bluuebunny/crossref_metadata_2025_split huggingface dataset:
P3494Dapagliflozin reduced lactate release by epicardial adipose tissue from CAD patients: switch from fatty acids to glucose aerobic oxidation
Authors: Couselo-Seijas M , Agra-Bermejo R M , Fernandez A L , Martinez-Cereijo J M , Soto-Rodriguez M , Rozados-Luis A , Gonzalez-Juanatey J R , Eiras S 
Published: October 2019

Abstract

Background
Dapagliflozin, a sodium-glucose co-transporter 2 inhibitor, improves the glucose uptake by epicardial adipose tissue (EAT). However, its metabolic pathways are still unknown. Our aim was to clarify the EAT glucose-lipid metabolism from patients with and without coronary artery disease (CAD).

Methods
Paired subcutaneous (SAT) and EAT biopsies from 49 patients undergoing heart surgery were cultured and treated with or without dapa at 10 or 100 μM for 6 hours. Glucose, lactate and oxygen were analyzed on supernatants by colorimetric or fluorescence assays. Glycolytic, lipolytic, glyceroneogenic and lipogenic genes or protein expression levels were determined on fat tissues by RT-qPCR or western blot, respectively.

Results
Glyceroneogenic and lipid metabolism-involved genes were higher expressed in SAT than in EAT. Dapa reduced their expression in SAT but not in EAT. Lipid-droplet protein levels, perilipin (PLN A) and hormone-sensitive lipase (HSL), were reduced in EAT. Mitochondrial biogenesis-related gene PGC1α was upregulated (p<0.05). Despite this drug improved glucose utilization, it reduced lactate release and oxygen consumption in both fat pads. After classifying patients according presence/absence of CAD, we observed a greater release of lactate by EAT in patients with CAD (3.22±2.40 mM) that was remarkably reduced after dapagliflozin treatment at 10 μM (2.17±1.53 mM, p<0.01) and 100 μM (2.45±2.11 mM, p<0.001).
Clinical characteristics regarding CAD presence (n=49) Non CAD patients (n=26) CAD patients (n=23) p value Gender (male) (n/%) 14/54 20/87 0.010* Age (years) 73±9 67±12 0.026* BMI (kg/m2) 29.±4 30±4 0.377 HTA (n/%) 21/80.8 17/73.9 0.578 T2DM (n/%) 12/46 9/39 0.629 HF (n/%) 2/8 6/26 0.096 L-Lactate (mM) 2±1.1 3.2±2.4 0.029* Glucose (mg/dL) 65±15 62±22 0.539 Oxygen (RFU) 47±9 46±14 0.899 CAD: Coronary artery disease, BMI: Body mass index, HTA: arterial hypertension, T2DM: Diabetes mellitus type 2, HF: Heart failure, RFU: relative fluorescence units.
Lactate in CAD

Conclusions
Dapagliflozin reduced the anaerobic glycolytic pathway, lowering the released lactate by EAT, overall in patients with CAD. This effect suggests a protective metabolic role since high lactate was found to be a marker of poor outcomes in HF patients.

Acknowledgement/Funding
Astrazeneca
P3496Empagliflozin improves cardiac function through the increased production of acetylcarnitine in a murine non-diabetic heart failure model
Authors: Nakao M , Shimizu I , Yoshida Y , Katsuumi G , Hayashi Y , Ikegami R , Suda M , Wakasugi T , Minamino T 
Published: October 2019

Abstract

Background
Empagliflozin is a renal sodium glucose transporter 2 (SGLT2) inhibitor, thereby mediates its anti-diabetic effect via excretion of glucose into urine. EMPA-REG OUTCOME study, the first big randomized control trial of empagliflozin have shown significant reduction of mortality and hospitalization due to heart failure in diabetic patients. This trial hasn't only had a huge impact to cardiovascular field, but also raised a number of questions about underlying mechanisms. It is also uncertain about the efficacy of empagliflozin in non-diabetic heart failure. In this study, we aimed to elucidate the biological effects and its underling mechanism of empagliflozin in a murine non-diabetic heart failure model.

