bluuebunny/crossref_metadata_2025_split huggingface dataset:
Myocardial single photon emission computed tomography imaging to identify non-responders to cardiac resynchronization therapy in patients with non-left bundle branch block
Authors: Nakamura T , Ishibashi K , Ueda N , Oka S , Miyazaki Y , Wakamiya A , Nakajima K , Kamakura T , Wada M , Inoue Y , Miyamoto K , Nagase S , Aiba T , Kusano K 
Published: October 2024

Abstract

Background
Non-response to cardiac resynchronization therapy (CRT) is an important issue in the treatment of heart failure with reduced ejection fraction (HFrEF) and non-left bundle branch block (LBBB). Although the QRS duration and morphology are crucial parameters for selecting CRT candidates, electrocardiogram (ECG) markers may inadequately represent the mechanical activation patterns within the heart. Owing to limitations associated with the ECG criteria, there is increasing interest in advanced multimodality imaging to improve patient selection. Recently, myocardial single-photon emission computed tomography imaging (G-MPI) is used for assessing left ventricular (LV) dyssynchrony. This technique is mostly automatic and has high intra- and inter-observer reproducibility and repeatability.

Objectives
This study aimed to examine whether preoperative G-MPI evaluation could predict non-responsiveness to CRT in patients with HFrEF with non-LBBB.

Methods
Between January 2021 and December 2022, 128 patients underwent CRT, of whom 73 with pre-operative evaluation using G-MPI were selected. Forty-three patients with non-LBBB (21 and 22 CRT responders and non-responders, respectively) were assessed. These patients were divided into CRT responder and non-responder groups. We evaluated the cut-off and clinical impact of pre-operative G-MPI parameters in predicting non-responsiveness to CRT. In addition, 30 patients with LBBB were analyzed.

Results
Among patients with non-LBBB, CRT responders and non-responders showed no significant differences in baseline characteristics, except for the LV dimension. A receiver operating characteristic curve analysis identified 108° and 27.7° as the optimal cut-offs for the bandwidth and phase standard deviation (SD), respectively, to predict non-responsiveness to CRT (area under the curve [AUC]=0.762; 95% confidence interval [CI]: 0.601–0.923 and AUC=0.742; 95% CI: 0.576–0.909, respectively). A multivariate analysis revealed that a cut-off bandwidth of ≥108° and phase SD of ≥27.7° are independent predictors of non-responsiveness to CRT in patients with non-LBBB (hazard ratios 5.65; 95% CI: 1.53–20.9; P=0.009). In contrast, there were no relationships between G-MPI parameters and non-responsiveness to CRT in patients with LBBB.

Conclusions
Pre-operative G-MPI findings were associated with non-responsiveness to CRT in patients with non-LBBB. The identification of potentially nonresponsive patients could influence patient management and alter outcomes.
Significant correlation between the extent of myocardial fibrosis and heart failure parameters in patients undergoing transcatheter aortic valve implantation
Authors: Yamaguchi K , Matsushita K , Terasaka K , Hanajima Y , Tsustsumi K , Kirigaya H , Nakahashi H , Gohbara M , Kimura Y , Okada K , Ebina T , Cho T , Uchida K , Sugano A , Hibi K 
Published: October 2024

Abstract

Background
Recent studies have demonstrated that the prognosis of patients undergoing transcatheter aortic valve implantation (TAVI) is determined by the presence of myocardial fibrosis. The aim of this study was to quantify myocardial fibrosis in tissues obtained through myocardial biopsy before TAVI and to evaluate the relationship between the extent of myocardial fibrosis and baseline cardiac parameters.

Methods
We performed a retrospective single-center study, including 93 patients who underwent cardiac biopsies before TAVI from December 2022 to December 2023. The extent of myocardial fibrosis was assessed on Masson’s trichrome-stained tissue specimens, using a validated software "ImageJ".

