bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ablation for atrial fibrillation improves the outcomes in patients with heart failure with preserved ejection fraction: a single-center cohort study
Authors: Xie Z , Qi B Z , Zhou J M 
Published: November 2023

Abstract

Introduction
Patients with heart failure and preserved ejection fraction (HFpEF) are frequently associated with atrial fibrillation (AF), and such clinical condition has worse clinical status than those with sinus rhythm. Whether the use of a strategy to maintain sinus rhythm in patients with HFpEF would affect outcomes remains uncertain.

Purpose
To investigate whether the strategy of AF ablation to maintain sinus rhythm compared to no ablation is associated with improvement of all-cause death and rehospitalization for worsening heart failure in patients with AF and HFpEF.

Methods
In this retrospective cohort study, a total of 1034 patients with HFpEF and AF (69 [63, 76] years, 478 [46.2%] female) were analyzed, 392 patients who received first-time AF ablation were assigned to the ablation group, and the remaining 642 patients with merely medical therapy were assigned to the no ablation group. The primary end point was a composite of all-cause mortality or rehospitalization for worsening heart failure and was assessed by the Kaplan-Meier method and Cox proportional hazard model. Baseline differences were adjusted by multivariable-adjustment analysis, propensity score-matched analysis, and inverse probability of treatment weighting analysis. Atrial tachycardia/AF recurrence was assessed in a multivariable-adjusted Fine & Gray model, with death treated as a competing risk factor.

Results
After a median follow-up period of 39 months, the cumulative incidence of the primary end point was significantly lower in the ablation group compared to the no ablation group after multivariable adjustment in the overall cohort (adjusted hazard ratio [HR], 0.65 [95% CI, 0.45-0.94], P = 0.02; incidence rate difference [IRD], -0.39 [95% CI, -0.54 to -0.25]). Analyses for secondary outcomes revealed that clinical benefit produced by AF ablation was mainly driven by rehospitalization for worsening heart failure (adjusted HR, 0.65 [95% CI, 0.44-0.96], P = 0.03) with an estimated IRD of -0.31 (95% CI, -0.45 to -0.18). Results were consistent in the propensity score-matched analysis and inverse probability of treatment weighting analysis. In addition, patients in the ablation group had a 34% relative decrease in the atrial tachycardia/AF recurrence (adjusted HR, 0.66 [95% CI, 0.55-0.81], P &lt; 0.001) relative to no ablation group in the multivariate-adjusted Fine & Gray model. Patients who received AF ablation and maintained sinus rhythm during the follow-up period had a lower risk of the primary end point (P &lt; 0.001 by log-rank test).

Conclusion(s)
Among HFpEF and AF patients, the strategy of AF ablation to maintain sinus rhythm led to a lower risk of the composite of death from any cause or hospitalization for worsening heart failure.Figure 1.Kaplan–Meier curvesTable 1.Incidence rate and hazard ratio
Empagliflozin improves diastolic function in obese ZSF1 rats by restoring the cardiac mitochondrial respiratory capacity
Authors: Schauer A , Langner E , Augstein A , Winzer E , Fabig G , Linke A , Adams V 
Published: November 2023

Abstract

Background
Clinical studies demonstrated beneficial effects of Sodium-Glucose-Transporter 2 inhibitors (SGLT2i) on the combined risk of cardiovascular death or heart failure hospitalization in patients with heart failure with preserved ejection fraction (HFpEF). However, underlying processes leading to cardioprotection remain unclear.

Purpose
The present study aimed to elucidate the impact of Empagliflozin on myocardial function and metabolism in a rat model (ZSF1 rat) with established HFpEF and to analyze underlying mechanisms.

Methods
24 week old, obese ZSF1 rats were randomized either receiving standard care (obese) or Empagliflozin (Empa, 30 mg/kg/d p.o.). ZSF1 lean rats (lean) served as healthy controls. All animals underwent a baseline, intermediate and final echocardiography. After 8 weeks of treatment, hemodynamics were measured invasively, blood samples were taken, cardiac mitochondrial function was assessed and left ventricular tissue was collected for molecular and histological analyses or for transmission electron microscopy (TEM).

