bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiplex screening for biomarkers associated with subsequent heart failure hospitalisation in patients with atrial fibrillation: insights from the ARISTOTLE trial
Authors: Pol T , Lindback J , Alexander J H , Granger C B , Lopes R D , Siegbahn A , Wallentin L , Hijazi Z 
Published: November 2023

Abstract

Background
Atrial fibrillation (AF) is associated with heart failure (HF) with a complex cause and effect relationship. We performed multiplex screening of plasma proteins in order to identify biomarkers and pathways associated with subsequent HF hospitalisation in patients with AF.

Methods
Using a case-cohort design of patients with AF from the ARISTOTLE trial, the study cohort consisted of 596 cases of HF hospitalisations during follow-up and 4029 randomly selected controls without HF hospitalization. The median follow-up time was 1.9 years. Plasma obtained at randomisation was analysed with conventional immunoassays and three OLINK proximity extension assay panels; CVDII, CVDIII and the inflammation panel. Biomarker associations with subsequent HF hospitalisation was evaluated using Random Survival Forest (RF), Boruta and Cox-regression analyses adjusted for baseline characteristics, renal function, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) as well as cardiac troponin-T (cTnT-hs).

Results
The biomarkers most associated with HF hospitalisation, using all three statistical methods (Table), were (hazard ratio for inter-quartile comparison [95% CI]), NT-proBNP (2.07 [1.76 - 2.4]), cTnT-hs (1.35 [1.15 - 1.58]), fibroblast growth factor 23 (FGF-23; 1.26 [1.15 - 1.39]), spondin-1 (SPON-1; 1.21 [1.10, 1.33]), TNF-related apoptosis-inducing ligand receptor 2 (TRAILR2; 1.19 [1.07 - 1.32]), insulin Growth Factor Binding Protein 7 (IGFBP7; 1.25 [1.13 - 1.39]), urokinase receptor (uPAR) 1.4 [1.19 - 1.66]), vascular Endothelial Growth Factor D (VEGF-D; 1.28 [1.08 - 1.53]), pro-adrenomedullin (ADM; 1.20 [1.03 - 1.40]), and C-C motif chemokine 3 (CCL3; 1.15 [1.06 - 1.24]).

Conclusions
Out of 269 evaluated biomarkers, this comprehensive screening study identified biomarkers representing cardiorenal dysfunction (NT-proBNP, cTnT-hs, FGF-23), cell adhesion (SPON-1), apoptosis (TRAILR2), growth factors (IGFBP7, VEGF-D), fibrinolysis (uPAR), vasodilation (ADM) and inflammation (CCL3) as being the most strongly associated with subsequent HF hospitalisation in patients with AF. These findings highlight the most important pathophysiological pathways involved in new or worsening HF in patients with AF.Biomarkers associated with HF hospitalis
Genome-wide association study of heart failure in a multiethnic south-east asian cohort
Authors: Loong S , Hong P , Goh V J L , Lee S S G , Loh S Y , Soon D , Chin C W L , Maurer-Stroh S , Amikeng F , Loh M , Wang D , Lam C S P , Richards M , Foo R 
Published: November 2023