Methods
We generated a heart failure murine model due to left ventricular (LV) pressure overload by performing transverse aortic constriction (TAC) operation to C57BL/6NCr mice. Two weeks after TAC operation we started empagliflozin administration mixed with diet at the ratio of 0.03% w/w. LV function was measured with echocardiography after administration of empagliflozin for two weeks (four weeks after TAC operation) and compared to a littermate control (no treatment) group. Then, heart samples were collected and subjected to further studies including metabolomic analysis. In-vitro studies including Seahorse Extracellular Flux Analyzer were also conducted with differentiated C2C12 cells and neonatal rat ventricular myocytes (NRVM).

Results
We found that empagliflozin treatment (Empa) significantly ameliorated LV systolic dysfunction induced by TAC compared to control group (Con) (figure.A) while heart weight/body weight ratio wasn't reduced. To explore key metabolites that can contribute to improvement of LV function, we conducted metabolomic analysis and found that empagliflozin significantly increased plasma acetylcarnitine level both in sham and TAC groups (figure.B). Previous studies have shown that acetylcarnitine acts as a substrate of acetyl CoA to fuel tricarboxylic acid cycle, and we tested the efficacy of acetylcarnitine for mitochondrial respiration capacity in differentiated C2C12 cells with Seahorse Extracellular Flux Analyzer. This analysis revealed that administration of acetylcarnitine resulted in a significant increase of oxygen consumption reflected by enhancing mitochondrial respiration. Similary, acetylcarnitine also markedly ameliorated impairment of mitochondrial respiration induced by isoproterenol in NRVM.

Conclusion
Our results indicated that empagliflozin has cardioprotective effect in murine heart failure model by enhancing mitochondrial respiration through the increased production of acetylcarnitine. We provide new evidence that empagliflozin would become a promising therapeutic agent to heart failure without diabetes.
P3500The primary cilium, a sensory apparatus of cells regulates the profibrotic capacity of fibroblasts in atrial fibrillation
Authors: Kawasaki M , Nariswari N A , Van Den Berg N W E , Neefs J , Meulendijks E R , Wesselink R , Baalman S W E , Van Boven W J P , Driessen A H G , De Groot J R 
Published: October 2019

Abstract

Background
Atrial fibrosis is a hallmark of atrial fibrillation (AF) and serves as an important arrhythmogenic substrate. It is formed by fibroblasts in response to tissue dyshomeostasis induced by multiple factors such as ageing, hypertension and inflammation. How fibroblasts phenotypically transform into an active form with enhanced profibrotic capacity in AF pathophysiology remains elusive. The primary cilium is an antenna-like small organelle, that function as a sensor to transduce external stimuli to intracellular signaling thereby potentially mediating the fibroblast's profibrotic capacity. Their involvement in AF pathophysiology is not known.

Objective
To explore the role of fibroblasts' primary cilium in the formation of the atrial fibrosis in AF.

Methods
Left atrial appendages (LAA) were obtained from persistent AF patients (AF: n=10) and patients without AF undergoing cardiac surgery (control: n=10). Primary cilia were immunostained with anti-acetylated a-tubulin in cryosections of the LAA. The loss of cilia in fibroblasts isolated from fresh LAA (AF: n=3, control: n=3) was induced by RNAi targeting IFT88, an essential factor for cilia formation. Gene expression and protein levels in LAA were quantified by qPCR and western blot, respectively (AF: n=20, control: n=20).

