bluuebunny/crossref_metadata_2025_split huggingface dataset:
Longitudinal modeling of cardiac function to identify trajectories with differential risk of heart failure
Authors: Reimer Jensen A , Ross J C , Arthur V , Hall M E , Matsushita K , Lutsey P L , Biering-Soerensen T , Shah A M 
Published: November 2023

Abstract

Background
Impairments in left ventricular (LV) systolic and diastolic function are common precursors of clinical heart failure (HF) and underlie HF risk. Little data exist regarding trajectories of cardiac function in mid- to late-life, when HF risk is greatest, and the extent to which such trajectories may differentially relate to risk of HF with preserved ejection fraction (HFpEF) or HF with reduced ejection fraction (HFrEF).

Purpose
To (1) identify multidimensional trajectories of cardiac function from mid- to late-life using serial echocardiographic data, (2) apply the resulting models to predict trajectory membership in a separate sample, and (3) determine associations between assigned trajectory and incident HFpEF and HFrEF.

Methods
We used a Bayesian nonparametric trajectory approach to jointly model longitudinal measures of LV ejection fraction (LVEF) and E/A ratio among 747 participants in two longitudinal cohort studies (the Atherosclerosis Risk in Communities [ARIC] study and Jackson Heart Study [JHS]) who underwent ≥2 echocardiograms in 2000-04 (mean age 65±5 years), 2011-2013 (age 75±5 years), and 2018-19 (age 81±5 years).
Using the trajectories inferred from this modeling, we applied Bayes theorem to assign 4,419 ARIC-only participants to their most likely trajectory using single time-point measures of LVEF and E/A ratio acquired in 2011-2013 (age 75±5 years). These assignments were treated as a categorical variable in subsequent analysis. In ARIC-only participants, we used Cox proportional hazards models adjusted for age, sex, obesity, hypertension, diabetes, chronic kidney disease, and coronary heart disease to assess the relationship between assigned trajectory and incident HF.

Results
In the discovery set (n=747), we identified six trajectories of cardiac function based jointly on longitudinal changes in LVEF and E/A ratio (Figure 1). The pink (prevalence 50%) and light green (17%) trajectories showed increasing LVEF and decreasing E/A ratio with increasing age, while the red trajectory (22%) demonstrated a lack of increase in LVEF. The dark green trajectory (4%) demonstrated progressive LVEF decline, the orange trajectory (2%) steep LVEF decline and rise in E/A ratio, and the blue trajectory (4%) rising E/A ratio despite increasing in LVEF. Analysis of the ARIC-only participants (n=4,419) showed that trajectory membership was differentially associated with risk of incident HFpEF and HFrEF (Figure 2). Compared to the pink trajectory, membership in the orange trajectory was associated with incident HFpEF and HFrEF, the red and the dark green trajectory associated with HFrEF alone, and the blue trajectory with HFpEF alone.

Conclusion(s)
These results demonstrate the feasibility of identifying trajectories of cardiac function with multidimensional longitudinal data and may have implications for HF risk prediction.
Comparing indices of systemic inflammation and cardiac phenotype between hypertensive and non-hypertensive hypertrophic cardiomyopathy
Authors: Zach D , Schwegel N , Hoeller V , Kolesnik E , Gollmer J , Reiter U , Seggewiss H , Batzner A , Zirlik A , Rainer P , Ablasser K , Verheyen N 
Published: November 2023

Abstract

Background
Arterial hypertension (HTN) is associated with excess mortality in hypertrophic cardiomyopathy (HCM), but underlying mechanisms are largely elusive.

Purpose
The purpose of this study was to investigate the association between HTN and indices of systemic inflammation and cardiac function in a HCM cohort.

Methods
This was a single-center cross-sectional case-control study comparing 30 adult HCM patients with HTN (HTN+) and 30 sex- and age-matched HCM patients without HTN (HTN-). Echocardiographic measures were assessed using post-processing analyses by a blinded investigator.

