheath appears safe, and provides unparalleled accuracy in endomyocardial sampling of cardiac tumours.Table 1Image 1
Atrial septal defect patients have an elevated risk for infective endocarditis
Authors: Muroke V , Jalanko M , Haukka J , Patila T , Hartikainen J , Tahvaneinen A , Ukkonen H , Ylitalo K , Anttila V , Pihkala J , Sinisalo J 
Published: November 2023

Abstract

Background
It has been unclear whether simple atrial septal defect (ASD) is an independent risk factor for infective endocarditis (IE). This study aimed to untangle the risk of endocarditis in a large nationwide cohort.

Methods
We acquired data from the Finnish hospital discharge register on all individuals with ASD diagnosis from 1969 to 2019. Patients with complex congenital cardiac abnormalities were ruled out. Five individualized controls from the general population were matched to the ASD patient's birth year, sex, and residence at the index date. All the patients with ICD-8, -9, or -10 diagnosis codes for IE were gathered from the hospital discharge registry.

Results
After exclusion, 8322 ASD patients and 39 237 individualized controls were enrolled in the study. Median follow-up was 21.6 years (IQR 11.8-36.9) from the first hospital contact.
In total, 24 (16 male) cases of infective endocarditis among ASD patients and 10 (8 male) cases among controls were diagnosed during the follow-up. The incidence of endocarditis was 0.11 per 1000 person-years in the ASD patients and 0.011 per 1000 person-years in the controls. The adjusted risk ratio for endocarditis was 13.51 (95% CI: 6.20–29.46) in ASD patients compared to the control cohort. Patients with ASD and endocarditis had higher long-term mortality than individualized control patients (MRR 2.25, 95% CI: 1.23-4.11).

Conclusions
The incidence of endocarditis in atrial septal defect patients is higher than in the general population, and ASD seems to carry an increased risk of developing endocarditis.Cumulative incidence of endocarditisSurvival after endocarditis diagnosis
Long-term outcomes and risk factors for reoperation after subaortic stenosis resection in children and adults
Authors: Esposito A , D'anna C , Chinali M , Franceschini A , Brancaccio G , Santilli A , Guccione P , Galletti L 
Published: November 2023

Abstract

Background
Sub-valvular aortic stenosis (SAS) is an extremely heterogeneous form of left ventricular outflow tract (LVOT) obstruction, which can lead to aortic valve damage. Although corrective surgery is considered the most effective treatment, rates of recurrence and reoperation are still high. Previous studies have focused on predictors of reoperation in several subgroups of patients with SAS, but rarely in the whole population of patients with SAS.

Purpose
We sought to describe long-term outcomes after SAS resection and to determine the predictors of reoperation after successful primary resection.

Methods
We retrospectively reviewed the records of patients who underwent SAS resection between 1994 and 2021 at our institution with at least 12 months’ follow-up. Patients with a single-ventricle physiology and idiopathic hypertrophic cardiomyopathy were excluded. Demographic, surgical and echocardiographic data were analyzed. Outcomes were reoperation after successful primary resection, death and morbidities, including postoperative complete heart block and aortic regurgitation (AR) grade at latest follow-up.

Results
Seventy-six patients (paediatric, n = 72 and adult, n = 4) who underwent SAS resection were included in the analysis. Median length of postoperative follow-up was 11.1 years (IQR range: 7.3 – 15.7 years), with two late deaths. Reoperation due to recurrent obstruction or severe AR occurred in 24 patients (31.6%). Median time to reoperation was 7.5 years (IQR range: 3.6 – 11 years). Overall freedom from reoperation at 5 years and 10 years was 84.6% and 69.1% respectively. Gender and association with other cardiac defects did not differ significantly between those with reoperation and those without. In multivariate analysis, independent predictors of reoperation were age at first surgery younger than 5 years (HR 3.54, 95% CI 1.06 – 11.83; P = 0.040) and tunnel-type lesions (HR 4.42, 95% CI 1.70 – 11.51; P = 0.002). Three patients (3.9%) had complete heart block and required placement of an implantable pacemaker. Following SAS resection, progression of AR was common (39/68, 57.3%) but only 5 patients (7.3%) developed sufficient regurgitation to require surgical repair or replacement.

Conclusions
Reoperation is not infrequent after surgical relief of SAS and reaches a plateau after 10 years. Younger age at first surgery and tunnel-type SAS independently predict reoperation. Progression of AR after corrective surgery of SAS is common, but fortunately only a minority of patients develop hemodynamically significant AR requiring reintervention.
Associations of maternal exposure to multiple plasma metals with the risk of fetal congenital heart defects: a prospective nested case-control study
Authors: Nie Z , Ou Y A N Q I U 
Published: November 2023

Abstract

Background
Congenital heart defects (CHDs) are the most common congenital anomalies with complex etiologies. There is knowledge gap with respect to the association between single and combined exposures to multiple heavy metals during pregnancy and the risk of CHDs in the fetus. Thus, we aimed to examine the association between maternal plasma heavy metal concentrations in mid-pregnancy and the risk of CHDs in the fetus.