Results
Compared to the obese control Empa treated obese rats demonstrated a significantly improved diastolic function already at 4 weeks of treatment (E/é: lean: 17.9 ± 0.8; obese: 23.7 ± 0.7, p&lt;0.001 vs. lean; Empa: 21.0 ± 1.1, p&lt;0.05 vs. lean; p&lt;0.05 vs. obese), which reached the level of healthy controls after 8 weeks of treatment (E/é: lean: 17.5 ± 0.7; obese: 24.4 ± 1.1, p&lt;0.001 vs. lean; Empa: 19.4 ± 0.8, p&lt;0.001 vs. obese). This was accompanied by reduced hypertrophy, fibrosis, left ventricular stiffness and inflammation as well as by improved hemodynamics. Except for a slightly improved myocardial ketone body utilization in Empa treated rats, there was no shift in metabolic substrate preference between groups. Cardiac mitochondrial respiratory function observed in untreated obese rats was significantly impaired compared to healthy controls but restored by Empa treatment (Vmax of complex II: lean: 0.15 ± 0.007 nmol O2/s/mg, obese: 0.12 ± 0.004 nmol O2/s/mg, p&lt;0.01 vs. lean; Empa: 0.17 ± 0.006 nmol O2/s/mg, p&lt;0.05 vs. lean, p&lt;0.001 vs. obese). Moreover, mitochondrial respiratory capacity correlated with diastolic function, suggesting a pivotal role of restored respiratory function for improved diastolic relaxation. TEM revealed reduced size of cardiac mitochondria in obese rats, which was significantly restored by Empa. Proteomic analysis demonstrated major changes in proteins involved in mitochondrial oxidative phosphorylation and antioxidant metabolism.

Conclusions
The present study demonstrates for the first time beneficial effects of Empaglifozin on cardiac remodeling, diastolic function and hemodynamics in an obese rat model of HFpEF. These effects were accompanied by improved mitochondrial respiratory function, enhanced ketone body utilization and improved antioxidant capacity.
A shortened electrocardiographic diastolic interval is involved in diastolic dysfunction and HFpEF
Authors: Van Ommen A M L , Bear L R , Carlos Sampedrano C , Onland-Moret N C , Cramer M J , Rutten F H , Dal Canto E , Tulevski I I , Somsen G A , Den Ruijter H M , Coronel R 
Published: November 2023

Abstract

Background
Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome characterized by left ventricular diastolic dysfunction (LVDD). We hypothesized that a short electrocardiographic diastolic time predisposes to LVDD and HFpEF by deteriorating diastolic function. This effect may be more pronounced in women than men, given longer QT interval in women.

Methods
To experimentally test if incremental shortening of the diastolic interval indeed worsens the diastolic function, we shortened electrical diastole using right atrial (RA) pacing and QT-prolonging medication (sotalol) in six pigs. We used 12-lead ECG and echocardiography to assess electrical diastole (TQ interval) and diastolic function. We next analyzed electrocardiograms and corresponding information on LVDD and HF in electronic health record data from 85,145 patients that visited one of 13 Cardiology Centers of the Netherlands. We sex-specifically assessed the association between TQ interval on the one hand and LVDD or HFpEF on the other.

Results
In pigs, baseline TQ interval was 257 (±SD 66) ms, which decreased to 232 (±SD 36) ms during RA pacing (100 bpm), and further to 193 (±SD 52) ms with concomitant sotalol administration (2 mg/kg iv, bolus). These changes in TQ interval resulted in reversal of E/A ratio, with a significant correlation between TQ interval and decreasing e’/a’ ratio (r=0.382, p=0.024) (Figure 1). In patients who underwent cardiac evaluation with ECG and echocardiography, diastolic abnormalities were documented as LVDD (n=26,009 (30%)) and HFpEF (n=2,551 (3%)). TQ intervals were significantly shorter in patients with LVDD and HFpEF (479 (±SD 128) and 485 ms (±SD 138), respectively) compared to the ones without LVDD or HFpEF (523 (±SD 137) ms). A shorter TQ interval increased the risk for having LVDD and HFpEF when adjusted for confounders (LVDD; ORadjusted= 1.37 (95% CI: 1.28, 1.45), HFpEF; ORadjusted= and 1.16 (95% CI: 1.01, 1.35) (Table 1). There was significant sex-interaction (p= 0.039) for TQ and LVDD risk, with stronger associations in women (ORadjusted= 1.43 (95% CI: 1.32, 1.56) compared to men (ORadjusted= 1.35 (95% CI: 1.10, 1.64) (Table 1).