Results
Median percent area of myocardial fibrosis in the entire cohort was 4.7% (interquartile range: 2.5 - 7.9). A significant correlation was found between the extent of myocardial fibrosis and brain natriuretic peptide (r= 0.41 p=0.0001), left ventricular ejection fraction (r=0.34, p=0.0009), aortic valve area index (r=0.33, p=0.0017), and global longitudinal strain (r=0.52, p&lt;0.001). Patients who experienced prior heart failure hospitalization had a significantly larger extent of myocardial fibrosis (3.3% vs. 7.0%, p=0.0002).

Conclusions
Extensive myocardial fibrosis was associated with various heart failure parameters in patients undergoing TAVI. Patients with a large extent of myocardial fibrosis may require early intervention and/or intensive heart failure medical therapy to prevent fibrosis progression.
Deletion of mitochondrial DNA methyltransferase 1 contributes the development of murine heart failure under pressure overloaded
Authors: Omiya S , Otsu K 
Published: October 2024

Abstract

Background
Mitochondrial DNA (mitDNA) has similarities to bacterial DNA, which contains inflammatogenic unmethylated CpG motifs. We found that mitDNA that escapes from autophagy causes inflammatory response and heart failure under pressure overload. DNA methyltransferase 1 (DNMT1) maintains methylation patterns in somatic cells. Deletion of DNMT1 results in embryonic lethality in mice and mitotic catastrophe in cultured cells. Additional possible translational start sites (ATG1, ATG2) are located upstream of the commonly accepted nuclear DNMT1 translational start site (ATG3) and there is a conserved mitochondrial translocation signal sequence between ATG1 and ATG3. The role of mitochondrial DNMT1 in the development of heart failure remains to be elucidated.

Purpose
The purpose of this study is to examine the in vivo role of mitochondrial DNMT1 in the heart under pressure overload.

Methods
We generated HA-tagged DNMT1 constructs, 1) starting from ATG1 (termed as whole) 2) from ATG3 (nuclear) and 3) from ATG3 and mutated in the nuclear translocation sequence (mitochondrial) and transfected HEK293 cells with the constructs. Localization of HA-tagged proteins was assessed by immunocytochemistry. We also generated mitochondrial DNMT1-deficient mice by inserting mutations into the ATG1 and ATG2. The mice were subjected to pressure overload by means of transverse aortic constriction (TAC) to induce heart failure. Cardiac remodelling was assessed by echocardiography as well as histological analyses 4 weeks after operation.

Results
Whole, nuclear and mitochondrial DMNT1 translocated to both mitochondria and nuclei, only nucleus and only mitochondria, respectively. Mitochondrial DNMT1-deficient mice were born at Mendelian frequency and grew to adulthood. Those showed no cardiac phenotypes under baseline conditions. However, the mice exhibited severe systolic dysfunction, indicated by left ventricular fractional shortening, 2 weeks after surgery compared with control littermates (control littermates 47.9% versus Mitochondrial DNMT1-deficient mice 32.3%, p&lt;0.05). Intermuscular cell infiltration was observed in TAC-operated mitochondrial DNMT1-deficient hearts.

Conclusions
Mitochondrial DNA methyltransferase 1 plays a protective role in failing hearts and mitDNA methylation might be a therapeutic target to treat patients with heart failure.
Proteomic profiling of extracellular vesicles in takotsubo syndrome
Authors: Zulfaj E , Nejat A , Pylova T , Krasnikova M , Elmahdy A , Espinosa A , Kakaei Y , Kalani M , Jha A , Haamid A , Redfors B , Omerovic E 
Published: October 2024

Abstract

Background/Purpose
Takotsubo syndrome (TS) is an acute form of heart failure characterized by transient regional wall motion abnormalities triggered by a stressful event. The mechanisms underlying its development and recovery are poorly understood, resulting in a lack of disease-specific treatments and diagnostic markers. Extracellular vesicles (EVs) play a significant role in cellular communication and have been shown to be important in various diseases. Their involvement in cardiac conditions like TS is an emerging area of research. The primary objective of this study is to isolate and characterize EVs, as well as profile their proteomic profile, from the heart tissue of rats induced with TS.