Results
The ratio of fibroblasts with primary cilium was significantly decreased in LAA of AF cohort (AF: 14.7%±4.6 vs control: 25.9%±3.6, p<0.01). Correspondingly, the protein levels of acetylated a-tubulin, an exclusive component of cilia, were significantly decreased both in whole LAA and fibroblast fraction of AF cohort compared to control (p<0.05). The loss of primary cilia induced by RNAi in fibroblasts resulted in increased differentiation of fibroblasts into myofibroblasts and the expression of extracellular matrix genes in response to TGF -b1.
Primary cilium is disassembled along with degradation of acetylated a-tubulin by HDAC6. Indeed, a negative correlation between the protein levels of acetylated a-tubulin and HDAC6 were observed in the LAA of AF cohort (p<0.05) but not in control. Furthermore, the gene expression of AURKA and HEF1, upstream activators of HDAC6, was increased by 1.5-fold (p=0.09) and 3-fold (p<0.001), respectively, in the LAA of AF cohort compared to control.

Conclusion
The formation of primary cilia in fibroblasts is actively suppressed in AF via HEF1/AURKA/HDAC6 cascade, which in turn enhances the profibrotic response of fibroblasts. This study provides an innovative paradigm for fibrosis formation in AF, and implicates that the primary cilium of fibroblasts potentially become a novel therapeutic target to treat the AF substrate.
P3510Cardiac function and Ca2+-cycling are different according to the level of cardiac-specific FKBP12.6 overexpression
Authors: Gandon-Renard M , Lefebvre F , Courilleau D , Gomez S , Gomez A M , Mercadier J J 
Published: October 2019

Abstract
Cardiac ryanodine receptors (RyR2) have a key role in excitation-contraction coupling by releasing Ca2+ from sarcoplasmic reticulum (SR). In cardiomyocytes, two FK506 binding protein (FKBP) isoforms have been shown to bind and to stabilize RyR2 opening: FKBP12 and FKBP12.6, the later having a stronger affinity for RyR2 despite its lower abundance. Cardiac-specific FKBP12.6 overexpressing mice have fewer arrhythmias induced by β-adrenergic stimulation than wild type (WT) mice, suggesting an implication of FKBP12.6 in an antiarrhythmic mechanism. Heart failure (HF) syndrome has a high incidence of arrhythmias, which may be explained by a decrease of FKBP isoform expression.
The precise mechanism of the antiarrhythmic effect of FKBP12.6 overexpression remains unknown.
To gain insight into this mechanism, we developed 2 transgenic mouse lines with cardiac-specific moderate- (TG1) and high- (TG2) FKBP12.6 overexpression levels. We characterized cardiac function, [Ca2+]i cycling and its response to β-adrenergic stimulation in both mouse lines.
TG1 and TG2 mice developed mild and marked cardiac hypertrophy, respectively, associated with basal cardiac function increase in TG1 mice only. In stimulated cardiomyocytes, [Ca2+]i transient amplitude, measured by confocal microscopy, was higher in TG1 than in WT mice, without a significant difference in their SR Ca2+ content. The effect of β-adrenergic stimulation (50 nM isoproterenol) was attenuated in TG1 mice compared to WT mice, in association with the prevention of pro-arrhythmogenic Ca2+ release events, such as Ca2+ waves. In contrast, TG2 mice showed [Ca2+]i handling characteristics similar to HF, with slower [Ca2+]i transient relaxation. Interestingly, and contrary to HF, pro-arrhythmogenic Ca2+ release events were also reduced in TG2.
These results indicate that the level of FKBP12.6 overexpression has distinct effects on cardiac function and on Ca2+-cycling and its response to β-adrenergic stimulation.
P3514Gender differences in prognosis for total mortality among patients with ADHF: results of four-year follow-up
Authors: Polyakov D , Fomin I 
Published: October 2019

Abstract

Aim
To obtain information on the effect of various predictors on the prognosis of a patient with acute decompensated heart failure (ADHF).

Methods
We investigated a sample of patients (n=719) hospitalized due to ADHF for 4 years (average observation duration was 2.3 years). 27 predictors were included in the model (clinical conditions and clinical signs of ADHF). We used regression tree method with CHAID algorithm with 10-fold cross-validation to determine the most important predictors of the prognosis.