Results
Mean age of the total sample was 54.6±10.1 years, 30% were women. Mean end-diastolic interventricular septum (IVSd) thickness was 2.1±0.4 cm, 18% previously underwent septal reduction therapy, and 47% had left ventricular outflow tract obstruction. HTN+ portrayed more severe IVSd thickness than HTN- [2.2±0.3 cm vs. 2.0±0.4 cm; p = 0.017], while echocardiographic measures of systolic and diastolic function, including speckle-tracking derived parameters, did not differ between groups. Moreover, levels of N-terminal pro B-type natriuretic peptide were balanced between groups. Compared with HTN-, HTN+ patients exhibited higher circulating plasma levels of interleukin-6 [2.8 pg/ml (2.0, 5.4) vs. 2.1 pg/ml (1.5, 3.4); p = 0.008] and high-sensitivity C-reactive protein [2.6 mg/l (1.4, 6.5) vs. 1.1 mg/l (0.9, 2.4); p = 0.004]

Conclusion
This study demonstrates that HTN is associated with low-grade systemic inflammation among HCM patients. Moreover, this analysis indicates that HTN+ do not exhibit an altered systolic and diastolic function compared to HTN-. Accordingly, the adverse impact of HTN in HCM patients may be a consequence of systemic effects rather than alterations of cardiac function.TableFigure
GFPT1 deficiency is a novel cause of a dilated cardiomyopathy and is required for myocardial adaptation to chronic pressure-overload stress-induced heart failure
Authors: Nabeebaccus A A , Verma S , Catibog N , Thompson R , Shah A M 
Published: November 2023

Abstract

Background
GFPT1 is the rate-limiting enzyme of a pathway called the hexosamine biosynthesis pathway (HBP) that turns fructose 6-phosphate derived from glucose into another monosaccharide called N-acetylglucosamine (GlcNAc). GlcNAc is an important substrate for modifying diverse cellular proteins on their serine and threonine residues termed O-GlcNAcylation often competing with phosphorylation and altering their activity or stability (Bond & Hanover; 2015). Increased GFPT1 activity is known to stimulate the cellular integrated stress response improving protein quality control and cell survival (Denzel et al 2014). In the heart, GFPT1 expression and O-GlcNAcylation increases in the early stages of chronic cardiac stress but the physiological role of GFPT1 in regulating heart function including its role during chronic stress remains unclear. Identifying molecular pathways that promote adaptive cardiac remodelling is a promising approach to discover novel therapies for heart failure.

Methods
Cardiomyocyte-specific GFPT1 knockout mice were generated to study the effects of GFPT1 deletion in hearts. Heart function was examined by echocardiography. HBP activity was quantified using Western blotting of O-GlcNAc-modified proteins. Abdominal aortic banding (AAB) was used to induce chronic pressure-overload heart failure.

Results
Homozygous GFPT1 KO mice spontaneously develop a dilated cardiomyopathy (DCM) with a 30% mortality rate (ejection fraction 32% compared with 62% for floxed controls and end diastolic volume 125 microL versus 60 microL; n=5-6 per group; p &lt;0.05). Hearts showed reduced levels of total protein O-GlcNAcylation suggesting impaired hexosamine biosynthesis pathway activity. Heart function could be rescued by supplementing their diets with oral glucosamine bypassing GFPT1 to provide metabolites required for hexosamine biosynthesis and normalising O-GlcNAcylation (ejection fraction improved to 40% in KO with supplementation versus KO without; n=4-6 per group; p &lt;0.05). Heterozygous KO mice do not develop a DCM but when subject to pressure-overload cardiac stress, develop worse heart failure with a 50% mortality rate over 9 weeks of pressure-overload (ejection fraction 43% in het KO versus 53% in floxed control; n= 3-6 per group; p = 0.0025).