Conclusion
Experimentally decreasing the electrical diastolic interval leads to diastolic function abnormalities in pigs. In humans, a shorter diastolic interval is associated with a higher risk of having either LVDD or HFpEF. Our findings imply that a shortened electrical diastolic interval may precede diastolic dysfunction and HFpEF. Therefore, prolonging or preserving electrical diastole may be effective in preventing or treating HFpEF, especially in women.Figure 1Table 1
Ventricular arterial coupling in patients with ischemia but no obstructive coronary artery disease: novel insight into heart failure progression
Authors: Iribarren A , Nelson M D , Oneglia A P , Palmero-Canton A , Obrutu O , Maughan J , Lauzon M , Pepine C J , Handberg E M , Bairey Merz C N , Wei J 
Published: November 2023

Abstract

Background
Ischemia with no obstructive coronary artery disease (INOCA) is prevalent in women and is associated with increased risk of developing heart failure with preserved ejection fraction (HFpEF). While the exact mechanism contributing to heart failure progression remains incompletely understood, we hypothesize that impaired ventricular-arterial coupling (VAC) plays a key role.

Purpose
To evaluate VAC across the INOCA-HFpEF continuum.

Methods
To accomplish our research objective, we leveraged cardiac magnetic resonance images from individuals with INOCA and HFpEF from the WISE Pre-HFpEF (NCT03876223) and WISE HFpEF (NCT02582021) studies, along with reference controls. Aortic pulse wave velocity (aPWV) was measured using velocity-encoded MRI, from the proximal ascending to distal descending aorta. Global longitudinal strain (GLS) was measured by feature tracking of horizontal and vertical long axis cine images. VAC was defined as the ratio between aPWV and GLS. To test for potential mediators, we assessed the relationship between VAC and age, risk factors, systolic blood pressure (SBP), diastolic blood pressure (DBP), myocardial perfusion reserve index (MPRI), LV end diastolic pressure (LVEDP), cardiac structure/function, and Kansas City Cardiomyopathy questionnaire (KCCQ).

Results
The baseline characteristics of the three study groups are described in the Table. Patients with INOCA had similar KCCQ scores as HFpEF patients, suggesting INOCA patients may have subclinical HFpEF. Consistent with our hypothesis, we observed a progressive impairment in VAC across the three groups (Controls vs INOCA vs HFpEF), being significantly worst in HFpEF(Figure). Importantly, VAC was inversely related with age, systolic/diastolic blood pressure, and LV mass index (R=-0.6, R=-0.4, R=-0.4, R=-0.3 respectively, all p &lt;0.001).

Conclusion
The data herein support the hypothesis that VAC contributes to heart failure progression, with age, arterial blood pressure and LV mass being key determinants. That VAC was not yet significantly different between INOCA, and reference controls highlights an important opportunity for intervention to prevent heart failure progression.
CPET as a prognosis assessing tool in patients with heart failure with preserved ejection fraction
Authors: Rozados Da Conceicao C , Krannich A , Zach V , Pinto R , Deichl A , Feuerstein A , Schleussner L , Edelmann F 
Published: November 2023

Abstract

Introduction
Patients with heart failure with preserved ejection fraction represent half of the heart failure patients nowadays, an at least steady trend due to the aging of the population. We investigated whether the parameters obtained from cardiopulmonary exercise testing (CPET) correlated with the prognosis of these patients. This prospective observational cohort study looks into the relationship between the CPET parameters peak VO2 and VE/VCO2 slope and the heart failure hospitalizations or cardiovascular death of these patients.

Methods
From August 2016 until May 2019, 99 patients of our outpatient clinic with newly diagnosed with heart failure with preserved ejection fraction underwent cardiopulmonary exercise testing. Median follow-up was 30 months (interquartile range, 24-38.5). We selected peak VO2 &lt;14 ml/min/kg and a VE/VCO2 slope &gt; 34 as threshold values for our primary endpoint, a composite of hospitalization for heart failure or cardiovascular death.

Results
The mean age was 75.07 ± 7.31 years, 48.5% were women, 24.2% were at NYHA class III and mean NTproBNP was 511 pg/mL. Mean peakVO2 was 15.09 ± 4.75 and mean VE/VCO2 was 36.05 ± 6.60. During follow-up, they were 67 hospitalizations, 53 cardiovascular hospitalizations, 24 heart failure hospitalizations and 4 deaths. Over a median follow-up of 30 months, the primary outcome event occurred in 5 of 40 patients (12.5%) with a VE/VCO2 Slope ≤ 34 and in 19 of 59 patients (32.2%) with a VE/VCO2 Slope &gt; 34 (hazard ratio, 2.688; 95% confidence interval (CI); P 0.04). On multivariate analysis, accounting for heart failure hospitalization or cardiovascular death as a terminal event, VE/VCO2 slope was independently associated with the risk of admission due to heart failure worsening.