Abstract
NMRC
Heart failure (HF) is a leading cause of morbidity and mortality worldwide (1). While existing genome-wide association studies (GWAS) have yielded many different loci and causal genes, most of such studies has been conducted in European populations (2). There has been little insight into the genetic architecture of complex diseases, especially HF among Asians, despite up to 60% of the world population consisting of Asians. Through this study, we aim to uncover the genomic basis of heart failure in a South-East Asian cohort, with deep phenotyping of cardiovascular, metabolic, immune, and inflammatory traits.
We conducted the largest multi-ancestry South-east Asian all-cause HF GWAS (n=2310, 1305 cases and 1005 controls), utilizing whole genome sequencing (WGS) data. Eleven independent loci were found to be associated with HF (P-value = 5e10-8). In-silico and functional studies were interrogated, allowing us to map most of the loci (n=9) to various genes implicated in various metabolic diseases - hypertension (HTN), diabetes mellitus (DM), and coronary artery disease (CAD). We further conducted a phenome-wide association study (PWAS) of significant loci, which revealed that they augment signals related to CAD, atrial fibrillation, DM and HTN, suggesting a shared genetic etiology between these metabolic risk factors and Asian HF. Of note, this the first HF GWAS to implicate the PDE9A gene, which was previously discovered as a potential biomarker for HF with preserved ejection fraction (HFpEF) through its involvement in the cGMP signaling pathways, and is currently being explored as a therapeutic target in the treatment of HFpEF (3).
Polygenic risk scores (PRS) were calculated for heart failure in this Asian cohort, which identified that the most optimized model (HF PRS), included 19,431 of the most significant genetic variants (p=0.073). The prediction power of the HF PRS on HF risk was tested in UKB Asian subjects (N=10,016; 413 cases and 9,603 controls). Our results showed that the highest 10% percentile HF PRS risk subjects in UKB Asian were at 1.56-fold risks (95% CI: 1.16-2.08) for HF.
This study provides a comprehensive understanding of the genetic architecture, and sheds light on novel biological pathways underlying HF in a south-east Asian population, indicating a highly metabolic underpinnings of this disease. It provides a step towards developing a precision-medicine based approach for risk stratification, prevention, and management of HF among Asians. Furthermore, this study provides evidence for the use of WGS in GWAS, to expand the discovery of novel targets for downstream interrogation, biomarker and drug development for complex diseases.
Analysis of the snoRNA profile in ischemic and dilated cardiomyopathy
Authors: Tarazon E , Perez Carrillo L , Alvarez I , Gimenez Escamilla I , Delgado Arija M , Gonzalez I , Portoles M , Rosello-Lleti E 
Published: November 2023

Abstract

Introduction
In last decade, knowledge of how non-coding RNAs (ncRNAs) contribute to the pathogenesis of cardiovascular disease has increased exponentially. However, other than miRNAs, relatively little is known about how other small RNAs specifically contribute to heart failure. snoRNAs have been known for decades, mainly for their role in biogenesis and ribosomal modification. Moreover, recent studies have provided fundamental information on how snoRNA regulated non-coding RNA expression. However, the contribution of these non-coding RNAs to human disease is a relatively new area of research, with heart failure being relatively unknown and understudied.

Purpose
We aimed to investigate whether snoRNA expression is regulated during heart failure from dilated (DCM) and ischemic (ICM) origin, and how its biogenesis is affected by the pathophysiology of the disease.

Methods
Heart tissue samples from ICM (n=22) and DCM (n=20) patients and control (CNT, n=8) subjects were analyzed by non-coding RNA-Sequencing (ncRNA-Seq) to evaluate transcriptome changes in snoRNA/scaRNA. In addition, through mRNA sequencing we analyzed the biogenesis pathway of these ncRNA in ICM (n=13) and DCM (n=13) patients compared to CNT (n=10). Microarray analysis was used to validate the alterations found in the snoRNA/scaRNA expression (ICM, n=24; DCM, n=20; CNT, n=10).

Results
A generalized alteration of the snoRNA biogenesis pathway was not observed, we only found NOLC1 underexpression in ICM patients (FC=-1.42, p&lt;0.05). NOLC1 encodes a nucleolar protein that acts as a regulator of RNA polymerase I and connects RNA polymerase I with enzymes responsible for ribosomal processing and modification. However, ncRNA-Seq data showed altered profiles of snoRNA/scaRNA in ICM and DCM patients. We identified 24 differentially expressed snoRNAs in ICM and 35 in DCM, while only 3 scaRNAs in DCM patients. We highlight SNORD14C that was upregulated in DCM patients (FC=2.37, p&lt;0.01) and we confirmed in the microarray analysis (FC=1.10, p&lt;0.05). Moreover, SNORD116-18 was related to ejection fraction in ICM patients (r=0.460, p&lt;0.05).

Conclusion
Our data indicate that there are changes in the expression of snoRNA and scaRNA with a specific profile for each etiology, ICM and DCM. However, a marked alteration in its biogenesis is not observed. Taken together and given the relationship of SNORD116-18 to ventricular function, our results offer a novel and promising insight into the differential involvement of these molecules in the pathophysiology of ICM and DCM.
Modeling cardiac injury using human cardiac slices to test therapeutic approaches for cardiac regeneration and repair
Authors: Lodrini A M , Meijboom E M , Bezhaeva T , Bogunovic N , Kruithof B P T , De Vries A A F , Quax P H A , Smits A M , Goumans M J 
Published: November 2023

Abstract

Background
Due to limited regenerative capacity of the adult human heart, myocardial infarction causes irreversible damage by inducing the death of cardiomyocytes and the formation of a fibrotic scar. These remodeling mechanisms cause loss of contractility and eventually heart failure ensues in a significant proportion of patients.

