bluuebunny/crossref_metadata_2025 huggingface dataset:
Genotype-phenotype relationship in hypertrophic cardiomyopathy
Authors: Zebrauskiene D , Sadauskiene E , Puronaite R , Masiuliene R , Kundelis R , Barysiene J , Jakaitiene A , Preiksaitiene E
Published: October 2024

Background/Introduction

Hypertrophic cardiomyopathy (HCM) is an inherited highly heterogeneous disease with variable penetrance and expression, but the exact relationship between the underlying genetic cause and the clinical course remains elusive.

Purpose

The aim of our study was to analyse the phenotypic and molecular characteristics of individuals with HCM examined and treated at our University Hospital.

Methods

Clinical data from adult HCM patients treated at our hospital between 2005 and 2023 were analysed. Informed consents to participate in the study were obtained from all participants. Clinical manifestation, instrumental examination and next generation sequencing (NGS) data of HCM related genes were collected. The Mann–Whitney U for two groups and Kruskal–Wallis tests for more than two groups were used to compare continuous variables. Univariate logistic regression was used to analyze categorical variables.

Results

The study involved 191 unrelated individuals, 58.6% males, the median age at HCM diagnosis was 50, interquartile range 37 – 60 years. A median follow-up was 3.9 [1.6-6.4] years. Pathogenic and likely pathogenic (P/LP) variants were identified in 45.5% (N=87) of affected individuals. Truncating variants were observed in 31 individuals. MYBPC3 P/LP variants were the most common (N=47), following by MYH7 (N=22) and other (N=18). Individuals with MYBPC3 P/LP truncating variants had higher HCM estimated 5-year risk of sudden cardiac death (SCD) during primary evaluation (3.1 [2.5-4.6]) compared to individuals with P/LP variants in other genes (2.4 [1.9-3.7]) and individuals with negative NGS results (1.8 [1.5-2.7], p<0,001). Patients with MYBPC3 P/LP variants experienced the earliest onset of symptoms (median age 37.0 [30.5-50.0] years) and HCM diagnosis (median age 38.0 [31.0-51.5] years) compared to individuals with other genes P/LP variants (median age 46.0 [31.0-56.2] years and 47.5 [31.5 – 59.5] years, respectively) and genotype negative individuals (median age 51.5 [44.0-61.0] years and 52.0 [45.0-63.2] years, respectively), p>0,001). The presence of P/LP variant was associated with significantly thicker left ventricular wall (maximal thickness) on cardiac imaging in comparison with negative NGS results (18.0 [15.0-21.0] mm vs. 16.0 [14.0-18.0] mm, p=0.002 on transthoracic echocardiography and 20.0 [17.0-22.5] mm vs. 18.0 [16.0-20.0] mm, p<0,001 on cardiac magnetic resonance). The presence of MYBPC3 truncating variants were associated with the greatest risk of ventricular tachycardia in comparison with negative NGS results (OR 3.05, 95% CI:1.3, 8.0, p=0.025).

Conclusion

More severe HCM phenotype is associated with detection of P/LP variants in HCM related genes. The presence of the MYBPC3 P/LP variant is associated with an earlier onset of the disease and truncating variants of this gene are related to a higher risk for ventricular tachycardia and an estimated 5-year risk of SCD.
Modulating TTN gene expression in human iPSC-CMs to investigate mechanisms and therapies in TTN-associated dilated cardiomyopathy
Authors: Kirk R B , Sparrow A J , Hooper C , Steeples V , Toepfer C N , Watkins H
Published: October 2024

Background

Familial dilated cardiomyopathy (DCM) is a common and harmful condition, and no available therapies target the underlying genetic mechanisms. Truncating variants in TTN are the most commonly identified genetic cause of DCM. However, it remains unclear how TTN variants drive disease. Contemporary thinking identifies haploinsufficiency, dominant negative effects, or a combination of both as likely driving mechanisms. There is competing evidence as to whether I-band and A-band mutations differ in severity or in the relative roles of haploinsufficiency and dominant-negative effects. Clarifying disease mechanisms will help pave the way to targeted genetic therapies.