Results
The most significant predictor for total mortality at the first branching was the gender of the patient. Mortality rate was 65.0% among males vs 47.9% among females (p<0.001). In the subgroup of males, the next most significant predictor for the prognosis was the level of systolic blood pressure (SBP): mortality rates was 79.6% with SBP ≤125 mm Hg vs. 57.2% with SBP >125 mm Hg (p=0.001). In the subgroup of males with SBP >125 mm Hg mortality rates differed depending on the presence of X-ray signs of congestion; when present, the total mortality was 65.7% vs. 47.8 in the absence (p=0.01). In the subgroup of females, the first most significant predictor of prognosis was diabetes mellitus (DM): mortality rates was 60.1% with DM vs. 41.2% without DM (p<0.001). The worst prognosis was found among those who are over 78 years old (55.8%) compared with younger (32.4%, p=0.001) for females with DM.
The model has high sensitivity (74.9%) but low specificity (50.3%). In the ROC analysis, AUC was 0.673 (95% CI: 0.634–0.712).
Regression tree for total mortality rate

Conclusion
The 4-year survival rate for patients with ADHF varies by gender. Among men, the most important predictors of prognosis were the level of SBP and the presence of congestion in the lungs at the hospital admission. Among women, DM and age had the greatest influence on the prognosis.
P3531Continual measurement of arterial dP/dtmax enables mini-invasive monitoring of left ventricular contractility in acute heart failure
Authors: Vondrakova D , Vondrakova D V , Kruger A K , Janotka M J , Neuzil P N , Ostadal P O 
Published: October 2019

Abstract

Introduction
Continuous reliable evaluating of left ventricular (LV) contractile function in patients with advanced heart failure requiring intensive care remains challenging. Recently, continual monitoring of dP/dtmax from arterial line became available for hemodynamic monitoring. However, the relation between arterial dP/dtmax and LV dP/dtmax measurement is not fully understood.

Purpose
The aim of our study was to determine the relation of arterial dP/dtmax and LV dP/dtmax assessed by echocardiography in patients with acute heart failure.

Methods
Forty-eight patients with acute heart failure requiring intensive care and hemodynamic monitoring were recruited into the study (mean age 70.4 years, 65% were males). Hemodynamic variables including arterial dP/dtmax were continually monitored using arterial line pressure waveform analysis. LV dP/dtmax was assessed using continuous-wave Doppler analysis of mitral regurgitation flow.

Results
The values from continual arterial dP/dtmax monitoring significantly correlated with the LV dP/dtmax assessed by echocardiography (r=0.72, 95% confidence interval [CI] 0.54–0.83, P<0.0001). Linear regression revealed that (LV dP/dtmax) = 0.87×(arterial dP/dtmax) + 291, P<0.0001. Arterial dP/dtmax significantly correlated also with the stroke volume (r=0.55, P<0.0001), cardiac output (r=0.32, P=0.0289), mean arterial blood pressure (r=0.43, P=0.0155) and systolic blood pressure (r=0.79, P<0001). On the other hand arterial dP/dtmax did not correlate with the systemic vascular resistance (SVR), heart rate, dynamic arterial elastance, diastolic blood pressure or central venous pressure.

Conclusion
Our results revealed that arterial dP/dtmax values tightly and highly significantly correlate with LV dP/dtmax. Arterial dP/dtmax could be, therefore, used for continual monitoring of LV contractility.

Acknowledgement/Funding
Institutional grant MH CZ - DRO (Na Homolce Hospital- NNH, 00023884), IG150501
P3536Prevalence and clinical impact of social frailty in elderly patients hospitalized for acute decompensated heart failure: a multicenter prospective cohort study
Authors: Hamada T , Kubo T , Nakaoka Y , Kawai K , Yabe T , Furuno T , Kondo F , Yamada E , Yamasaki N , Kitaoka H 
Published: October 2019

Abstract

Purpose
The aim of this study was to investigate clinical characteristics of socially frail patients and an association with social frailty and short-term rehospitalization for worsening heart failure.