Conclusion
In patients with heart failure with preserved ejection fraction, a VE/VCO2 Slope &gt; 34 predicts heart failure hospitalizations and cardiovascular death.Primary Endpoint
AAV.Cas9 and AAV.SERCA2a strategies to mitigate heart failure in DMD pigs
Authors: Baehr A , Hornaschewitz N , Stirm M , Hoppmann P , Bozoglu T , Klymiuk N , Laugwitz K L , Moretti A , Wolf E , Hajjar R , Kupatt C 
Published: November 2023

Abstract

Aims
Duchenne muscular dystrophy is a devastating disease affecting skeletal muscle and heart, which is caused by loss-of-function mutations in the dystrophin (DMD) gene. Since pharmacologic treatment is ineffective over time, gene therapy including gene editing is rapidly evolving. In DMDdelta52 pigs, we have previously demonstrated efficacy of an AAV9-Cas9-gRNA approach, which by excision of exon 51 provided a shortened, but stable dystrophin D51-52. Here, we set out to compare this approach to germline excision of exon 51 in the DMDdelta52 pig, resulting in ubiquitous dystrophin D51-52 expression, a porcine model of Becker muscle dystrophy (BMD). Alternately, we provided locoregional AAV.SERCA2a gene therapy to the DMDdelta52 pigs.

Methods and results
We generated pigs lacking exon 52 of the DMD gene. Male offspring are characterized by heart failure (EF33±3%), arrhythmogenesis due to distinct regions of low or no-amplitude action potentials and by sudden cardiac death before 4 months of age. Germline correction of the loss of function mutation by additional excision of neighbouring exon 51 induced a Becker phenotype (BMD), with a mildly reduced ejection cardiac function (EF 45±3%) a reduction of vulnerable areas in electrophysiology mapping and a prolonged lifespan. Postnatal AAV9.Cas9-gE51 also improved EF (40±2%) and reduced electrophysiological vulnerability, increasing survival significantly. Using intracoronary delivery of AAV1.SERCA2a at a dose of 3x1013 virus genomes (vg) per pig by slow antegrade infusion of LAD & LCx improved left ventricular ejection fraction (EF 46±5% +AAV1.SERCA2a), but did not alter the amount of no-amplitude areas per LV.

Conclusions
Compared to ubiquitous excision of exon 51 (DMDdelta51-52) or postnatal AAV.Cas9-gE51 treatment of a DMDdelta52 pig model, which both improved ejection fraction EF and almost normalized action potential amplitudes, a moderate dose of AAV1.SERCA2a sufficed to normalize left ventricular function, but did not affect electrical vulnerability of the heart. Hence, AAV.SERCA2a combined with antitachycardic pacemaker protection may serve as a safe treatment option for DMD cardiomyopathy, whereas Cas9-mediated gene editing may provide additional therapy of electrical vulnerability. Further translational studies will establish novel gene therapeutic options for DMD patients.
Transcriptional regulation of macrophage inflammation in the heart failure with preserved ejection fraction: a translational study
Authors: Gorica E , Mohammed S A , Mengozzi A , Ambrosini S , Wenzl F A , Mongelli A , Ruschitzka F , Hamdani N , Costantino S , Paneni F 
Published: November 2023

Abstract

Background/Introduction
Inflammatory response is a key player in heart failure with preserved ejection fraction (HFpEF) but the underlying mechanisms are poorly understood (1). Recent studies have shown a critical involvement of cardiac macrophage recruitment and activation in myocardial remodelling (2,3).

Purpose
here we sought to determine the role of macrophage inflammation in experimental and human HFpEF.