Purpose

To modulate TTN gene expression in human-induced stem cell-derived cardiomyocyte (hiPSC-CM) models of TTN-associated DCM carrying I-band or A-band variants to provide insight into the comparative roles of haploinsufficiency and dominant negative mechanisms in DCM, and to identify novel therapeutic strategies.

Methods

We used CRISPR-Cas9 gene-editing to generate hiPSC lines with known disease-causing heterozygous truncating mutations in the I-band or A-band of TTN. These were screened for off-target mutations and pluripotency. hiPSCs were differentiated into hiPSC-CMs for phenotyping. We assayed TTN mRNA and titin protein levels. We trialled approaches for modulating TTN expression including CRISPR activation.

Results

Two hiPSC lines with heterozygous mutations in the I-band and A-band of TTN were generated using CRISPR/Cas-9 gene-editing. These hiPSC lines were successfully differentiated into hiPSC-CMs. Both cell lines demonstrated unchanged TTN mRNA expression compared to wildtype controls, but had reduced expression of full-length titin protein and identifiable truncated protein products. TTN mRNA expression was subsequently increased in these models using modulators of gene expression.

Conclusions

hiPSC-CM models of DCM with truncating mutations in the I-band or A-band of TTN were generated and phenotyped. These models were then used to trial gene expression modulation methods. This provides a human cellular system that can be used to better understand disease mechanisms of TTN-associated DCM, with the ultimate aim of establishing gene therapies for TTN-associated DCM.
Clinical value of anti-DSG2 antibodies in arrhythmogenic right ventricular cardiomyopathy: a real-life experience
Authors: Borowiec K , Joseph S , Wozniak O , Chatterjee D , Fatah M , Silbiger V , Kowalik I , Skrzypczynska-Banasik U , Kowalik E , Kowalski M , Biernacka E K , Hamilton R M
Published: October 2024

Background/Introduction

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited myocardial disease leading to ventricular arrhythmias and heart failure. The diagnosis is challenging and currently based on a set of clinical criteria with limited sensitivity and specificity. Anti-desmoglein-2 (DSG2) antibodies were previously found in patients diagnosed with ARVC, while they were absent in both healthy controls and athletes.

Purpose

The study aimed to evaluate the diagnostic value of anti-DSG2 antibodies by comparing their concentration in patients with ARVC and other right ventricular diseases. Additionally, the prognostic value of the biomarker was assessed.

Methods

A cohort of 101 patients with a definite diagnosis of ARVC according to the 2010 Task Force criteria was enrolled (64 males, mean age 47 ± 16 years). The control group included patients with Ebstein anomaly and Eisenmenger syndrome (16 and 21 subjects, respectively). Anti-DSG2 antibody concentration was assessed using enzyme-linked immunosorbent assay (ELISA). After that, an ARVC cohort was followed for 3.9 ± 1.6 years for the occurrence of the primary endpoint of cardiac death or heart transplantation (HTx) and major arrhythmic events (MAEs) defined as ventricular fibrillation, sustained ventricular tachycardia (sVT) or appropriate implantable cardioverter-defibrillator intervention.

Results

The median anti-DSG2 antibody concentration presented as ELISA optical density (OD) reached 1.36 [0.54-2.15] in the ARVC cohort, while it was 0.4 [0.34-0.54] in Ebstein anomaly group and 0.36 [0.28-0.58] in the Eisenmenger syndrome group. There was a significant difference in antibody levels between ARVC and both control groups (p < 0.001, Figure 1). The cutoff value for the diagnosis of ARVC was 0.774, with 72.3% sensitivity and 100% specificity (AUC = 0.823).

After dividing the ARVC cohort according to the designated cutoff point, the anti-DSG2-positive subgroup was significantly younger (44.5 ± 15.4 vs. 52.8 ± 15.5 years, p = 0.017) and more likely to have a history of sVT (68.5% vs. 46.4%, p = 0.041). There was no difference regarding sex, presence of PKP2 or DSG2 mutations, previous sports activities, history of sudden cardiac arrest or syncope, right ventricular dimensions and systolic function, left ventricular ejection fraction and heart failure symptoms. This threshold was not predictive for the primary endpoint and MAEs. However, a more stringent cutoff value for anti-DSG2 level (1.021) was found to predict death or HTx (HR [95% CI] 4.56 [1.05-19.76], p = 0.026, Figure 2).

