bluuebunny/crossref_metadata_2025_split huggingface dataset:
P1629Crispr/Cas9 to elucidate cardiac specific effects of Gdf11
Authors: Camparini L , Ciacci L , Sorrentino S , Ciucci G , Cannata A , Sinagra G , Loffredo F S 
Published: October 2019

Abstract

Background
Heart failure with preserved ejection fraction (HFpEF) is a prevalent clinical condition in the aging population. HFpEF lacks specific therapies with a significant impact on survival, different therapeutic approaches have indeed failed, indicating a specific need in understanding the pathophysiology of the disease. Cardiac hypertrophy is one of the main features of HFpEF that contributes to impair diastolic function. Reducing ventricular stiffness associated with cardiomyocyte hypertrophy may indeed result in improved diastolic filling. Growth differentiation factor 11 (Gdf11), a TGF-β family factor, has been identified as a circulating factor able to reduce cardiac hypertrophy.

Purpose
Similar to myostatin (Gdf8), Gdf11 promotes the activation of atrophy pathways that induce ubiquitination of sarcomeric proteins. Gdf11 and Gdf8 activate both type I and II Tgf-β receptors, specifically by interacting with Acvr2a and Acvr2b (type II) and Alk 4/5/7 (type I), they activate Smad 3/4 pathway. Our data indicate a specific and more potent effect of Gdf11 in reducing cardiomyocytes size that is not recapitulated by Gdf8. Understanding the specific effect of Gdf11 on cardiomyocytes is crucial to develop therapeutic strategies to target the hypertrophic phenotype.

Methods
To investigate the effects of specific type I receptor KO on Smad signaling cascade we performed our preliminary experiment on HL-1 cells, a cardiac muscle cell line carrying a doxycycline inducible Cas9 transgene. Cell sensitivity of HL-1 to Gdf11 and Gdf8 was tested by performing a dose-response curve using a luciferase reporter for Smad 3/4 pathway activation (CAGA12). Selective Tgf-β type I receptor KO was induced using, for each receptor, two sgRNAs that have been designed to cleave the receptor coding sequence creating INDEL mutations and disrupt proper translation of the protein and confirmed by western blotting. Smad 3/4 activity was measured using a CAGA12-luciferase assay on HL-1-Cas9 transduced cells.

Results
Our data in HL-1 cells confirm a more potent effect of Gdf11 in activating Smad 3/4 pathway when compared to Gdf8 (Fig. 1A). Selective Alk4 and Alk5 KO induced a similar reduction in Smad 3/4 activation for both Gdf11 and Gdf8. Interestingly, Alk7 KO significantly reduced Gdf11 signaling that was not recapitulated when using Gdf8, suggesting that Alk7 receptor is crucial for Gdf11-dependent Smad 3/4 activation in HL-1 cells (Fig. 1B).
Figure 1

Conclusions
Our preliminary results indicate that part of Gdf11 cardiac specificity when compared to Gdf8 may reside in the usage of Alk7 for signaling. Alk7 has proposed as a protective factor for pathological cardiac hypertrophy by negatively regulating Mek-Erk1/2 signalling. Our results are now under investigation in vitro using mouse neonatal cardiomyocytes expressing Cas-9 and in vivo using cardiac-specific-Cas9-expressing C57 transgenic mice, in resting condition and after induction of pathological hypertrophy.
P1638Predictors of in-hospital and late mortality in acutely decompensated chronic heart failure
Authors: Fernandez-Berges D , Felix Redondo F J , Gonzalez M R , Consuegra-Sanchez L , Buitrago F , Lozano L , Ortiz Cortes C , Alvarez Palacios P , Corraliza M , Gamero M C , Mellado P 
Published: October 2019

Abstract

Background
Heart failure (HF) is a global pandemic, and the cause of the greater health expenditure on hospitalization.

Purpose
To determine, in patients admitted due to decompensated heart failure (dHF), the predictors of in-hospital and late all-cause mortality.

Methods
Retrospective and longitudinal observational study of consecutive patients admitted with a diagnosis of dHF in a General Hospital between 2000–2015. Primary objective was in-hospital and late mortality.