Methods
Rats underwent TS induction through the infusion of 1 mg/kg isoprenaline over 15 minutes (TS24h), or were given saline (control). High-resolution echocardiography verified apical ballooning at 6 hours. After 24 hours, heart tissues from apical and basal segments were collected and processed. EV isolation involved tissue slicing, enzymatic digestion, and differential centrifugation steps, including a final iodixanol cushion separation for large and small EVs (Figure 1). Tandem mass tags and mass spectrometry were utilized for global proteomics and any differentially expressed proteins (DEPs) were identified. Analytical techniques such as volcano plots, heatmaps, enrichment analysis, and protein clustering/networks were employed. The strongest clusters (lowest False Discovery Rate and highest intensity) were selected, and their Gene Ontology (GO) terms/pathways were identified.

Results
Pure, cup-shaped, vesicles ranging from 50-800nm were successfully isolated (figure 1). EVs from apex of control and TS24h hearts had lower protein concentrations compared to their corresponding basal segments. Global proteomic analysis revealed a distinct protein profile in EVs from the apical segment of TS hearts at 24 hours. A total of 256 (TS24h-apex vs control-apex) and 561 proteins (TS24h-apex vs TS24h-base) were differentially expressed. No DEPs were observed when comparing the basal segments of TS24h and control hearts. Functional enrichment analysis of the DEPs showed an abundant change of biological processes related to metabolic lipid processes, inflammatory response, complement activation, reorganization of extracellular matrix. A downregulation was seen for biological processes related to mitochondrial ATP synthesis coupled electron transport and muscle contraction.

Conclusion
This study demonstrates a distinct EV protein profile in the apical segments of TS hearts, with marked changes in proteins related to metabolic lipid processes, inflammation, and mitochondrial activity. This extensive catalogue of novel proteins sets the stage for future research aimed at identifying potential therapeutic targets and diagnostic biomarkers, and enabling proof-of-concept studies in TS.
Protease-activated receptor 2 (PAR2) inhibition reduces complement-associated cardiac remodelling in obesity-related heart failure
Authors: Ghanbari E , Meyer U , Doerner A , Kasner M , Barbieri F , Puccini M , Jakobs K , Witkowski M , Friebel J , Petzold T , Kraenkel N , Rauch B , Landmesser U , Rauch U 
Published: October 2024

Abstract

Background and Aims
Obesity is considered a major risk factor for the development of heart failure (HF) due to lipid accumulation, oxidative stress and inflammation which results in cardiac remodeling. Protease activated receptor 2 (PAR2) has been linked to various cardiovascular and inflammatory diseases. The role of PAR2 has not yet been studied in obesity-related HF.

Methods
In the experimental mouse study, we used 1-year-old ApoE knockout (ApoE-/-) and ApoE PAR2 double knockout (ApoE-/-PAR2-/-) mice with a C57BL/6J background on a high fat (HF) diet (n=5/ group). Cell culture experiments were performed with human primary cardiac fibroblasts and HepG2 hepatocytes. Patients (n=50) included in the clinical study had a BMI &gt; 25kg/m², symptoms of heart failure (HF), coronary angiography (CA) that excluded coronary artery disease (CAD) and endomyocardial biopsy (EMB) that confirmed the absence of active myocarditis or primary cardiac amyloidosis. Patients were divided into PAR2low (n=22) and PAR2high (n=22) based on the median PAR2 expression measured via qPCR in the EMB of the cohort, and six patients served as healthy controls.

