bluuebunny/crossref_metadata_2025_split huggingface dataset:
514 ATAXIA TELANGIECTASIA MUTATED PROTEIN MODULATES GLUCOSE AND LIPID METABOLISM IN THE HEART
Authors: Paolillo Roberta , D´apice Stefania , Caterino Marianna , Pezone Antonio , Iole Danila , Polese Pina , Pentella Tommaso , Ruoppolo Margherita , Enrico Avvedimento Vittorio , Esposito Giovanni , Perrino Cinzia 
Published: December 2022

Abstract

Background
Ataxia Telangiectasia Mutated (ATM) protein kinase is the major sensor of DNA damage response (DDR) and oxidative stress, variously implicated in cellular metabolism. Previous studies on ATM functions in the heart have produced conflicting results. Here we hypothesized that ATM might regulate cardiomyocyte metabolic homeostasis and function.

Methods
Atm-mutated mice (Atm-/-) and their wild-type littermates (Atm+/+) were used to assess the effects of ATM inactivation on cardiomyocyte hypertrophy, cardiac structure, function, DDR and metabolism under sham conditions or after pressure overload by transverse aortic constriction (TAC).

Results
ATM inactivation induced cardiomyocyte hypertrophy (FIG.1 A), fetal gene expression re-activation and a specific metabolomic signature in the heart, characterized by significant accumulation of pyruvate, branched chain amino-acids, short-medium acyl-carnitines and metabolites of tricarboxylic acid cycle (FIG.1 C, D),. Importantly, pyruvate was trapped in the cytosol because mitochondrial carriers were suppressed and the enzymes that process pyruvate were dysregulated. As a consequence of pyruvate metabolic block, fatty acids oxidation was inefficient and resulted in the accumulation of acyl-carnitines and insulin resistance. Although these metabolic changes were present constitutively in Atm-/- mice, they were amplified by TAC, which rapidly induced heart failure (FIG.1 B) in Atm-/- mice. ATM inactivation also increased basal and TAC-induced genomic stress in cardiomyocytes, as shown by the levels of p-γ-H2AX, 8-oxodG glycosylase (OGG1/2) and apurinic site nuclease (APE1). Cardiac metabolic changes induced by ATM loss (rise of pyruvate, lactate and succinate levels) were also present in Atm-/- brains, although the basal conditions were different.

Conclusions
ATM rewires the metabolism of cardiac cells by inducing glycolysis and fatty acids oxidation. Combining metabolomic, DNA damage and cardiac phenotypes, we deduce that ATM stimulates glycolysis to repair DNA lesions and protect the heart against stress-induced dysfunction.
527 CIRCULATING SMALL NUCLEOLAR RNA SNORD3A AS A NOVEL PREDICTIVE BIOMARKERS OF HEART FAILURE
Authors: Paolillo Roberta , D´apice Stefania , Schiattarella Giacomo Gabriele , Holley Christopher , Della Corte Alessandro , Bancone Ciro , Esposito Giovanni , Perrino Cinzia 
Published: December 2022

Abstract

Background
Despite optimal therapy, heart failure (HF) remains a relentless and deadly disease. Given the relative inaccessibility of myocardial human tissues, identification of circulating biomarkers mirroring myocardial pathological signaling pathways, especially in peripheral blood mononuclear cells (PBMC) is expected to be extremely relevant. Small Nucleolar RNAs (snoRNAs) have been shown to play important roles in various cellular physiological processes. However, the connection between snoRNAs and pathological dysfunction in the heart or peripheral blood mononuclear cells (PBMC) is still poorly understood.

Purpose
To identify novel circulating PBMC biomarkers linked to myocardial dysfunction and HF.