Methods
We analyzed 169 elderly patients (≥65 years old) hospitalized for acute decompensated heart failure (ADHF) between June 2017 and August 2018 in our prospective HF registry in Japan. The patients with activities of daily living dependence and without data of social frailty and outcome were excluded. Social frailty was determined based on their responses to the 5 questions (living alone, eating alone, going out less frequently, rarely visiting friends, not helpful to friends or family). Patients with none of these components were considered social non-frailty; those with one component were considered social prefrailty; those with two or more components were considered social frailty. The outcome was rehospitalization for worsening HF within 6 months after discharge.

Results
The mean age was 79±8 years old. Social frailty in 86 patients (50.8%), social prefrailty in 41 patients (24.3%), and social non-frailty in 42 patients (24.9%) were observed. Age, body mass index, geriatrics nutritional risk index, Hasegawa dementia rating scale-revised score, gait speed, and handgrip strength values were significantly different among the these three groups (all Ps for trend <0.01). Left ventricular ejection fraction, brain natriuretic peptide values, and the proportion of the patients with the symptom of New York Heart Association class III/IV did not vary significantly between the groups. Kaplan-Meier analysis revealed that higher prevalence of rehospitalization for worsening HF within 6 months in the social frailty group compared to that in the social non-frailty group (Log-rank p<0.05). In a Cox proportional hazard model after adjusting covariates, patients with social frailty (hazard ratio 4.77; 95% CI 1.61–14.12, p<0.005) and social prefrailty (hazard ratio 3.73; 95% CI 1.12–12.41, p<0.05) had an increased risk of rehospitalization for worsening HF within 6 months compared with those with social non-frailty.

Conclusion
This study revealed that social frailty was common in elderly patients hospitalized for ADHF, and social frailty was an independent predictor of rehospitalization for worsening HF within 6 months after discharge.
P3546EPIT-HF survey of chronic heart failure with preserved, mid-range and reduced ejection fraction. Focus on therapy
Authors: Dubrava J , Sidlo R 
Published: October 2019

Abstract

Background
There is only a limited range of data on comparison of therapy for all three phenotypes of chronic heart failure (HF).

Purpose
In a prospective survey, to determine and compare pharmacological and non-pharmacological treatment for three phenotypes of chronic HF– HF with reduced, mid-range and preserved ejection fraction (HFrEF, HFmrEF and HFpEF).

Methods
The survey was performed by 115 cardiologists and 46 internists. Consecutive outpatients diagnosed with chronic HF aged at least 18 years were enrolled. There were no exclusion criteria. The HF phenotypes were defined according to LVEF: HFrEF – LVEF <40%, HFmrEF – LVEF 40–49%, HFpEF – LVEF ≥50%. A total of 2 677 patients were enrolled. The subgroups of HFrEF, HFmrEF and HFpEF comprised of 1 169 (43.7%), 720 (26.9%) and 788 (29.4%) of patients, respectively.

Results
The pharmacotherapy and electroimpulse therapy was significantly different between the HF phenotypes. The most striking differences were found between HFrEF and HFpEF. Among these phenotypes, there were significant differences in the treatment prevalence across all drug classes, CRT-D, CRT-P and ICD. HFmrEF resembled HFrEF more than HFpEF in terms of pharmacotherapy. The prevalence of therapy for HFmrEF by any drug class, CRT-D, CRT-P and ICD, was always intermediate between HFrEF and HFpEF.
Comparison of therapy HFrEF (1) HFmrEF (2) HFpEF (3) p (n=1169) (n=720) (n=788) Overall 1 vs 2 1 vs 3 2 vs 3 BB 91.9% 90.4% 83.4% <0.001 0.275 <0.001 <0.001 ACEI 77.4% 71.1% 62.9% <0.001 0.003 <0.001 <0.001 ARB 18.7% 23.3% 29.1% <0.001 0.016 <0.001 0.012 ACEI/ARB 92.8% 92.9% 87.7% <0.001 1.0 <0.001 <0.001 MRA 80.1% 55.4% 28.9% <0.001 <0.001 <0.001 <0.001 Ivabradine 39.7% 34.7% 28.1% <0.001 0.032 <0.001 0.005 Furosemide 89.9% 75.0% 54.7% <0.001 <0.001 <0.001 <0.001 CRT-D 8.2% 0.8% 0.4% <0.001 <0.001 <0.001 0.324 ICD 16.2% 2.2% 0.8% <0.001 <0.001 <0.001 0.029 HTx 0.3% 0% 0.6% 0.104 0.304 0.498 0.063 Assist devices 0.3% 0% 0.1% 0.367 0.292 0.653 1.0