Conclusions

The concentration of anti-DSG2 antibodies is significantly higher in ARVC compared to other right ventricular diseases. A high antibody level is prognostic for death or HTx in ARVC.Figure 1Figure 2
Hereditary transthyretin amyloidosis caused by Val142Ile variant in Spain: phenotypic characteristics, geographic distribution and population frequency
Authors: De Frutos Seminario F , Peiro Aventin B , Eiros R , Limeres Freire J , Sevilla T , Carbayo A , Llongueras P , Garcia-Alvarez A , Ripoll-Vera T , Macias R , Vilches S , Ruiz-Bustillo S , Arana Achaga X , Gayan Ordas J , Gonzalez-Costello J
Published: October 2024

Background

During recent years, several cases of hereditary transthyretin amyloidosis (ATTRv) due to p.Val142Ile have been described in patients without African ancestry in countries like Japan, Spain or Italy (1,2,3,4). All this evidence suggests that p.Val142Ile might be more prevalent than expected worldwide.

Objectives

The aim of this study was to analyze the impact of ATTRv caused p.Val142Ile in Spain to define its phenotypic characteristics, to explore endemic geographical areas and define its population frequency.

Methods

Patients diagnosed with ATTRv caused by p.Val142Ile and carriers irrespective of their phenotype were recruited from 16 centers in Spain. Baseline characteristics and events during follow-up were retrieved. Population frequency was assessed through the Spanish National DNA bank (N=3,569) and the Catalan Health Databank (N=790).

Results

The cohort included information regarding 164 subjects (75 probands [45.7%] and 89 relatives [54.3%]). Among probands, mean age was 73.9 ± 8.5 years and 47 (62.7%) were males. 67 probands (89.3%) had self-declared European ancestry and only 6 cases (8%) referred African or Afro-American ancestry. Cardiac symptoms were the most frequent reason leading to ATTRv diagnosis (N=64, 85.3%) followed by incidental finding (N=8, 10.7%) and neurologic symptoms (N=3, 4%). (Figure 1). Median follow-up was 1.6 years (Interquartile range 0.6-3.2). Neurologic involvement was observed in 35 probands (46.7%) at first evaluation or during follow-up. Overall penetrance at 65, 75 and 85 years was 12.8%, 44.3% and 94.2% respectively. Male sex was associated with earlier penetrance than women (P = 0.02). 38 patients initiated treatment with tafamidis during follow-up (28 [73.7%] 20 mg and 10 [26.3%] 61 mg), despite treatment, disease progression at 1 year (cardiovascular death or 30% increase of NTProBNP) was observed in 10 patients (40%). Population frequency was estimated between 0.0% and 0.12% based on the Spanish and Catalan databases respectively. Birthplace of probands suggests a higher prevalence in the Mediterranean basin. (Figure 2)

Conclusions

Our data suggests that ATTRv caused by p.Val142Ile has a significant prevalence in Spain, mostly in some specific regions. Phenotypic features are defined by late onset, male predominance, and cardiac involvement although a significant proportion develop neuropathy. Disease progression was observed in 40% of patients despite disease-modifying therapies.
In-depth morphological and functional analysis of ATTR-CA myocardial cells and niche by electron microscopic 3D reconstruction
Authors: Sawaki D , Matsumura T , Kamioka M , Komori T , Harada K , Imai Y , Kario K , Ohno N
Published: October 2024

Background

Cell-cell interactions and interplay with extracellular matrix are known to be important in the steady state and pathological conditions, including wild-type transthyretin cardiac amyloidosis (wtATTR-CA). However, alterations of the microstructure of cardiomyocytes (CMs) and cardiac niches have not been well analyzed. Normal histological staining is usually limited in resolution, and 2D electron microscopy cannot capture stereoscopic images or the distribution of target particles and organelles in intra- and extracellular 3D space, so novel methods are being attempted.