Methods
: Myocardial left ventricle (LV) samples and PBMC were obtained from patients affected by ischemic HF (HF, n =13) undergoing heart transplantation and control donors (CD, n=7) and analyzed by RNA sequencing analysis (RNASeq). SNORD3A expression levels in the different groups were evaluated by quantitative real-time PCR. HF was induced in 8-week-old wild type C57BL/6 mice by transverse aortic constriction (TAC). Sham-operated mice (sham) were used as controls. After twelve-week-TAC (12w) or sham operation, mice were anesthetized, cardiac function was analyzed by echocardiography, and cardiac/PBMC samples were collected after sacrifice. In order to test the role of SNORD3A in cardiomyocyte hypoxia, H9C2 cardiomyoblasts were transfected with SNORD3A-targeted antisense oligonucleotides (ASO) and cell survival was analyzed.

Results
RnaSeq analysis identified a small set of genes differentially expressed in the heart and PBMC from HF patients. Among these, SNORD3A was up-regulated in cardiac and PBMC samples from HF patients compared to CD (Figure 1A). Similarly, in murine HF induced by 12w TAC, SNORD3A levels were increased by rtPCR, both in the heart and PBMC (Figure 1B). SNORD3A expression levels were also significantly increased in H9C2 cells exposed to in vitro hypoxia (Figure 1C). Interestingly, H9C2 transfection with SNORD3A-specific ASO significantly reduced hypoxia-induced SNORD3A upregulation and reduced hypoxia-induced cell death (Figure 1D).

Conclusions
In this study, we identify SNORD3A as a novel possible biomarker in human HF, similarly up-regulated in the heart and PBMC, induced by hypoxia in vitro and modulating cell survival.
953 KEY ROLE OF GENETIC ANALYSIS IN A FAMILIAR CASE OF HYPERTROPHIC CARDIAC PHENOTYPE AND VENTRICULAR PREEXCITATION RELATED TO PRKAG2 GENE MUTATION
Authors: Scimé Irene , Rubino Claudia , Micciché Serena , Lo Nigro Maria Claudia , Crea Pasquale , Dattilo Giuseppe , Carerj Scipione , Luzza Francesco , Micari Antonio , Di Bella Gianluca 
Published: December 2022

Abstract
A 38-year-old male patient (A2) was referred to our ambulatory for paroxysmal atrial fibrillation in young age and ventricular preexcitation.
Echocardiographic evaluation showed left ventricle hypertrophy (localized particularly at inter-ventricular septum (SIV) and normal LV ejection fraction. He also had a positive family history of hypertrophic cardiomyopathy since the latter was already diagnosed with the maternal grandmother (M0), the mother (M1) and the two brothers (A1 and A3). His father was apparently healthy (P1- consanguineous third degree of the mother M1). Specifically, the mother (M1) was suffering from non-obstructive hypertrophic cardiomyopathy, and tachy-brady (paroxysmal atrial flutter, sinus arrest) syndrome requiring pacemaker implantation. The firstborn (A1) was affected by paroxysmal atrial fibrillation, ventricular prexcitation and mild hypertrophy of the interventricular septum (SIV). The third child (A3) had a diagnosis of hypertrophic cardiomyopathy and a history of successfully ablation of a left postero-septal accessory pathway. A3 suffered also by paroxysmal typical atrial common flutter.
Genetic analysis of the proband A2 confirmed a heterozygous pathological mutation of the PRKAG2 gene. Thus, genetic analysis was extended to the other two brothers A1 and A3 and the mother. We proposed to the all three brothers electrophysiological study in order to assess arrhythmic substrate and appropriate therapy (strict FUP, PM or ICD implantation).
Mutation of the PRKAG2 gene is a rare disease, classified as non-lysosomal cardiac glycogenosis with clinical onset in late adolescence or in the third decade of life and presents an autosomal dominant inheritance with complete penetrance. It is associated with cardiac arrhythmias, such as ventricular preexcitation (Wolff-Parkinson-White syndrome), sinus node disease, atrioventricular block, atrial fibrillation.
Genetic analysis has a crucial role especially in the evaluation of inheritance with autosomal dominant transmission and regarding the prognostic impact, since PRKAG2 gene mutation involved a greater arrhythmic risk comparing with other subtypes of hypertrophic cardiomyopathy. Affected patients should be closely monitored to facilitate early detection of arrhythmia and conduction problems.
PRKAG2 mutation should be considered in patients with LVH who develop AF or require permanent pacemakers at a young age. Early recognition is important to allow prompt identification and appropriate management of genetic carriers.
1021 VASODILATOR CHALLENGE TEST WITH ISOSORBIDE DINITRATE DURING RIGHT HEART CATHETERIZATION: ANY ROLE IN POST-CAPILLARY PULMONARY HYPERTENSION PHENOTYPING?
Authors: Giudice Francesco Lo , Baccelli Andrea 
Published: December 2022