Purpose
There is a need for a reliable model that can replicate the adult cardiac pathophysiology in order to test treatments against cardiac remodeling. Here, we developed a cardiac tissue culture model that can simulate in vitro the molecular changes occurring after cardiac injury using human cultured cardiac slices.

Methods
We obtained cardiac slices by sectioning ventricular myocardium from the surgical waste material of adult patients undergoing valve surgery or Morrow myectomy. Cardiac slices were cultured at a liquid-air interface and were viable up to 7 days of culture, even in the absence of stimulation. During this time cardiac slices underwent mechanical and chemical treatments to induce ischemia and/or local injury.

Results
We found that following these treatments we were able to simulate cardiac remodeling in terms of cardiomyocyte death, activation of cardiac fibroblasts and induction of inflammation and oxidative stress. Following small molecule screening, we discovered that addition of compounds with anti-inflammatory properties (e.g. dexamethasone) or targeting the TGF-β pathway (e.g. SB-431542) into our culture medium helped in preserving the microscopic structure of the slices. Additionally, we found that treatment with these compounds protected cardiac slices against remodeling following ischemic injury.

Conclusions
In conclusion, our model can emulate cardiac pathophysiology in culture, providing us a reliable platform to test therapies for cardiac regeneration and repair in an adult, multicellular, 3-D environment.
Plasma levels of intact parathyroid hormone and congestion burden in heart failure: clinical correlations and prognostic role
Authors: Ciccone M M , Capriati G , Gambacorta S , Antonica C , De Palo M , Massari F , Scicchitano P 
Published: November 2023

Abstract
Circulating parathyroid hormone (PTH) concentrations increase in heart failure (HF) and are related to disease severity. The relationship between PTH and congestion is still a matter of debate. The objective of this analysis was to evaluate the role of PTH as a marker of congestion and prognosis in HF. We enrolled 228 patients with HF. Intact PTH concentrations and HYDRA score (constituted by: B-type natriuretic peptide, blood urea nitrogen-creatinine ratio, estimated plasma volume status, and hydration status) were evaluated. The study endpoint was all-cause mortality. PTH levels were higher in acute compared with chronic HF and in patients with clinical signs of congestion (i.e., peripheral oedema and orthopnea). PTH concentrations significantly correlated with NYHA class and HYDRA score. At multivariate analysis of HYDRA score, estimated glomerular filtration rate (eGFR), and corrected serum calcium were independently determinants of PTH variability. Fifty patients (22%) died after a median follow-up of 408 days (interquartile range: 283-573). Using univariate Cox regression analysis, PTH concentrations were associated with mortality (hazard ratio [HR]: 1.003, optimal cut-off: &gt;249 pg/mL-area under-the-curve = 0.64). Using multivariate Cox regression analysis, PTH was no longer associated with death, whereas HYDRA score, left ventricular ejection fraction, and eGFR acted as independent predictors for mortality (HR: 1.96, 0.97, and 0.98, respectively). Our study demonstrated that intact PTH was related to clinical and subclinical markers of congestion. However, intact PTH did not act as an independent determinant of all-cause death in HF patients.
The SGLT2I Dapagliflozin reverses metabolic stress driving myocardial inflammation in a mouse model of heart failure with preserved ejection fraction: insights from single-cell RNA sequencing
Authors: Panico C , Felicetta F , Kunderfranco P , Salvarani N , Carullo P , Rubino M , Cremonesi M , Peano C , Colombo F , Passaretti M , Doro R , Villaschi A , Kallikourdis M , Greco C M , Condorelli G 
Published: November 2023

Abstract

Background
Heart failure with preserved ejection fraction (HFpEF) is often associated with metabolic distress and represents a therapeutic challenge. Metabolism-induced systemic inflammation links comorbidities with HFpEF. How metabolic changes impact myocardial inflammation in the context of HFpEF is not known.

Methods
We generated a model of metabolic HFpEF by feeding ApoE knockout (ApoE KO) mice a high-fat diet (HFD), and used single-cell expression analysis (scRNA-seq) on CD45+ cardiac cells to evaluate the involvement of inflammation. By focusing our analysis on macrophages, we obtained high-resolution identification of subsets of these cells in the heart, enabling us to study the outcomes of metabolic distress on the cardiac macrophage infiltrate and identify a macrophage-to-cardiomyocyte (CMC) regulatory axis. To test whether a clinically relevant sodium glucose cotransporter-2 inhibitor (SGLT2i) could ameliorate the cardiac immune infiltrate profile in our model, ApoE KO-HDF mice were randomized to receive the SGLT2i dapagliflozin (DAPA) or vehicle for 8 weeks.