Results
A total of 3705 patients were included (76.9 + 10.1 years, 54.1% women). Diabetes was present in 1611 (43.5%) patients, hypertension in 3210 (86.6%), active smoking in 221 (6%), COPD in 989 (26.7%), neoplasms in 415 (11.2%), chronic renal failure (CRF) in 628 (17%), previous myocardial infarction (pMI) in 449 (12.1%), stroke in 416 (11.2%), previous heart failure (pHF) in 1015 (27.4%), atrial fibrillation in 1672 (45.1%). A total of 239 (6.5%) lived in a nursing home (NH). The rate of 6-months readmission due to heart failure was 473 (12.8%). The in-hospital all-cause mortality rate was 9.3% (345). During a median follow-up of 930 days (RI 230–2611), 2165 (58.4%) patients died.
The following variables were independent predictors of in-hospital mortality (Odds ratio, 95% CI): age 1.03 (1.02–1.05), basal creatinine 1.18 (1.01–1.39) and urea 1.014 (1.011–1.018) (model AUC 0.78 (0.75–0.81)). We identified the following predictors of late mortality (Hazard ratio, 95% CI): age 1,029 (1,022–1,035), diabetes mellitus 1,13 (1,02–1,25), COPD 1,15 (1,03–1,28), neoplasms 1,17 (1,008–1,361), pMI 1.19 (1.02–1.38), pHF 1.25 (1.12–1.39), NH 1.24 (1.03–1.49), readmission 1.73 (1.51–1.97), urea 1.003 (1.001–1.005) (model AUC 0.73 (0.71–0.75)).

Conclusions
In-hospital mortality was significantly associated with age and markers of renal function, while for late mortality the predictors were comorbidities, hospital readmissions and living in a nursing home.
P1641What is the best BNP cutoff value to rule out or rule in the diagnosis of heart failure in the community?
Authors: Martins W A , Lagoeiro Jorge A , Villacorta H , Rosa M L G , Chermont S , Leite A R , Correia D M , Saad M A N , Avila D X , Venicio D P , Coelho L P , Mesquita E T 
Published: October 2019

Abstract

Background
There is no consensus on the cutoff value of B-type natriuretic peptide (BNP) to rule in or rule out the diagnosis of heart failure (HF) in the community. For instance, the ESC guidelines propose a cutoff of 35 pg/mL and the Canadian Guidelines propose 50 pg/mL.

Objectives
To evaluate the performance of several BNP cutoffs to rule in or rule out the diagnosis of HF in the community.

Methods
A total of 633 randomly selected individuals, aged 45 to 99 years, of both sexes, enrolled in a primary care program in several regions of a medium-sized city with 487,562 inhabitants were evaluated. A cross-sectional study, in which one-day clinical data collection, laboratory tests, BNP tests and tissue Doppler echocardiogram (TDE) were performed. The final diagnosis of HF was adjudicated by two independent cardiologists. Sensitivity (SEN), specificity (SPE), negative predictive value (NPV) and positive predictive value (PPV) were evaluated for different BNP cutoffs. A ROC curve was used to determine the best cutoff value.

Results
The mean age was 59.6±10.4 years and 62% were women. The incidence for ACC/AHA HF stages Zero, A, B, C and D were, respectively, 11.8%, 36.3%, 42.6%, 9.3% and 0%. There was a predominance of HF with preserved versus reduced ejection fraction (59% vs 41%). For the identification of the 59 patients with symptomatic HF, the cutoff of 35pg/mL presented SEN 98%, SPE 87%, NPV 100% and PPV 44%. For cutoff of 50pg/mL these values were SEN 78%, SPE 94%, NPV 98% and PPV 58%. The best combination of SEN and SPE was with a cutoff of 42pg/mL (SEN 92% and SPE 91%). Only one patient with HF had BNP<35pg/mL. With the cutoff of 50pg/mL, 13 (22%) of the 59 pts with symptomatic HF would not have been diagnosed.

Conclusions
The cutoff with higher specificity to rule in the diagnosis of HF was 50pg/mL. However, with this cutoff an expressive number of patients with HF would have been missed. For screening purpose in the community, the best cutoff to rule out HF was 35pg/mL, as proposed in the ESC guidelines
P1648Prevalence of increased filling pressure assessed by echocardiography in acute dyspnoea cohort
Authors: Cerlinskaite K , Gabartaite D , Bugaite J , Verikas D , Krivickiene A , Motiejunaite J , Zaliaduonyte-Peksiene D , Zakarkaite D , Mebazaa A , Kavoliuniene A , Celutkiene J 
Published: October 2019

Abstract

Introduction
Acute heart failure (AHF) is frequently associated with congestion leading to elevation of cardiac filling pressure. The present study investigates echocardiographic parameters of diastolic function in patients with AHF or non-AHF aetiology of acute dyspnoea.

Purpose
To determine the patterns of diastolic dysfunction in different profiles of acute dyspnoea.

Methods
Prospective multicentre observational study included 1455 acutely dyspnoeic patients in emergency departments from 2015 to 2017. Echocardiography was performed during the first 48 hours in 452 (31%) patients assessing left ventricular (LV) parameters. They were compared in four patient profiles based on dyspnoea cause and history of chronic HF (CHF): 1) AHF; 2) acute coronary syndrome without adjudicated AHF (Non-AHF+ACS); 3) non-AHF with CHF (Non-AHF+CHF); 4) other non-AHF patients (Non-AHF+other). Data were analysed using R statistical package.