Abstract

Background and aims
Despite recent advances in the diagnosis and treatment of pulmonary arterial hypertension (PAH), pulmonary hypertension associated with heart failure with preserved ejection fraction (HFpEF-PH) still represents a diagnostic and therapeutic dilemma. Among HFpEF-PH patients, discriminating between isolated post-capillary (IpcPH) from combined post-/pre-capillary (CpcPH) PH, and especially a better understanding of the latter, is still challenging. Such a distinction can have an important therapeutic impact, as new evidence suggests that therapy with PDE5i might be beneficial in specific CpcPH patients [Humbert M, Kovacs G, Hoeper M et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J, 2022]. Our study sought to comprehensively assess and explore the role of Isosorbide Dinitrate (ISDN) testing in HFpEF-PH phenotyping.

Methods
From November 2019, all patients referred to our service to investigate PH and elevated pulmonary artery wedge pressures (PAWP) at rest or after fluid challenge at the time of the right heart catheterization, had a vasodilator test with a slow IV bolus of ISDN (with a specific protocol). Clinical, echocardiographic and hemodynamic data were collected.

Results
38 patients (25 CpcPH, 13 IpcPH) were included in the analysis. Baseline characteristics are shown in table 1. Based on ISDN response, patients were stratified into three groups (Table 2). Group 1 showed a lack of significant pressures reduction after ISDN (“vasodilator negative Cpc-PH”). Group 2 displayed a significant reduction of PAWP &lt; 15 mmHg, but persistent PH and high Pulmonary Vascular Resistance (PVR) (“vasodilator positive Cpc-PH”). Group 3 were patients whose pulmonary pressures normalized after ISDN (Ipc-PH).

Conclusions
albeit on a small group of patients, our preliminary results warrant further studies on the potential role of ISDN in better phenotyping HFpEF-PH and identify subgroups of patients who might benefit from PH specific therapies (“vasodilator positive Cpc-PH”) after treatment of the underling left heart disease.
488 NOVEL POTASSIUM BINDERS IMPROVES RAASI THERAPY OPTIMIZATION IN HEART FAILURE: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Esposito Immacolata , Dell´aversana Simona , Basile Christian , Chirico Alfonsina , Colella Angela , Ambrosio Antonio , Esposito Gennaro , Marzano Federica , Amato Chiara , Gargiulo Paola , Perrone-filardi Pasquale , Paolillo Stefania 
Published: December 2022

Abstract

Background
Hyperkalemia (HK) often occurs among patients with heart failure (HF), particularly when treated with renin-angiotensin-aldosterone system inhibitors (RAASi). Even modest variations from normal potassium levels raise the risk of mortality and prompt patients to limit or cease disease-modifying treatment. Novel potassium binders (NPB), patiromer and sodium zirconium cyclosilicate, are approved for treatment of HK, but whether this results in a real optimization of HF treatment remains to be seen.

Objectives
To assess the efficacy of NPB on the persistence of therapy with RAASi in HF patients.

Methods
PubMed and Web of Science were searched without restrictions from inception to 06 August 2022 to identify valuable articles. The studies that met the inclusion criteria were analyzed. The prespecified main outcome was the proportion of HF patients achieving target dose of RAASi. Secondary outcomes were the reduction in potassium levels, hyperkalemia events and persistence of therapy with RAASi in the overall population.

Results
Eight studies, with a total of 2247 patients were included. NPB improved optimization of RAASi therapy in HF compared to placebo by 21% (95% CI: 5% – 39%), decreased potassium levels by 0.48 mEq/L (95% CI: 0.28–0.67) and decreased hyperkalemia events by 53% (95% CI: 34% – 64%) and improved the proportion of the overall study population on RAASi therapy by 28% (95% CI: 7% – 52%).