Results
We describe a new metabolic HFpEF model: mice present with reduced diastolic function, reduced exercise tolerance, and increased pulmonary congestion associated with cardiac lipid overload and reduced polyunsaturated fatty acids. The main immune cell types infiltrating the heart included 4 sub-populations of resident and monocyte-derived macrophages displaying a pro-inflammatory profile exclusively in ApoE KO-HFD mice. Lipid overload had a direct effect on inflammatory gene activation in macrophages, mediated through endoplasmic-reticulum stress pathways. Investigation of the macrophage-to-CMC regulatory axis revealed the potential effects on CMCs of multiple inflammatory cytokines secreted by macrophages, impacting pathways such as hypertrophy, fibrosis, and autophagy. Finally, we describe the anti-inflammatory effect of SGLT2i.

Conclusions
Through a newly described model of HFpEF based on metabolic stress, and using scRNA-seq, we have determined the effects of metabolic distress on cardiac inflammatory cells, in particular on macrophages, and suggest SGLT2i as potential therapeutic agents for the targeting of a specific phenotype of HFpEF.
Left atrial strain and its correlates to cardiorespiratory endurance in HFpEF patients with paroxysmal atrial fibrillation
Authors: Katbeh A , Moya A , Kodeboina M , Penicka M , Verstreken S , Vanderheyden M 
Published: November 2023

Abstract

Introduction
Patients (pts) with paroxysmal atrial fibrillation are at risk for developing heart failure with preserved ejection fraction (HFpEF) and often have an impaired exercise capacity. Since left atrial (LA) pressure plays a major role in the exercise intolerance, we aimed to characterize the contribution of resting LA mechanical properties, assessed by two dimensional speckle tracking echocardiography upon exercise capacity.

Purpose
To evaluate relationship between LA mechanics, measured by LA strain (LAS) and parameters of exercise capacity in pts with paroxysmal atrial fibrillation.

Methods
The study included 54 pts (64 ± 10 years, 76 % males) with dyspnea (NYHA≥II), paroxysmal atrial fibrillation and preserved LV ejection fraction (≥50%). The likelihood of HFpEF was estimated using H2FPEF score. During sinus rhythm, all patients underwent speckle tracking echocardiography and cardiopulmonary exercise testing (CPET). Peak oxygen uptake (VO2 peak) served as measure of functional capacity and ventilation/carbon dioxide output slope (VE/VCO2) as surrogate of ventilation/perfusion mismatch.

Results
LA contractile strain (S) and strain rate (SR) showed significant correlation with VO2 peak (both p &lt; 0.05). LA reservoir, conduit and contractile LAS, all had significant relationship with VE/VCO2 slope
(all p&lt;0.050). Pts with LASR above the median had significantly higher VE/VCO2 (p=0.025) and lower VO2 peak (p=0.010). In contrast, no correlations were observed between exercise parameters and LA volumes or any other echocardiographic indices.

Conclusions
In HFpEF, VO2 peak and VE/VCO2 are closely related to LA contractile strain, suggesting that abnormalities in LA mechanics may contribute to the blunted exercise capacity. Therefore, we speculate that these markers can be used as an echocardiographic surrogate of functional capacity in HFpEF pts.
Figure 1: Relationship between left atrial reservoir (LASr) and contractile (LASct) strain and peak oxygen consumption (VO2 peak) and ventilatory efficiency (VE/VCO2 slope).
Figure 2: Peak oxygen consumption (VO2 peak) and ventilatory efficiency (VE/VCO2slope) in pts with and without left atrial strain rate above the median.
Triglyceride glucose index, a novel marker of insulin resistance, predicts outcomes in patients with heart failure with preserved ejection fraction
Authors: Iwakura K , Okada M , Tanaka N , Koyama Y , Okamura A , Watanabe H , Tamaki S , Yano M , Hayashi T , Yamada T , Yasumura Y , Sotomi Y , Hikoso S , Sakata Y 
Published: November 2023

Abstract

Background
Insulin resistance (IR) is a characteristic feature of heart failure (HF), and it is present both in diabetic- and non-diabetic patients with HF. It is observed in patients with HF with preserved ejection fraction (HFpEF) as well as in those with HF with reduced ejection fraction (HFrEF). It is still not fully understood how IR can affect the clinical outcome in patients with HFpEF. Triglyceride glucose index (TyG index) is a novel, simple marker of IR which is well correlated with HOMA-IR.