Conclusion
Deficiency of GFPT1 is a novel cause of a spontaneous dilated cardiomyopathy. GFPT1 is required for physiological growth of the heart that may in part involve the O-GlcNAcylation of proteins. Partial GFPT1 deficiency is associated with adverse cardiac remodelling following pressure-overload stress. Increasing GFPT1 activity may be a key therapeutic target in developing novel heart failure treatments.
Intravenous iron administration in patients with heart failure alters endothelial homeostasis with early release of endothelial microvesicles and subsequent mobilization of endothelial progenitor cell
Authors: Mause S , Berger M , Lim H Y , Vogt F , Marx N , Brandenburg V , Stoehr R 
Published: November 2023

Abstract

Background
Intravenous iron supplementation is an established therapy for patients with heart failure (HF) with reduced ejection fraction (LV-EF&lt;50%) and iron deficiency, resulting in reduced risk of HF hospitalization. Since iron may induce oxidative stress, inflammation and apoptosis in endothelial cells, concerns persist regarding potential adverse vascular effects of iron therapy. To evaluate endothelial health following ferric carboxymaltose (FCM) administration, we assessed the profile of circulating endothelial microvesicles (EMVs) and endothelial progenitor cells (EPCs) in a cohort of 23 HF patients using flow cytometry.

Results
Compared to healthy control subjects (HC; n=15), baseline levels of CD31+/CD41- EMVs were significantly higher and EMVs featured a more apoptotic phenotype in HF patients. Following administration of 1000mg FCM, EMV levels showed an early but transient increase (Fig. 1) and displayed an altered phenotype profile with dominant augmentation of EMVs expressing the inducible markers CD62E and CD54, indicating endothelial activation and injury. Levels of circulating vasoregenerative CD45lowCD34+KDR+ EPCs were lower in HF patients and FCM application resulted in an early decrease of EPCs followed by substantial mobilization into the circulation after one week (Fig. 2). Levels of EMVs and EPCs returned to baseline values within two and four weeks, respectively. Compared to HF patients with preserved renal function, the EMV/EPC ratio was higher in HF patients whereas EPC mobilization was diminished with additional chronic kidney disease, suggesting impaired vascular repair capacity. In vitro experiments with cultured endothelial cells revealed that FCM at therapeutic concentrations dose-dependently promotes endothelial apoptosis, increases expression of adhesion molecules and CXCL12, and triggers the generation of EMVs.

Conclusion
Intravenous iron supplementation with FCM in HF patients provokes a biphasic response with early release of CD62E+ and CD54+ enriched EMVs and subsequent mobilization of EPCs, suggesting temporary aggravation of endothelial dysfunction upon FCM supplementation and consecutive engagement of a vascular defense program.
The central role of FAP dysregulation and cardiac fibroblast activation in heart failure patients
Authors: Rosello-Lleti E , Delgado Arija M , Genoves Martinez P , Perez Carrillo L , Gimenez Escamilla I , Gonzalez I , Portoles M , Tarazon E 
Published: November 2023

Abstract

Background
Excessive cardiac fibrosis is an important factor in the progression of heart failure (HF). Fibroblast activation protein (FAP) is a type-II transmembrane serine protease expressed almost exclusively to pathological conditions, being robustly expressed by activated fibroblasts of scarring tissue. Previously different studies have reported alterations of fibrillar and non-fibrillar collagen expression in heart failure linked to fibrosis. However, despite its relevance, the role of FAP in cardiac fibrosis is not fully elucidated.

Purpose
We hypothesized that FAP expression level was altered in heart tissue of heart failure (HF) patients. Furthermore, given the central role of FAP in fibroblast activation, we also studied the expression levels of profibrotic genes and microRNAs associated with fibrosis process, and the relationships between FAP and these altered molecules.

Methods
We analysed transcriptome-level differences in genes involved in fibrosis between HF (n=26) and controls (n=10) in human hearts by RNA-sequencing, and a total of 50 samples were also analysed (HF, n=42; and controls, n=8) by ncRNA sequencing to study the expressions of microRNAs.