Methods and Results

Using Serial Block Face-Scanning Electron Microscopy (SBF-SEM) and a 3D structural reconstruction system, we for the first time investigated the microstructure of human myocardial tissue from control hypertrophied heart (hypertensive heart disease) and wtATTR-CA patients. The microstructure of myocardial niche, cell morphology/numbers, and the distribution of intracellular organelles such as intercalated discs (ICDs) were compared to control endomyocardial biopsy (EMB) samples (2 controls vs 5 wtATTR-CA patients). In all wtATTR-CA samples, amyloid fibers were deposited originating around the capillary structures with various electron densities, compressing myocardial cells not only from the periphery but also dividing them from the center of the cell body, and CMs showed degeneration and dwarfing according to the severity of amyloid fiber deposition (Figure 1). The capillary structures showed degeneration and narrowing with stratified basement membrane, and rarefaction (3378±216.5 vs 1448±116.8/mm2, p<0.0001). Notably, the stromal cells (pericytes, fibroblasts, macrophages) were more likely buried by amyloid fibers than CMs, and their numbers were also reduced, indicating a loss of adjacent and intercellular interaction with capillaries and CMs (Fig. 2, 1892±194.4 vs 1189±107.4 mm2, p=0.0043). This method can also be used to analyze intracellular organelles and microstructures in CMs. In ATTR-CA, morphological abnormalities were observed in ICDs (Figure 3) and mitochondria.

Conclusion

In the ATTR-CM patients, there was a significant decrease in the number of capillaries in accordance with the deposition of myocardial amyloid fibers, as well as a decrease in stromal cells. These results support the hypothesis that amyloid fibril deposition not only causes chronic myocardial ischemia, but also reduces the number of niche cells, which play a supportive role for CM function and entirely exacerbate the damage. The SBF-SEM is an innovative tool for 3D imaging and quantitative analysis of myocardial ultrastructure and functions.Methods & Figure 1Figure 2 and Figure 3
CCTA and CTP imaging for detecting clinically suspected in-stent restenosis: a meta-analysis
Authors: Dahdal J , Jukema R , Remmelzwaal S , Raijmakers P G , Van Der Harst P , Guglielmo M , Cramer M J , Chamuleau S A J , Van Diemen P A , Knaapen P , Danad I
Published: October 2024

Background

The evaluation of coronary artery stents via Coronary Computed Tomography Angiography (CCTA) can be compromised by artefacts, potentially undermining its diagnostic accuracy. The integration of CT Perfusion (CTP) with CCTA (CCTA+CTP) has been proposed to enhance the diagnostic yield in detecting in-stent restenosis (ISR).

Purpose

This meta-analysis aims to assess the diagnostic performance of CCTA and combined CCTA+CTP in detecting ISR.

Methods

A comprehensive literature search of studies from 2005 to 2022 identified 13,747 articles. Inclusion criteria comprised the utilization of multidetector CT scanners with ≥64 slices and invasive coronary angiography as the reference standard. Studies that systematically evaluated stent patency in asymptomatic patients as part of their protocol were excluded.

Results

After removing duplicates, screening titles and abstracts, and conducting full-text reviews, 20 studies met the inclusion criteria (17 CCTA, 3 CCTA+CTP). Data on 2,674 CCTA-assessed stents and 752 CCTA+CTP-assessed stents were analyzed. The meta-analysis revealed that CCTA alone achieved a sensitivity of 90% (95% CI; 84-94%) and a specificity of 89% (95% CI; 86-92%)(Figure 1). CCTA+CTP exhibited comparable diagnostic performance, with a per-stent sensitivity of 88% (95% CI; 80-94%) and a specificity of 88% (95% CI; 84-93%) (Figure 2). The summary Receiver Operating Characteristic (sROC) Area Under the Curve (AUC) was 0.96 (95% CI; 0.94-0.97) for CCTA and 0.96 (95% CI; 0.89-1.00) for CCTA+CTP, indicating a high overall performance for both diagnostic modalities.