Methods
We employed a translational approach combining human and murine LV myocardial tissue, FACS analysis of cardiac immune cells, in vitro experiments in primary macrophages and cardiac cells as well as ex vivo functional analyses in LV tissues. Human LV myocardial samples were used to evaluate the pro-inflammatory activity of macrophages in the HFpEF myocardium. Induction of HFpEF in mice was done through a validated mouse model combining metabolic (high-fat diet) and hemodynamic stress (L-NAME). Cardiac function was investigated by high resolution ultrasound imaging (Vevo3100) and the LV myocardial samples were used to study the macrophage polarization and their inflammatory activity. Based on interrogation of available RNA-seq datasets –showing the transcriptional repressor NCOR1 as a relevant signature in macrophages during cardiac inflammation, we generated myeloid cell-specific NCOR1 knockout (Ncor1-KO) transgenic mice to investigate the in vivo effects of NCOR1 deletion on the HFpEF phenotype. In vitro experiments included RAW 264.7 cells polarization through a metabolic stress model via palmitic acid (PA) and the assessment of macrophage phenotype switching in the presence or the absence of NCOR1. To study the crosstalk of macrophages with the surrounding cardiac cells, cardiomyocytes (H9c2) and endothelial cells (HAECS) were exposed to conditioned media from cultured RAW. Afterwards, cellular function and the pro-inflammatory cytokine levels were investigated.

Results
The expression of macrophage markers in human LV specimens showed an increase in pro-inflammatory macrophages (M1) and a decrease in regulatory macrophages (M2) as compared to age-matched control mice. HFpEF mice showed increased expression of vascular adhesion molecules (ICAM1, ICAM2, E-selectin) and a significant recruitment of M1 macrophages to the myocardium. Of interest, cardiac function and myocardial inflammation (TNF-a, IL6, IL-1b) were significantly reduced in Ncor1-KO mice. In vitro assays showed that stimulation of macrophages with PA induced M1 type switch and increased NCOR1, TNF-a, IL-6, and IL-1b levels, whereas NCOR1 depletion prevented detrimental changes of macrophage secretome (Fig.2).

Conclusion
NCOR1 is a crucial co-regulator of immune response and macrophage inflammation in the heart. Our findings pave the way for mechanism-based therapies to prevent HFpEF development.
Mitochondrial dynamics and myocardial metabolism alterations during anthracycline-cardiotoxicity
Authors: Diaz-Guerra Priego A , Villena-Gutierrez R , Cadiz L , Gomez M , Oliver E , Ibanez B 
Published: November 2023

Abstract

Background
Despite the increased effectiveness of chemotherapeutic agents, cancer represents a lethal illness worldwide and anticancer strategies still present severe adverse effects. Cardiac dysfunction is a dose-dependent common affliction of anthracyclines treatment. Anthracycline-induced cardiotoxicity (AIC) and consequent heart failure has recently been suggested to be mediated by mitochondrial dysfunction; however, the molecular mechanisms driving this connection are incompletely understood.

Purpose
To study the early molecular changes (before onset of overt heart failure phenotype) related to mitochondrial biology and cardiac metabolism in a mouse model of AIC.

Methods
CD1 mice underwent 5 weekly i.p. injections (5 mg/kg) of doxorubicin. Cardiac anatomic and functional changes were evaluated by echocardiography at 1, 9 and 15 weeks-after last doxorubicin injection. At each time-point, some animals were sacrificed and hearts were collected for characterisation of mitochondrial dynamics and metabolic substrate utilization by western blot, PCR, immunocytochemistry, high-resolution respirometry, transmission electron microscopy and PET/CT.

Results
Doxorubicin administration resulted in an early reduction in left ventricle (LV) mass which was the result of marked cardiomyocyte atrophy as early as 1 week after doxorubicin completion. Cardiac atrophy preceded functional abnormalities, which were apparent in the form of reduction in LV ejection fraction at 9 weeks. Mitochondrial dynamics (fusion/fission) and membranes were altered as early as 1 week after doxorubicin completion (i.e. long before changes in LV function). Moreover, mitochondrial respiratory rate was decreased in these animals, together with a decrease in mitochondrial DNA content and biogenesis at early timepoints. Early (1 week) mitochondrial molecular changes were accompanied by altered cardiac metabolism (i.e. switch in substrate utilization to glucose).

Conclusions
Here we have characterized the dynamics of molecular, anatomical and functional changes during AIC. LV systolic dysfunction is a late phenomenon happening long after molecular and metabolic changes in the heart. Cardiomyocyte atrophy, altered mitochondrial dynamics and respiration, and metabolic switching occur long before overt heart failure phenotype. These early changes appear as promising therapeutic targets to prevent overt AIC and heart failure.