Methods
A prospective nested case-control study was conducted in a cohort of 11,578 newborns. Exposure odds ratios (ORs) were compared between 164 CHD cases and 164 non-malformed controls delivered at the same hospital, individually matched by maternal age (±5 years) and parity. Concentrations of 21 metals were determined in maternal peripheral blood plasma via an ultra-performance liquid chromatography inductively coupled to mass spectrometry (ICP-MS). Single- and multiple-metal logistic regressions, the adaptive least absolute shrinkage and selection operator (LASSO) penalized regression analysis and restricted cubic spline (RCS) analysis were applied to explore the associations and dose-response relationships of plasma metals with CHD. We also applied Bayesian Kernel Machine Regression (BKMR) model to evaluate the cumulative effect of the exposure metals.

Results
Median (interquartile range, IQR) Vanadium (V) [0.3 (0.3-0.4) vs. 0.3 (0.3-0.4) μg/L, P = 0.027] and cadmium (Cd) [0.1 (0.0-0.1) vs. 0.1 (0.0-0.1) μg/L, P = 0.036] levels were different between the CHDs and control groups. Compared with the first quartile, the Directed acyclic graph(DAG) model-adjusted ORs (95% CI) were 3.12 (1.72-5.64) for kalium (K), 2.21 (1.23-3.94) for manganese (Mn), 0.55 (0.33-0.94) for cerium (Ce), 1.96 (1.06-3.64) for lead (Pb) in the second quartile, and ORs (95%CIs) were 1.88 (1.08-3.26) for V, 0.53 (0.30-0.93) for Cr, 1.92 (1.10-3.35) for copper (Cu), 2.09 (1.18-3.70) for Cd, 2.14 (1.24-3.70) for stannum (Sn) and 3.05 (1.69-5.49) for Pb in the third quartile. In the multi-metal model, compared to the lowest quartile, the ORs for Sn and Pb in the second quartile were 1.32 (95% CI: 0.69-2.55) and 1.94 (95% CI: 0.98-3.84), respectively, and the ORs for both metals in the third quartiles were 2.15 (95% CI: 1.16-3.98) and 3.32 (OR=0.66, 95% CI: 1.68-6.55), suggesting that Sn and Pb had relatively stable positive results with a linear dose progression. BKMR models with 2 cluster for 9 metals showed that the overall effect of metal mixture was not statistically significant at or below 35th percentile and at or above the 70th percentile, compared to their median levels. Pb was the major contributor to the combined effect.

Conclusions
Elevated level of plasma plumbum was associated with increased risk of CHDs. Further investigations in larger perspective cohorts are needed to confirm our findings.fig 1fig 2
Risk stratification of non-cardiac surgeries in adult congenital heart disease
Authors: Fischer A J , Koeppe J , Gerss J , Freisinger E , Reinecke H , Baumgartner H , Diller G 
Published: November 2023

Abstract

Background
Adults with congenital heart disease (ACHD) face multiple surgeries throughout their lifetime. Data on the specific risk of undergoing non-cardiac surgery and impact of severity of ACHD on outcome are limited. We aimed to assess frequency and outcome of non-cardiac surgery and to identify ACHD patients specifically at risk.

Methods
Based on data including all hospital admissions in Germany from 2011 to 2018, we identified all ACHD cases that were admitted for non-cardiac surgery. Non-cardiac surgery was categorized in low-, medium and high-risk based on a clinically implemented risk score validated for non-congenital cardiac patients. The analyzed data contained information on patient demographics, diagnoses, in-hospital complications, and mortality. The primary endpoints of the study were major adverse cardiovascular events (MACE), major infection, major bleeding, thromboembolism and in-hospital death. Outcomes of ACHD were compared to a propensity score matched cohort of non-ACHD.

Results
Overall, 13,041 ACHD inpatient cases were included in the analysis (simple n=9,333 (72%), moderate n=2,741 (21%), and complex heart defects n=966 (7%)). 23.0% simple ACHD underwent low-risk surgery, whilst 31.1% were intermediate and 45.0% high-risk procedures. In the medium complexity ACHD cohort, 35.8% received low-risk, 42.3% intermediate risk and 21.8% high-risk surgery. In complex ACHD, 42.4% underwent low-risk, 41.2% intermediate risk and 16.4% high-risk surgery. Simple ACHD more frequently presented with typical cardiovascular risk factors such as dyslipidemia, arterial hypertension and diabetes mellitus compared to moderately and severely complex ACHD at time of non-cardiac surgery (p&lt;0.001 for all). Compared to a propensity score matched cohort of non-ACHD, congenital cardiac patients more often met the endpoints with an increasing frequency depending on complexity of disease and pre-defined risk of surgery. After adjustment on multivariable logistic regression analysis, moderate and severe complexity of the congenital cardiac defect was associated with an adverse outcome. Risk for death was increased in moderately complex (OR 1.44, 95% CI 1.15 - 1.81, p=0.001) and severely complex ACHD (OR 2.28, 95% CI 1.63 - 3.20, p&lt;0.001) compared to non-ACHD. Compared to low-risk surgeries, patients were at increased risk for death when undergoing mid- (OR 7.66, 95% CI 5.18 - 11.34, p&lt;0.001) or high-risk surgeries (OR 8.03, 95% CI 5.42 - 11.90, p&lt;0.001).