Results
We found an overexpression of FAP gene (FC=1.98, p&lt;0.05), and observed that the expression of other molecules, whose activity is also relevant in the activation of fibroblasts, were overexpressed, such as POSTN (FC=3.05, p&lt;0.05), THY1 (FC=4.33, p&lt;0.001) and VIM (FC=1.33, p&lt;0.05). On the other hand, we found several fibrosis-associated genes whose expression was also altered in HF patients. Specifically, THBS4 (FC=3.03, p&lt;0.001), AEBP1 (FC=1.9, p&lt;0.01), ELN (FC=2.1, p&lt;0.01), COL1A1 (FC=1.72, p&lt;0.01), COL1A2 (FC=1.97, p&lt;0.01), COL3A1 (FC=2.1, p&lt;0.01), and MFAP5 (FC=2.34, p&lt;0.001). Interestingly, most of these overexpressed genes showed a correlation (p&lt;0.05) with FAP mRNA expression. We highlight the positive correlations between COL1A2 (r=0.643, p&lt;0.001) and COL3A1 (r=0.651, p&lt;0.001) with FAP expression. Furthermore, we observed dysregulation in several microRNAs related with an antifibrotic or profibrotic function. Specifically, we showed underexpression of a microRNA with antifibrotic function, miR-29c-3p (FC=-1.2, p&lt;0.01), which has COL1A1, COL1A2, COL3A1 as target genes.

Conclusions
In this study, we showed significant alterations in FAP and other specific genes involved in fibroblast activation in HF. We also identified correlations between FAP and key fibrosis markers, giving FAP a central role in cardiac fibrosis process. Fibroblast activation molecules could serve as a potential therapeutic target for the prevention of cardiac fibrosis and cardiac diseases.
Alterations of mitochondrial bioenergetics in human hearts with ischemic and dilated cardiomyopathy
Authors: Tarazon E , Perez Carrillo L , Benedicto C , Gimenez Escamilla I , Delgado Arija M , Gonzalez I , Portoles M , Rosello-Lleti E 
Published: November 2023

Abstract

Background
Heart failure (HF) is a complex multifactorial syndrome characterized by mechanical dysfunction of the myocardium and the inability of the heart to provide adequate blood supply to meet the body's metabolic needs. Defects in mechanisms such as bioenergetics are important pathogenic factors in myocardial dysfunction, since the heart needs a continuous energy supply, which is fulfilled by ATP synthesis through mitochondrial oxidative phosphorylation, a process that takes place in the inner membrane of the mitochondria, whose structure is also affected during the development of HF.

Purpose
The aim of this study was to analyze the alterations in the expression level of mRNAs and proteins involved in mitochondrial function, focusing on bioenergetics and formation of cristae formation in patients with ischemic and dilated cardiomyopathy.

Methods
Transcriptome-level differences between HF and controls (CNT) were investigated in 36 heart samples with RNA-sequencing technology (mRNA-seq; ICM, n=13; DCM, n=13; CNT, n=10). In addition, ATP5I and ATPIF1 protein levels were determined in 30 heart samples (ICM, n=24; CNT, n=6) by Western Blot assay. The miRNAs implicated in the mRNA posttranscriptional regulation were studied through non-coding RNA-seq (ICM, n=22; DCM, n=20; CNT, n=8).

Results
11 mitochondria genes were detected as altered in bioenergetics and mitochondrial cristae formation in HF. Specifically, we found an overexpression of ATP5I (ICM, FC=2.04, p&lt;0.001) and ATPIF1 (ICM, FC=1.81, p&lt;0.01) mRNA levels that correlated with both diastolic (r=-0.577 and r=-0.562, respectively; p&lt;0.01) and systolic diameter (r=-0.574 and r=-0.563, respectively; p&lt;0.01) and with ejection fraction (r=0.442 and r=0.410, respectively; p&lt;0.05). The analysis of ATP5I and ATPIF1 protein expression showed that only ATPIF1 presented differences in expression when comparing patients with ischemic HF with the control group (FC=, 1.75, p&lt;0.01). Furthermore, we observed alterations in ATP5I target miRNA, miR-483-3p (FC=1.37, p&lt;0.01), which can induce dysregulation in its protein level.