Conclusion
The present meta-analysis suggests that NPB are favorable in improving the proportion of patients on RAASi therapy, whether they have HF or not, in reducing potassium levels and hyperkalemia events.
782 RATIONALE AND DESIGN OF EFI-CHF (ENDOTHELIAL FUNCTION IN PATIENTS WITH CHRONIC HEART FAILURE TREATED BY SGLT2I)STUDY
Authors: Di Nunno Nicola , D´alessandro Damiano , Granatiero Michele , Tricarico Lucia , Mazzeo Pietro , Ceci Vincenzo , Amatruda Marco , Pugliese Rosanna , Alfieri Simona , Croella Francesca , Mallardi Adriana , Leopizzi Alessandra , Correale Michele , Iacoviello Massimo , Di Biase Matteo , Stabile Eugenio , Brunetti Natale D 
Published: December 2022

Abstract

Background
Chronic heart failure (CHF) is characterized by endothelial dysfunction (ED). Sodium-glucose cotransporter type 2 inhibitors (SGLT-2i) represent a unique class of anti-hyperglycemic agents for type 2 diabetes mellitus (T2DM) that selectively inhibit renal glucose reabsorption, thereby increasing urinary excretion of glucose. Several studies have demonstrated the cardioprotective effects of SGLT-2i in patients with heart failure (HF), unrelated to its glucosuric effect. Nevertheless, it is unclear whether the benefits of SGLT-2i therapy also rely on the endothelial function in patients with CHF.

Aim of the study
To evaluate the effect of SGLT-2i on endothelial function through flow-mediated dilatation (FMD) in patients with CHF at baseline and after 3 months.

Design and Methods
EFI-CHF is a multi-center, prospective study that will evaluate the effect of SGLT-2i on endothelial function in patients with chronic stable heart failure across the left ventricular ejection fraction (LVEF) spectrum. Patients with NYHA class II/III symptoms, eGFR&gt; 25 mL/min/1.73 m2, age &gt;18 years will be enroll. Exclusion criteria are type 1 diabetes mellitus (T1DM), previous amputation surgery, recurrent urinary tract infections. For each patient medical history, clinical and biochemistry data will be collected. Starting treatment with SGLT2 inhibitors will be included. All patients will undergo FMD in an ambulatory setting, at time of enrolment and after 3 months of begin of study.

Results
The primary endpoint will be the improvement of endothelial function as assessed by FMD. An univariate and multivariate analysis will be performed to search for predictors of improvement of endothelian function.

Conclusions
The EFI-CHF will determine whether SGLT2i therapy improves endothelian function in patients with CHF starting SGLT2i therapy.
974 SACUBITRIL-VALSARTAN AMELIORATES MITOCHONDRIAL FUNCTION IN A MURINE MODEL OF ISOPROTERENOL-INDUCED LEFT VENTRICULAR DYSFUNCTION
Authors: Del Franco AnnaMaria , Carecci Alessandro , Ferrari Chen Yu Fu , Forini Francesca , Nicolini Giuseppina , Castiglione Vincenzo , Gentile Francesco , Kusmic Claudia , Emdin Michele , Vergaro Giuseppe 
Published: December 2022

Abstract

Background
Sacubitril/valsartan, a first-in-class angiotensin receptor neprilysin inhibitor, has proven to promote left ventricular (LV) reverse remodelling in patients with heart failure (HF) with reduced ejection fraction. However, its molecular and tissue effects have not been fully elucidated yet, due to the paucity of preclinical studies, mostly based on ischaemic models.

Aim
To evaluate the effects of sacubitril/valsartan on LV remodelling and cardiac mitochondrial function in a murine model of non-ischaemic LV dysfunction.