Results
Evaluation of endomyocardial biopsies (EMB) from overweight/ obese non-ischemic cardiomyopathy (NICM) patients with heart failure (HF) (n=44) revealed that a reduced cardiac PAR2 expression is associated with less cardiac C3 (p≤0.054), C4 (p≤0.041) and C5 gene expression (p≤0.045), as well as plasma levels of complement C3 (1.1g/l± 0.7 vs 2.1g/l±0.2; p≤0.016) and C5b-9 (303.4ng/ml± 215.7 vs 992.7ng/ml± 756.2; p≤0.0002) and as a result, better systolic function i.e. LVEF (46.1%±17.1 vs 36.8%±15.2; p≤0.046) and LV GLS (-14.9%± 5.7 vs -9.5%± 4.6; p≤0.009), less cardiac remodeling and damage. Correspondingly, aged ApoE-/-PAR2-/-mice on a Western diet showed less hepatic and cardiac complement expression (i.e. C1q, C3, C4, C5, C9), cardiac C3 deposition (p≤0.047) and C5b-9 plasma levels (p≤0.049), as well as less cardiac necrosis (p≤0.046) and lower BNP (p≤0.016) than ApoE-/-. PAR2 overexpression in human cardiac fibroblasts (HCFs) independently enhanced and PAR2 antagonism reduced interferon γ (IFNγ)-mediated STAT1-dependent complement C3, C4 and C5 expression.

Conclusions
Protease-activated receptor 2 regulates complement-mediated cardiac damage and remodeling in HF. The PAR2-IFNγ/STAT1/C3-C4-C5 complement-axis might be a promising prognostic and therapeutic approach to identify and treat high-risk cases of HF in overweight/obese patients.
Coronary microvascular dysfunction in patients with heart failure with reduced and mildly reduced ejection fraction: results from the PANACEA study
Authors: Nordberg Backelin C , Svedlund S , Bollano E , Hjalmarsson C , Pirazzi C , Brodin T , Dahllof K J , Lagerstrom Fermer M , Michaelsson E , Ohagen P , Wolfhagen Sand F , Lund L , Hage C , Ljungman C 
Published: October 2024

Abstract

Aims
Coronary microvascular dysfunction (CMD) is common and associated with impaired survival in patients with heart failure with preserved ejection fraction (HFpEF). In patients with heart failure with reduced ejection fraction (HFrEF) and mildly reduced ejection fraction (HFmrEF) the impact of CMD is not fully known.

Purpose
We aimed to investigate the prevalence of CMD and its association with phenotype, biomarkers, endothelial function and echocardiographic measurements in patients with HFrEF or HFmrEF.

Method
A prospective, exploratory bi-center study in patients with chronic stable heart failure, New York Heart Association (NYHA) Class II-IV, and ejection fraction (EF) &lt;50% was performed. Study procedures included echocardiography, adenosine-based transthoracic Doppler echocardiography to assess coronary flow reserve (CFR), physical examination, fasting blood and urine sample, pulse wave velocity (PWV) and hemodynamic measurements. The cutoff of CFR&lt;2.5 was used to diagnose CMD. A multivariable linear regression analysis with CFR as dependent variable, adjusted for age, sex, body mass index, smoking, atrial fibrillation and left ventricular mass, was performed to explore biomarkers, endothelial function, and echocardiographic measurements associated with CMD.

Results
Of 112 included patients, 87 (78%) were men, with a mean age of 73.3 (±7.5) years. Among patients with a successful CFR measurement (n=62), CMD was present in 40 (65%), mean age of 75.4 (±5.8) years (Table 1). Patients with CMD had higher N-terminal pro B-type natriuretic peptide (NTproBNP) and Troponin T (p&lt;0.05), and more often HFrEF ( p=0.06). Patients with CMD had larger ventricles with greater left ventricular mass and larger end-diastolic volumes (p&lt;0.05). In a linear regression analysis CMD was associated with higher NTproBNP, lower EF, PWV and global strain (table 2).