Conclusion

Utilizing contemporary imaging hardware, both CCTA and CCTA+CTP demonstrate high diagnostic performance in evaluating ISR. The findings suggest that the presence of coronary artery stents should not preclude the use of these non-invasive diagnostic tests in clinical practice.Figure 1Figure 2
Incidence and clinical characteristics of cardiac amyloidosis in Tuscany and Umbria
Authors: Castiglione V , Chubuchna O , Mandoli G E , Ferrari Chen Y F , Aimo A , Milli M , Palazzuoli A , Carluccio E , Zuchi C , Di Mario C , Ambrosio G , Cappelli F , Emdin M , Cameli M , Vergaro G
Published: October 2024

Background

Recent advances in imaging and increased disease awareness have led to a significant rise in newly diagnosed cases of cardiac amyloidosis (CA) over the past decade. However, there remains a lack of epidemiological data regarding the true incidence of the disease.

Purpose

To determine the incidence and clinical characteristics of newly diagnosed cases of CA in a large Italian population.

Methods

Subjects with suspected CA underwent diagnostic work-up in 20 Centers in Tuscany and Umbria regions within the Cardiac Amyloidosis RegistRY (CARRY), between January 1st 2022 and December 31st 2022.

Results

A total of 551 subjects were enrolled in the registry, with complete data on the final diagnosis available for 448 individuals. CA was diagnosed in 179 patients (40%), with 28 (16%) classified as light chain CA (AL-CA), 114 (64%) wild-type transthyretin CA (ATTR-CA), 12 (7%) variant ATTR-CA, and 25 (13%) undetermined CA. Considering a reference population in Tuscany and Umbria in 2022 (4,518,388, according to the Italian National Institute of Statistics), this yields an estimated cumulative incidence of 39.6 cases per million inhabitants per year. Alternative diagnoses in the remaining patients mostly included hypertensive heart disease (n=157, 58%), hypertrophic cardiomyopathy (n=25, 9%), moderate-to-severe valvular heart disease (n=11, 4%), or a mixed phenotype (n=72, 27%). The primary referral pathway for the suspicion of CA was cardiological (n=345, 77%), followed by incidental finding during screening visits (n=58, 13%), and haematology referral (n=33, 7%). Patients with confirmed CA were older (81 [75-85] vs. 77 [72-83] years, p<0.001), and more frequently reported musculoskeletal red flags of CA, such as carpal tunnel syndrome (85 [48%] vs. 53 [20%] years, p<0.001), and spontaneous tendon rupture (39 [22%] vs. 18 [7%] years, p<0.001). Median time to diagnosis from clinical suspicion was 73 (37-140) days for CA and 84 (36-156) days for alternative diagnoses (p=0.564).

Conclusions

The diagnosis of CA is on the rise globally, with an estimated incidence of 39.6 new cases per million inhabitants per year in two large regions of Italy. These findings should inform policymakers in redefining the status of CA as a rare disease, potentially influencing patient care and treatment costs.
Prognostic utility of heart-type fatty acid binding protein in patients with cardiac amyloidosis
Authors: Li X , He C , Xin A , Huang L , Feng J , Zhou Q , Lu H , Huang Y , Zhang Y
Published: October 2024

Background

Heart-type fatty acid binding protein (H-FABP) is a biomarker that has been shown to provide long-term prognostic information in patients with heart failure (HF), yet its role in patients with cardiac amyloidosis (CA) is unknown.

Purpose

We aim to investigate the association of H-FABP levels with prognosis in patients with CA.

Methods

Consecutive patients diagnosed with cardiac amyloidosis from October 2015 to May 2022 at Heart Failure Center, of our hospital were enrolled. Patients were categorized into 2 categories based on H-FABP levels measured in the baseline blood sample: < or = 7 ng/ml (low H-FABP), >7 ng/ml (high H-FABP). Univariate and multivariate Cox models were used to identify predictors of survival. Kaplan-Meier analysis was performed to compare survival between patients with low or high H-FABP.