Conclusions
ACHD patients are at increased risk of adverse complications when undergoing non-cardiac surgery. Risk for adverse outcomes increased with complexity of disease and was generally higher than in non-ACHD individuals. The presented data show that surgical risk classifications implemented for non-congenital cardiac patients were also associated with a much higher adverse outcome in cases undergoing high- versus low-risk procedures.
Neo-aortic dimensions and coronary take-off angle in adolescent and young adult patients with transposition of the great arteries after the arterial switch operation
Authors: Verheijen D , Engele L J , Stoger J L , Mertens B , Koolbergen D R , Hazekamp M G , Jukema J W , Egorova A D , Vliegen H W , Bouma B J , Jongbloed M R M , Kies P 
Published: November 2023

Abstract

Objective
Aim of this study was (1) to assess the relation between neo-aortic dimensions and coronary angle take-off in adult patients with transposition of the great arteries (TGA) late after the arterial switch operation (ASO) and (2) to evaluate if temporal increase in the neo-aortic dimensions is associated with a decrease of the coronary angle take off.

Methods
In this retrospective two-center cohort study, all patients with TGA who underwent ASO and had ≥1 CT-angiography (CTA) of the coronary arteries at the age of ≥ 16 years old were included. Neo-aortic dimensions and coronary angle take-off were measured with CTA, Figure 1.

Results
Eighty-one patients, 69% male and median age 21.0 (18.5-22.8) years, were included. Maximum neo-aortic diameter was 39.2±5.3mm (corrected for BSA 20.9±2.7mm/m2). Sixty-one (76%) patients had a coronary take-off angle of &lt;45° at baseline. No correlation between the maximum neo-aortic diameter and coronary take-off angle of the right coronary artery (RCA) (R=0.161, p=0.150) and left coronary artery (LCA) (R=0.089, p=0.428) was found, Figure 2A-B. During a mean follow up of 7.9±3.1 years in patients with 2 CTAs (n=26), the average increase of maximum neo-aortic diameter at the level of sinus of Valsalva was 0.16±0.20mm/year and a poor correlation between the change in maximum aortic diameter and change in coronary take-off angle of the RCA (R=0.126, p=0.541) and LCA (R=0.311, p=0.158) was observed, Figure 2C-D.

Conclusions
This study reports slightly increased neo-aortic dimensions and high prevalence of acute coronary angle take-off in young adults late after ASO. The average neo-aortic growth rate of 0.16 mm/year at the level of the sinus of Valsalva is twice as fast as reported for healthy adults. However, no significant correlation was found between the neo-aortic dimensions and coronary take-off angle at baseline or during follow-up of almost 8 years in this group.Figure 1Figure 2
Fractional flow reserve in anomalous aortic origin of coronary arteries to evaluate hemodynamic consequences of high risk anatomical features
Authors: Verheijen D , Egorova A D , Jongbloed M R M , Voskuil M , Van Der Kley F , Kies P , Vliegen H W 
Published: November 2023

Abstract

Introduction
In patients with anomalous aortic origin of a coronary artery (AAOCA) fractional flow reserve (FFR) can be performed for further risk stratification of myocardial ischemia and sudden cardiac death. The aim of this study was to evaluate the hemodynamic consequences (accessed with FFR) of the high-risk anatomical features in AAOCA.

Methods
In this prospective cohort study, all consecutive patients with AAOCA in whom diagnostic work-up according to the MuSCAT trial, including FFR, was performed between July 2020 and January 2023 in our tertiary AAOCA referral center, were included. Presence and length of the intramural segment was assessed using the interluminal space (ILS) on the CTA and orifice geometry using IVUS.

Results
Thirty patients, 57% female and mean age at AAOCA diagnosis of 48.7±15.3 years, were included. Twenty-seven (90%) patients presented with an anomalous aortic origin of the right coronary artery. FFR adenosine was measured in all patients (Figure 1), and showed a significant relation with: 1. hypoplasia of the proximal segment on CTA (R=0.400, p=0.029); 2. the ILS at 2mm from the ostium on CTA (R=0.517, p=0.003); 3. the length of the intramural course on CTA (R=0.500, p=0.005); 4. the orifice shape on IVUS (R=0.460, p=0.011) and 5. the minimal lumen area on IVUS (R=0.371, p=0.044).

Conclusions
FFR was significantly reduced in AAOCA with the following high-risk anatomical features: increased hypoplasia of the proximal segment on CTA, lower ILS at 2mm from the ostium on CTA, longer intramural course on CTA, increased slitlike orifice shape on IVUS and lower minimal lumen area on IVUS. These anatomical high-risk features appear to be hemodynamically relevant in the pathophysiology of AAOCA.Figure 1