Conclusion
CMD was common and present in two thirds of patients with HFrEF or HFmrEF. Further CMD was associated with markers of more severe heart failure and systemic endothelial dysfunction indicating that CMD may be an important predictor of outcome in patients with HFrEF and HFmrEF.
Neurodegeneration is highly associated with comorbidity burden in HFrEF patients
Authors: Prausmueller S , Wurm R , Ponleitner M , Spinka G , Weidenhammer A , Arfsten H , Heitzinger G , Panagiotides N , Bartko P , Goliasch G , Stoegmann E , Hengstenberg C , Huelsmann M , Pavo N 
Published: October 2024

Abstract

Background
Heart failure (HF) is associated with cognitive decline and risk for dementia. Blood levels of amyloid beta 40 and 42 (Aβ40, Aβ42), tau protein (tau), and neurofilament light chain (NfL) have been found to be altered in neurodegenerative disease. Previous research has established a clear association between these neuromarkers and the risk of developing cognitive dysfunction and mortality in the general population.

Objective
The aim of this study was to investigate the association between the respective neuromarkers and comorbidity burden, as well as to explore whether comorbidity burden impacts the relationship between neuromarkers and outcome in HF patients.

Methods
Plasma levels of Aβ40, Aβ42, tau, and NfL were quantified using a single-molecule array assay. The primary outcome parameter was all-cause mortality.

Results
A total of 470 HFrEF patients were enrolled in the study, with a median age of 62 years (IQR: 52–72); 77% were male. Median NT-proBNP concentration was 1812 pg/ml (IQR: 718–3881). Elevated levels of all biomarkers were closely associated with comorbidity burden (Figure 1). All neuromarkers showed increased levels in individuals with chronic kidney disease (CKD) and known carotid artery stenosis (CAS), except for Aβ40, which did not show significant elevation in CAS (NfL: p&lt;0.001 for both; t-tau: p&lt;0.001 and p=0.041; Aβ40: p&lt;0.001 and p=0.050; Aβ42: p&lt;0.001 and p=0.033, respectively). In patients with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD), only NfL levels were significantly elevated (p&lt;0.001 for both), whereas atrial fibrillation (AF) was associated with higher levels of NfL and t-tau (p&lt;0.001 for both). In individuals with iron deficiency, only Aβ42 levels were significantly higher (p=0.025). All biomarkers showed significant associations with all-cause mortality [crude HR for an increase in 1-log unit (95%CI): NfL 4.44 (3.02-6.53), t-tau 5.04 (2.97-8.58), Aβ40 3.90 (2.27-6.72), Aβ42 5.14 (2.84-9.32); p&lt;0.001 for all] (Figure 2). These associations remained statistically significant after adjusting for comorbidity burden including AF, T2DM, CAD, CKD, CAS and ID [adjusted HR for an increase in 1-log unit (95%CI): NfL 3.28 (1.93-5.57), t-tau 3.96 (2.07-7.57), Aβ40 2.42 (1.34-4.38), Aβ42 3.05 (1.56-5.97); p&lt;0.01 for all].

Conclusion
The findings suggest a close connection between elevated levels of markers of neurodegeneration and increased comorbidity burden in HFrEF patients. While this association may indicate the cumulative risk leading to neuronal injury and HFrEF progression, a causal relationship cannot be excluded. The observed accelerated neurodegeneration in HFrEF underscores the need for further investigation into this complex interplay.Figure 1Figure 2
Twelve-lead electrocardiography-based artificial intelligence predicts the upcoming future of patients with heart failure with mildly reduced ejection fraction
Authors: Baek Y , Kim D Y , Lee S W , Lee S C , Choi W I , Kim D H 
Published: October 2024

Abstract

Background
Heart failure with mildly reduced ejection fraction (HFmrEF) has emerged as the predominant subtype of heart failure (HF), but there is a paucity of data for identifying it using artificial intelligence (AI) based electrocardiogram (ECG).

Purpose
This study aimed to develop artificial intelligence (AI)-ECG to identify and predict the prognosis of patients with HFmrEF.