Methods
Adult male transgenic mice with cardiac-specific hyperaldosteronism (AS mice) received subcutaneous isoproterenol injection (300 mg/kg BID over two days), to induce LV systolic dysfunction. Mice were then randomized to a 2-week treatment with saline (0,2 mL BID) (ISO-AS n=15), valsartan (26 mg/kg in 0,2 mL of saline) (ISO+V n=12) or sacubitril/valsartan (57 mg/kg in 0,2 mL of saline) (ISO+S/V n=12). Echocardiography was performed at baseline, day 7, 15 and 21 of treatment. Mice were sacrificed at day 21, and histological and immunochemical assays were performed. A control group (Ctrl-AS n=8), not receiving isoproterenol nor pharmacological treatment, was obtained.

Results
Treatment with sacubitril/valsartan, but not with valsartan, induced a significant improvement of LV ejection fraction (p=0.009 vs ISO-AS) and fractional shortening (p= 0.032 vs ISO-AS) after 2-week treatment. In both ISO+V and ISO+S/V groups, a trend toward reduction of the extent of myocardial fibrosis was detected at histological analysis, confirmed by the lower cardiac collagen 1/3 expression ratio (p= 0.074). ISO+V and ISO+S/V groups showed a significant recovery of mitochondrial morphology and inner membrane function meant for oxidative phosphorylation. Additionally, both treatments reverted the alterations of the expression of genes involved in mitochondrial distribution, transport of organic/inorganic compounds, myocardial cell death, and response to the superoxide.

Conclusion
In a murine model of non-ischaemic HF, sacubitril/valsartan proved to have beneficial effects on LV remodelling and on cardiac energetics by improving mitochondrial activity.
1153 SODIUM GLUCOSE COTRANSPORTER-2 INHIBITORS ELIGIBILITY IN PATIENTS WITH HEART FAILURE ACROSS THE SPECTRUM OF EJECTION FRACTION
Authors: Ferrari Ilaria , Monzo Luca 
Published: December 2022

Abstract

Background
Large randomized clinical trials demonstrated that sodium–glucose co-transporter-2 (SGLT2) inhibitors reduced adverse cardiovascular outcomes in patients with heart failure (HF) with both reduced (HFrEF) and preserved (HFpEF) ejection fraction. Despite the high potential to change clinical practice, the strict trial selection criteria might reduce external validity of these findings.

Purpose
The aim of the study was to evaluate the proportion of outpatients with HF that would be eligible for SGLT2 inhibitors across the spectrum of left ventricular ejection fraction (LVEF) in a contemporary real-world population.

Methods
We retrospectively evaluated patients with chronic stable HF followed-up at the outpatient clinic of our institution. HFrEF (LVEF &lt;40%) patients’ eligibility was assessed according to the entry criteria of DAPA-HF (dapagliflozin) and EMPEROR-Reduced (empagliflozin) trials and to US Food and Drug Administration (FDA) label criteria (only dapagliflozin). In HFpEF group (LVEF&gt;40%), Eligibility to SGLT2 inhibitors was based both strict and pragmatic (most likely influencing treatment decisions in clinical practice)
EMPEROR- Preserved inclusion/exclusion criteria (empagliflozin).

Results
A total of 642 HF patients (441 HFrEF; 201 HFpEF) was studied. Among HFrEF patients, according to the major inclusion and exclusion criteria from DAPA-HF and EMPEROR-Reduced trials, 198 (45%) patients would be candidates for initiation of both dapagliflozin and empagliflozin, 61 (14%) would be eligible only to dapagliflozin and 23 (5%) only to empagliflozin, On the other hand, in HFpEF patients, 125 (62%) patients would be candidates for initiation of empagliflozin based on the EMPEROR-Preserved trial selection criteria. No significant differences were found between diabetic and non-diabetic patients in both HFrEF (p=0.23) and HFpEF (p=0.37). In patients not suitable for gliflozins treatment the major determinant of ineligibility was the failure to achieve the predefined NTproBNP inclusion threshold. Excluding NTproBNP as per FDA label criteria, dapagliflozin eligibility increased to 86%. Similarly, applying EMPEROR-Preserved criteria most likely influencing treatment decisions in clinical practice (symptomatic HF; eGFR &lt;20 mL/min/1.73 m2; symptomatic hypotension; history of ketoacidosis) the proportion of HFpEF patients potentially eligible to empagliflozin rose to 85%.

