bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hemodynamic effects of right and biventricular pacing during exercise in hypertrophic obstructive cardiomyopathy
Authors: Ahmed T A , Ross S , Helle-Valle T , Gude E , Holm T , Lyseggen E , Andreassen A K , Broch K , Ravnestad H , Almaas V M , Haugaa K H , Edvardsen T , Kongsgaard E , Stokke M K , Dejgaard L A 
Published: October 2024

Abstract

Background
One third of patients with hypertrophic cardiomyopathy present with dynamic left ventricular outflow tract obstruction (LVOTO), referred to as hypertrophic obstructive cardiomyopathy (HOCM). Symptomatic treatment aims at reducing LVOTO with either medications, invasive septal reduction, or pacing. The importance of pacing site is unclear, and effects of pacing during physical activity have not been investigated.

Purpose
To determine the effect of right ventricular (RV) and biventricular (BiV) pacing, respectively, on LVOTO and cardiac output (CO) during exercise in patients with HOCM.

Methods
Patients with symptomatic HOCM, sinus rhythm, and no bundle branch block, scheduled for alcohol septal ablation (ASA), were eligible for inclusion. The day before ASA, we placed temporary pacing leads in the right atrium, the RV apex, and on the left ventricle’s lateral wall via the coronary sinus. LVOTO was assessed by echocardiography, and CO was measured by thermodilution with a pulmonary artery catheter. Patients performed supine cycling for 2 minutes until heart rate (HR) increased ≥20 bpm. We measured LVOTO and CO in sinus rhythm, and during cycling with atrial sensed RV pacing, and atrial sensed BiV pacing. The order of pacing sites was randomized, and the personnel performing echocardiography and CO measurements were blinded to the order of pacing.

Results
We included six patients (54±15 years) with a mean maximal left ventricular wall thickness of 16.7±1.8 mm. Resting LVOTO was 55.7±30.9 mmHg. The figures show LVOTO and CO in sinus rhythm (HR 85±10 bpm), RV pacing (HR 90±10 bpm), and BiV pacing (HR 91±9 bpm) during supine cycling. The LVOTO declined from 56±34 mmHg in sinus rhythm to 27±12 mmHg and 25±5 mmHg respectively for atrial sensed RV and BiV pacing. CO remained unchanged during sinus rhythm (9.0±1.2 L/min), atrial sensed RV pacing (9.0±1.7 L/min), and BiV pacing (8.9±1.5 L/min).

Conclusion
In this ongoing study evaluating cardiac pacing in HOCM, preliminary data indicate that both RV and BiV pacing are effective in reducing LVOTO during exercise, without compromising CO.
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

Abstract

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&lt;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&gt;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&lt;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

Abstract

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

Abstract

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 &lt; 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

Abstract

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

Abstract

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&lt;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

Abstract

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

Abstract

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&lt;0.001), and more frequently reported musculoskeletal red flags of CA, such as carpal tunnel syndrome (85 [48%] vs. 53 [20%] years, p&lt;0.001), and spontaneous tendon rupture (39 [22%] vs. 18 [7%] years, p&lt;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

Abstract

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: &lt; or = 7 ng/ml (low H-FABP), &gt;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 (&gt;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&lt;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