Methods
We collected 104,336 12-lead electrocardiography (ECG) datasets from April 2009 to December 2021 in a tertiary center. The AI-ECG encompasses a novel model that combines an automatic labelling preprocessing method with a transformer architecture incorporating a triplet loss for HFmrEF analysis.

Results
The receiver operating characteristic analyses revealed that the area under the curve of AI-ECG for identifying all types of HF were acceptable (0.87, 95% confidence interval [CI]: 0.86-0.89), but that for identifying those with HFmrEF was relatively lower (0.83, 95% CI: 0.78-0.86) than those with HF with reduced ejection fraction (HFrEF) (0.89, 95% CI: 0.85-0.82) and those with normal ejection fraction (EF) (0.87, 95% CI: 0.85-0.89). The analysis of ECG features showed significant increases in QRS duration (p=0.001), QT interval (p=0.045), and corrected QT interval (p=0.041) with increasing ‘Severity by Euclidean distance’. Following the predictability analysis with another group of 1,134 patients for improvements of follow-up EF in HFmrEF, the patients were grouped into three clusters based on the AI- Euclidean distance; Cluster 1 had the most severe cases and poorer outcomes than Clusters 2 (p&lt;0.001) and 3 (p&lt;0.001).

Conclusion
AI-ECG presents an innovative approach for the prognostic stratification of cardiac contractility in patients with HFmrEF. By using AI-ECG, patients with HFmrEF will be able to predict upcoming disease progression.
Prognostic impact of myocarditis as aetiology compared with dilated cardiomyopathy and ischaemic heart disease in heart failure
Authors: Fu M , Pivodic A , Bollano E 
Published: October 2024

Abstract

Background
A subgroup of myocarditis can lead to heart failure. However, whether prognosis of myocarditis-induced heart failure differs from other heart failure remains largely unknown.

Aim
This study aimed to investigate the prognostic impact of myocarditis induced heart failure compared with heart failure with dilated cardiomyopathy and ischaemic heart disease as causes respectively in the overall population and a propensity score-matched cohort, based on patient-level data from the Swedish Heart Failure Registry (SwedeHF).

Methods
Patients with heart failure (HF) were enrolled from the SwedeHF (2003-2020) linked with the National Patient Register, and the Swedish Cause of Death Register. Endpoints were all-cause mortality, cardiovascular death, and hospital re-admissions, followed up from the index date until censoring or event.

Results
Of 54416 patients identified through the SwedeHF with HF, 418 hade myocarditis as aetiology (MC-HF), 6,871 with dilated cardiomyopathy (DCM-HF) and 47127 with ischemic heart diseases (IHD-HF). In general patients with MC-HF have shorter disease duration and less comorbidities compared with DCM-HF and IHD-HF, but older than DCM-HF and younger than IHD-HF. Compared with DCM-HF, MC-HF are associated with 29% higher risk for all cause mortality [(1.29 (1.07 - 1.55), p=0.0079] and 40% higher risk for cardiovascular death [ 1.40 (1.09 - 1.80), p=0.0088], and 19 % higher risk for heart failure rehospitalization [1.19 (1.03 - 1.37), p=0.018] and even higher risk by censoring within one-year . However, compared with IHD-HF, patients with MC-HF have similar risk for all cause mortality [0.95 (0.80 - 1.13), p=0.54], cardiovascular death [0.95 (0.75 - 1.20), p=0.65], and heart failure rehospitalization [0.93 (0.81 - 1.06), p=0.29]. Similar results were obtained from a propensity 1:2 matched cohort. No significant interactions were found regardless of age (&lt; and &lt; 70 years) , sex, LVEF (≥50%, 40-49%, 30-39% and &lt; 30%) for all cause mortality comparing MC-HF vs DCM-HF, and MC-HF vs IHD-HF.

Conclusion
Patients with myocarditis-induced heart failure have worse outcome than heart failure due to dilated cardiomyopathy, with even higher risk during one year. This finding highlights the importance of early and more effective customized management of patients with myocarditis in particular those with high risk to develope heart failure.