Conclusions
The alterations of mitochondrial bioenergetics and cristae formation related molecules could reflect damage of the cardiac mitochondria function in HF, interfering in the critical activities of the cardiomyocyte and showing a significant relationship with the ventricular function.
DNA methylation profiling of circulating CD4+ T cells and network analysis reveal that JUNB, SETD7, and MEF2D genes predict patients with heart failure preserved vs. reduced ejection fraction
Authors: Benincasa G , Pepin M E , Cacciatore F , Russo V , D'alto M , Argiento P , Romeo E , Chiappetti R , Laezza N , Coscioni E , Golino P , Napoli C 
Published: November 2023

Abstract

Background
Heart failure (HF) with preserved ejection fraction (HFpEF) represents about 50% of new HF diagnosis but still lacks specific biomarkers and effective therapy. Epigenetic-sensitive changes accumulated over time, mainly guided by DNA methylation and demethylation, can lead to chromatin remodelling and affect transcriptional molecular networks underlying microvascular inflammation, oxidative stress, and maladaptive cardiac remodelling which predispose synergistically to HFpEF.

Purpose
We hypothesize that circulating genome-wide DNA methylation profiles may identify novel biomarkers for discriminating HFpEF vs. HF with reduced EF (HFrEF) and provide insight into the underlying pathophysiology of disease.

Methods
A total of n=47 subjects were enrolled including patients with HFpEF (n=22) and HFrEF (n=13) as well as healthy subjects (n=12) serving as control group (CON). Starting from pheripheral blood biospecimens, we isolated CD4+ T cells and extracted genomic DNA for genome-wide methylome analysis and total RNA for experimental validation set.

Results
The reduced representation bisulfite sequencing (RRBS) revealed that patients with HFpEF had unique variations in DNA methylation profiles as compared to HFrEF and CON groups and reflected distinct pathogenic mechanisms. Using the list of differentially methylated CpG sites in HFpEF, we performed a complex network analysis to indentify the "HFpEF interactome" (Fig.1 A-B). Then, using the DisGeNET database we extracted n=12 candidate genes which were already associated with diastolic dysfunction, cardiac hypertrophy, cardiac fibrosis, inflammation, obesity, and hypertension, as key pathophenotypes of HFpEF (Fig.1 C). The hub genes included the ACTB, VAV2, JUNB, HOOK2, SETD7, PNKP, ASAP1, PAICS, DNM1L, HIF1AN, MEF2D, and NRG1. Validation experiment set by qRT-PCR revealed that elevated mRNA levels of the JUNB, SETD7, and MEF2D hypermethylated genes significantly discriminated HFpEF patients vs. CON (p&lt;0.01, p&lt;0.01, p&lt;0.001, respectively) and vs. HFrEF patients (p&lt;0.05, p&lt;0.01, p&lt;0.001, respectively) (Fig. 2A). Receiver operating characteristic (ROC) curve showed that network-oriented JUNB (AUC: 1, p&lt;0.001), SETD7 (AUC: 0.97, p&lt;0.01), and MEF2D (AUC: 1, p&lt;0.001) genes have a high diagnostic accuracy in discriminating HFpEF vs. CON as well as HFpEF vs. HFrEF (AUC: 1, p&lt;0.01, AUC: 0.97, p&lt;0.01, AUC: 1, p&lt;0.001, respectively) (Fig. 2B).