Conclusions
In our real-world analysis the proportion of HF patients potentially candidate for initiation of SGLT2 inhibitors is consistent across the entire spectrum of LVEF. Our findings might herald an extensive use of gliflozins in HF treatment, with a consequent strong beneficial impact on cardiovascular outcomes in eligible patients.
427 MUTUAL INTERDEPENDENCE OF BNP, PLASMA VOLUME, RENAL FUNCTION AND LVEF IN HEALTHY SUBJECTS
Authors: Fumarulo Isabella , Aspromonte Nadia , Valle Roberto 
Published: December 2022

Abstract

Background
Natriuretic peptides play an important role in cardiovascular control, stimulating diuresis and vasodilatation and suppressing the renin-angiotensin-aldosterone system. They are also pivotal markers in diagnosis, prognosis and therapy of heart failure (HF), specially BNP and its precursor pro-hormone Nt-proBNP. .Many factors can affect BNP levels in HF patients, potentially reducing its diagnostic accuracy. The main important ones include left ventricular ejection fraction (LVEF), glomerular filtration rate (GFR) and plasma volume (PV). Though the mutual relationship between BNP levels and these drivers is well studied in HF patients, paradoxically little is known about this relationship in physiological conditions in healthy subjects. We tried to elucidate mutual interdependence of BNP, PV, renal function and LVEF in healthy subjects.

Methods
A total of 200 healthy adult males underwent clinical assessment, measurement of serum levels of BNP, creatinine, uricemia, hemochrome and echocardiography for LVEF assessment. GFR was calculated according to EPI-CKD formula. PV was estimated with both the Hakim formula and the Kaplan formula. The ideal PV (iPV) i.e. the normal PV was calculated using body weight and sex: iPV (in ml) = c × body weight (in kg), where c = 39 in males and 40 in females.

Results
Mean levels of BP, LVEF, BNP, serum creatinine, GFR, uricemia and PV were all within the normal range. PV1 and PV2 were significantly different from each other and both differed from iPV (Friedman ANOVA; | = 28.4; df = 2; P &lt;0.01 for all the comparisons). Nevertheless, the three estimates of PV were all significantly and strictly correlated to each other (Spearman correlation coefficient, Rho &gt;0.82 and P&lt;0.001 for all the correlations). BNP levels were positively correlated with age and inversely with both uricemia and iPV. The latter ones were positively correlated to each other. GFR was inversely correlated with both age and uricemia (but not with PV nor with BNP levels). No correlation was found between LVEF and BNP levels or PV.

Conclusions
In homeostatic conditions, BNP and PV are inversely correlated in healthy adult males (contrary to the positive correlation existing in HF patients due to the predominant effects of angiotensin II and aldosterone), whereas opposite correlations between uricemia and both PV (positive) and GFR (negative) exist. The positive correlation between uricemia and PV could be explained by the strict dependence of tubular reabsorption of uric acid on serum levels of sodium, which is in turn strictly related to the extracellular fluid volume. The negative correlation between uricemia and GFR can be explained by the mutual influence of these two factors, since hyperuricemia seems to be both a cause and a consequence of chronic kidney disease (CKD).
539 GOING BEYOND CRT NON-RESPONSE: ECHO-GUIDED LEFT BUNDLE-BRANCH PACING
Authors: Latini Alessia Chiara , Poggio Luca , Riccardo Mantovani , Bragato Renato Maria , Frontera Antonio 
Published: December 2022

Abstract
We present the case of a 56-year-old man affected by heart failure (HF) with reduced ejection fraction (HFrEF) and permanent atrial fibrillation, who previously underwent a CRT-D implant with left ventricular stimulation delivered by an epicardial pacing lead due to an unfavourable CS anatomy. We upgraded this system to left bundle branch pacing. The LBB lead was connected to the atrial plug in of the device in order to deliver multisite left ventricular pacing. The device was programmed in DDDR mode and the delay between the two LV pacing sites was chosen (modifying atrioventricular delay) after multimodality assessment (both electrocardiographic and echocardiographic) to obtain the best resynchronization and systolic performance.