Results

Overall, ninety-five patients were included. H-FABP was elevated (>7 ng/ml) in 37 patients (39%). Patients with high H-FABP were more likely to present with higher levels of high-sensitivity troponin-T (hs-TNT)(0.17ng/mL vs. 0.11ng/mL, p =0.01) and higher levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) (18098.76pg/mL vs. 6211.69pg/mL, p<0.001). Patients were followed for an average follow-up period of 440 days, in which 53 (56%) patients died. Univariate and multivariate analysis demonstrated that H-FABP levels (HR 1.48, 95% CI 1.03-2.13, per 1-SD greater) was independently associated with prognosis, even after adjusting for NT-proBNP, hs-TNT and renal function.

Conclusions

Elevation of H-FABP is associated with an increased risk of death in patients with cardiac amyloidosis. H-FABP can serve as a novel biomarker independent of other established predictors for prognosis in cardiac amyloidosis.Kaplan-Meier curves for overall survival
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

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
Unraveling Marfan hearts: ultrastructural evidence for myocardial remodeling and cardiomyopathy
Authors: Deleeuw V , D'hulst S , Demolder A , Steijns F , Renard M , De Rycke R , Van Dorpe J , Muino-Mosquera L , Francois K , Benke K , Szabolcs Z , Sips P , De Backer J
Published: October 2024

Background

Despite improved life expectancy for patients with Marfan syndrome (MFS), significant morbidity and mortality persist. Although primarily attributed to aortic dissection and rupture, recent studies highlight the emerging role of arrhythmias and heart failure as additional contributors to morbidity and mortality in MFS. While severe valvular heart disease is an established cause of heart failure, there is a growing recognition of primary cardiomyopathy in patients with MFS. The mechanisms underlying cardiomyopathy in MFS remain poorly understood.

Purpose

This study aimed to reveal insights into the ultrastructural myocardial architecture in patients with MFS, thereby elucidating the role of cardiomyopathy in MFS.

Methods

This study enrolled 44 patients who underwent cardiac surgery at 2 centers (Marfan syndrome patients n=27 (MFS), ascending thoracic aortic aneurysm repair patients n=5 (non-MFS), patients post-orthotopic heart transplant n=12 (controls)). Myocardial biopsy samples were subjected to histopathological analysis using transmission electron microscopy and conventional histology.

Results

Conventional histological analysis revealed subtle abnormalities in the cardiomyocyte morphology of MFS patients, compared to non-MFS and controls. Overall, a slight increase in interstitial fibrosis and mild myocyte hypertrophy were observed in MFS patients. Ultrastructural examination of both MFS and non-MFS patients revealed significant structural remodeling and degenerative changes in the myocardium. These changes included: extensive myofibril lysis, compromised cell membrane integrity and nuclear chromatin condensation. Degenerative lesions were often accompanied by cytoplasmic debris, lysosomal residual bodies, autophagic vacuoles, and severe mitochondrial pathology. Dense accumulation of glycogen granules and lipofuscin was evident in areas of focal myofibril lysis. Notably, only MFS patients exhibited recruitment of granulocytes, including mast cells, eosinophils and neutrophils. A subset of MFS patients displayed advanced stages of myocardial degeneration. However, these changes did not correlate with clinical myocardial failure.

Conclusions

To the best of our knowledge, this study represents the first evidence of ultrastructural changes in the myocardium of patients with MFS. Our data indicate various degenerative changes in the myocardial architecture, including structural and metabolic myocardial remodeling, along with inflammatory cell infiltration. We believe that our findings of ultrastructural lesions reflect the complexity of myocardial disease in MFS and emphasize the importance of careful surveillance for cardiomyopathy in MFS patients. Further studies are warranted to confirm whether the observed granulocyte influx is specific to MFS and to clarify its role in MFS myocardial disease pathophysiology.Graphical abstract
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

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 < 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

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 < .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

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<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<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

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 (>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

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<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

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

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 < 0.01), peak hemoglobin (P = 0.04), increased oxygen delivery index during rewarming (P < 0.05). The washed group exhibited significantly lower early postoperative lactate levels and VIS scores (P < 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

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<0.001), while similar sST2 levels were observed in both groups (29±14 vs30±12, ng/ml, p>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<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.