Conclusions
Circulating CD4+ T cell-derived hypermethylation of JUNB, SETD7, and MEF2D may reveal novel molecular drivers of HFpEF and suggest possible biomarkers to optimize patient phenotyping.
Hypoxemia in patients with heart failure and preserved ejection fraction
Authors: Omar M , Omote K , Sorimachi H , Popovic D , Kanwar A , Alogna A , Reddy Y N , Lim K G , Shah S , Borlaug B B 
Published: November 2023

Abstract

Background
Pulmonary abnormalities are common in patients with prevalent heart failure (HF). Arterial hypoxemia is considered rare in HF, but this has not been rigorously evaluated in patients with HF and preserved EF (HFpEF).

Methods

Results
Patients with HFpEF (n=539) and no clinically-relevant lung disease underwent invasive cardiopulmonary exercise testing with simultaneous blood and expired gas analysis. Exertional hypoxemia was defined by oxyhaeemoglobin saturation &lt;94%. As compared to those without hypoxemia (n=403), patients with hypoxemia (n=136, 25%) were slightly older, heavier, and had higher NT-proBNP levels. They had higher cardiac filling pressures, higher pulmonary vascular pressures, greater alveolar-arterial O2 difference compared to those without hypoxemia. These differences were replicated in a sensitivity analysis where patients with any spirometric abnormalities were excluded. Regression analyses revealed that increases in pulmonary arterial and capillary pressures were related to lower PaO2. The presence of exertional hypoxemia was associated with two-fold increased risk for death over 2.8 (IQR 0.7-5.5) years of follow up, (Adjusted:HR 2.00 (95%CI: 1.01−3.96), p=0.046).

Conclusion
One quarter of HFpEF patients displayed arterial desaturation during exercise. Patients with hypoxemia display more severely abnormal hemodynamics and increased mortality. Further study is required to better understand the mechanisms in patients with HFpEF.Hemodynamic changes at rest/exerciseRisk of death in HFpEF with hypoxemia
Contribution of reduced skeletal muscle perfusion reserve to exercise intolerance in HFpEF
Authors: Serafin A , Jasic-Szpak E , Przewlocka-Kosmala M , Ponikowski P , Kosmala W 
Published: November 2023

Abstract

Methods
Transthoracic echocardiography and skeletal muscle microvascular perfusion by contrast-enhanced ultrasound were performed at rest and immediately post exercise test in 77 HFpEF patients in NYHA class II and III, and in 20 age- and sex-matched individuals with a similar profile of comorbidities, but normal exercise tolerance. Exercise reserve of cardiac function parameters and skeletal muscle perfusion was calculated by subtracting resting value from exercise value.

Results
HFpEF patients demonstrated impairment of left ventricular (LV) and left atrial (LA) function reserve as reflected by lower exercise-induced increases in LV global longitudinal strain, LA reservoir strain, cardiac output and e’ mitral annular velocity, and higher increase in E/e’ ratio (Table). Similarly, skeletal muscle microvascular blood flow (MBF) reserve was lower in HFpEF patients than in the referents. There was no significant difference between the study group and the control group in resting MBF. MBF reserve was significantly associated with exercise capacity (r = 0.34; p = 0.004) and cardiac output reserve (r = 0.24; p = 0.04). In multivariable analysis including clinical and demographic variables, LV and LA components of cardiac functional reserve (LV global longitudinal strain, LA reservoir strain, cardiac output, e’ and E/e’) and MBF reserve, change from rest to exercise in MBF (beta 0.32, SE 0.10, p = 0.003) was in addition to patient age, sex and LV strain reserve among the independent correlates of exercise capacity.

Conclusions
Skeletal muscle perfusion reserve is impaired in HFpEF, and is associated with reduced exercise capacity independent of clinical, demographic and "central" cardiac factors. Accordingly, our results provide a rationale for extending the spectrum of pathophysiological milieu to be considered when planning patient management strategies in HFpEF over skeletal muscle-associated contributors to exercise intolerance.