Purpose
To investigate the correlation between TyG index and clinical outcome in patients with hospitalized HFpEF.

Methods
We enrolled 1231 patients registered in the PURSUIT-HFpEF (Prospective, Multicenter, Observational Study of Patients with Heart Failure with Preserved Ejection Fraction) study, which is a multicenter registration of patients hospitalized for acute decompensated HFpEF, for the present study. TyG index was calculated as Ln(serum triglyceride [mg/dL] x fasting blood glucose [mg/dL]/2) using blood sample before discharge. We followed the study patients for median of 387 days (IQR 239-727 days) to observe all-cause death and the major adverse cardiovascular events (MACE; composite of death, heart failure hospitalization and stroke).

Results
We could calculate TyG index in 917 patients (81±9 year old, 55.3% female) with the mean value of 8.5±1.5. Diabetes was observed in 360 (39.3%) patients, and they had higher TyG index than non-diabetic patients (8.8±0.6 vs. 8.4±.05, p&lt;0.0001). Cox proportional hazard model selected TyG index score as an independent predictor for all-cause death regardless of history of diabetes, hypertension and dyslipidemia (p=0.004). We divided patients into 4 groups based on TyG index. Kaplan-Meier curves indicated the difference in all-cause mortality among 4 groups (Figure Left, p=0.0003 by log-rank test). Incidence of MACE was also significantly different among 4 groups (Figure Right, p=0.007 by log-rank test).

Conclusion
TyG index predicted all-cause mortality and MACE in patients with HFpEF regardless of diabetic state.Kaplan-Meier curves for death and MACE
Left atrioventricular coupling index as a prognostic marker of cardiovascular events in heart failure with preserved ejection fraction
Authors: Okada M , Tanaka N , Iwakura K , Seo M , Hayashi T , Yano M , Nakagawa A , Nakagawa Y , Tamaki S , Yamada T , Yasumura Y , Sotomi Y , Hikoso S , Sakata Y 
Published: November 2023

Abstract

Background
Left atrial (LA) structural remodeling is common and considered a marker of increased mortality in patients with heart failure with preserved ejection fraction (HFpEF). However, the left atrium is directly connected to the left ventricle during diastole and their functions are tightly coupled. A single left atrioventricular coupling index (LACI), defined by the ratio between the LA end-diastolic volume (LAV) and the LV end-diastolic volume (LVEDV) assessed by echocardiography, could be useful in the clinical routine to improve the risk stratification of HFpEF.

Methods
An analysis was performed from a prospective multicenter observational registry for HFpEF (PURSUIT-HFpEF Registry) conducted in the Osaka region of Japan. A total of 1231 patients hospitalized for acute heart failure (diagnosed by using the Framingham criteria) met the inclusion criteria: left ventricular ejection fraction (LVEF) ≥50% and brain natriuretic peptide ≥100 pg/ml. After excluding patients without persistent atrial fibrillation, we enrolled 863 patients (age, 81 ± 9 years; females, 56.1%; atrial fibrillation, 37.2%) whose LAV and LVEDV using the Simpson’s method were available at discharge. Heart failure hospitalizations and cardiovascular deaths were the primary endpoint.

Results
There was little correlation between the LAVI (median 50.2, interquartile range [IQR] 37.1–65.4 ml) and LVEDV (median 80.0, IQR 58.3–102.8 ml) (r = 0.16, p &lt;0.001). As a result, the overall LACI was 0.94 (IQR 0.65–1.34). During a median follow-up of 729 (IQR 407–1180) days after discharge, 304 patients experienced the primary endpoint. The incidence incrementally increased with the LACI quartile groups (Q1: 26.9%, Q2: 37.5%, Q3: 34.0%, Q4: 42.6%, log-rank p = 0.005). After adjusting for age, gender, body mass index, left ventricular filling pressure, and serum brain natriuretic peptide levels, the LACI (hazard ratio, 1.19 per quartile increase; 95% confidence interval, 1.03-1.38; p = 0.021) was a significant predictor of the primary endpoint.

Conclusions
In the PURSUIT-HFpEF Registry, the degree of LA and LV structural remodeling differed between individuals. The LACI was a novel index for predicting cardiovascular outcomes in patients with HFpEF.