Conclusion
We presented the real-world data on pharmacological and non-pharmacological treatment of all three phenotypes of HF. The therapy for HFrEF, HFmrEF and HFpEF differed significantly. Pharmacotherapy for HFmrEF has been more closely related to HFrEF treatment than to HFpEF treatment.

Acknowledgement/Funding
EPIT-HF survey was supported by the educational grant of Servier.
P3549Impact of mitral regurgitation on alveolo-capillar membrane diffusion: an hemodynamic and functional study
Authors: Bandera F , Ghizzardi G , Agnifili M , Pizzocri S , Giammarresi A , Boveri S , Losito M , Labate V , Alfonzetti E , Guazzi M 
Published: October 2019

Abstract

Background
In HFrEF patients, high pulmonary vascular resistances (PVR) reflect a combined increase of pre- and post-capillary pressures, associated with worse outcome. Mitral regurgitation (MR) may play a role in this complex physiopathology. We sought to investigate MR impact on lung DLCO and pulmonary vascular hemodynamic in HFrEF patient.

Methods
22 HFrEF patients (age 67±11; LV EF) underwent right heart catheterization, rest and exercise echocardiography, right ventricle 3D assessment and lung alveolo-capillary membrane DLCO. We identified 2 subgroups according to normal (<3 WU, n=17) or abnormal (>3 WU, n=5) PVR.

Results
Abnormal PVR patients showed increased pulmonary artery pressures and TPG, reduced CO and pulmonary artery compliance. Total DLCO was not significantly different between groups. The membrane component (Dm) and the alveolar volume (Va) were significantly reduced in abnormal PVR group, while the capillary volume (VC) showed a strong trend toward higher values. Abnormal PVR group had a very high percentage of moderate-to-severe MR. The TASPE/SPAP ratio and the circumferential component of RV systolic function were significantly reduced in abnormal PVR group.
Normal PVR (n=17) Abnormal PVR (n=5) p NTproBNP, ng/L 3021±2527 7023±8785 0.55 MR moderate-to-severe, n (%) 3 (19%) 4 (80%) 0.025 TAPSE/SPAP, mm/mmHg 0.4761±0.1695 0.2956±0.0739 0.019 3D RV global EF, % 40.616±9.350 29.486±14.062 0.119 3D RV longitudinal EF, % 15.611±7.773 12.086±9.694 0.497 3D RV circumferential EF, % 31.0567±6.5744 21.1746±11.5823 0.019 Lung diffusion of CO (DLCO), ml/min/mmHg 19.021±4.643 15.233±1.761 0.197 Dm ml/min/mmHg 26.8±8.2 17.8±4.1 0.047 VC, ml 110±77 247±152 0.121
Graphics

Conclusion
The presence of severe MR, in this cohort of HFrEF patients, is associated with alveolar-capillary membrane remodeling (lower Dm), worse hemodynamic profile (higher PA pressures, lower PA compliance and higher PA resistance) and worse right ventricle to pulmonary circulation coupling (lower TAPSE/SPAP and lower 3D RV circumferential EF), confirming the use of therapeutic strategies aimed at correction of valvular disease.