Results
Significant differences in LV morphology and function were observed in the groups (Table 1). Increased LV filling pressure (E/E' >13) was found in most of AHF and Non-AHF+ACS patients, and in around 1/4 of Non-AHF+CHF group. Furthermore, more pronounced left-sided remodelling was observed in the first two groups. 1/3 of AHF patients had restrictive pattern of LV filling. Normal filling pressure dominated in Non-AHF+CHF and Non-AHF+other subgroups.
LV parameters in acute dyspnoea profiles Parameter AHF (n=291) Non-AHF + ACS (n=43) Non-AHF + CHF (n=44) Non-AHF + other (n=74) p value Age, years 71 [62–78] 72 [64–78] 71 [65–80] 68 [56–74] 0.045 LVEF, % 38 [25–55] 47 [32–55] 55 [45–55] 55 [50–55] <0.001 LV MMI, g/m2 126 [104.6–150.4] 99.1 [82.9–124] 94.4 [78.3–108.6] 79.6 [70.7–99.4] <0.001 LAVi, cm3 61.7 [50.9–81.1] 40.4 [35.5–46.8] 43.2 [39.8–58.9] 37.2 [32.6–43.8] <0.001 E/E' >13, % 57.7% 57.1% 23.1% 2.9% <0.001 E/E' <10, % 23.4% 38.1% 76.9% 70.6% <0.001 E/A >2, % 34.4% 14.8% 12.5% 3.9% <0.001 E/A <1, % 30.3% 59.3% 66.7% 74.5% <0.001 LVEF, left ventricular ejection fraction; LVdd, left ventricular diastolic diameter; LV MMI, left ventricular myocardial mass index; LAVi, left atrial volume index; AHF, acute heart failure; ACS, acute coronary syndrome; CHF, chronic heart failure.

Conclusions
Our data confirm the predominance of an increased cardiac filling pressure in acute heart failure patients, differently from chronic heart failure patients admitted due to other causes of dyspnoea. Patients with dyspnoea due to acute coronary syndrome frequently demonstrate elevated left-sided filling pressure.

Acknowledgement/Funding
The work was supported by the Research Council of Lithuania, grant Nr. MIP-049/2015 and approved by Lithuanian Bioethics Committee, Nr. L-15-01.
P1656Incremental value of interleukin-6 and C-reactive protein to the MEESSI acute heart failure risk score
Authors: Wussler D N , Kozhuharov N , Sabti Z , Walter J , Strebel I , Miro O , Rossello X , Martin-Sanchez F J , Pocock S , Nowak A , Twerenbold R , Flores D , Pfister O , Breidthardt T , Mueller C 
Published: October 2019

Abstract

Background
The MEESSI-acute heart failure (AHF) risk score has high accuracy in the prediction of 30-day mortality in patients presenting with AHF and may be considered the current gold standard for this indication.

Purpose
As the original MEESSI model does not include measurements of inflammatory biomarkers, the impact of interleukin-6 or C-reactive protein (CRP) on the model's goodness of fit is unknown.

Methods
In a prospective multicenter diagnostic study the presence of AHF was centrally adjudicated by two independent cardiologists among patients presenting with acute dyspnea to the ED. The MEESSI-AHF risk score was calculated using a recalibrated model containing 12 independent risk factors. The incremental value of interleukin-6 and CRP was examined by the use of logistic regression analysis and enter method variable selection with an entry criterion of p<0.05. Goodness of fit tests were performed to measure the updated model's discrimination and calibration.

Results
In 1247 patients with adjudicated AHF, the MEESSI-AHF risk score was calculated. Of these, 1113 patients (89.3%) had available measurements of interleukin-6 and CRP. In the logistic regression analysis both biomarkers had a highly significant impact on the MEESSI model (p<0.001, respectively). Compared to the original MEESSI-Model (c-statistic, 0.79 (95% CI, 0.75–0.83)) the addition of interleukin-6 (c-statistic, 0.81 (95% CI, 0.77–0.85)) or CRP (c-statistic, 0.83 (95% CI, 0.79–0.86)) significantly improved the model's discrimination (p=0.022 and p=0.011, respectively). When assessing the cumulative mortality, the gradient in 30-day mortality over six predefined risk groups was increased by addition of interleukin-6 or CRP. 30-day mortality rates in the lowest and highest risk groups of the original model were 0.4% and 32.5% compared to 0% and 34.9% in the model updated with interleukin-6 and 0.6% and 37.6% in the model updated with CRP. All compared models showed good overall calibration (Hosmer-Lemeshow p=0.302 (original model), p=0.136 (model updated by interleukin-6) and p=0.902 (model updated by CRP)).
Discrimination original_updated

Conclusion
There is significant incremental value of interleukin-6 and CRP to the MEESSI score as indicated by the improved goodness of fit compared to the original model.

Acknowledgement/Funding
European Union, the Swiss National Science Foundation, the Swiss Heart Foundation, the Cardiovascular Research Foundation Basel,
P1658Pharmacological treatment of patients with HFrEF: is it really optimized in case of CRT and/or ICD implantation?
Authors: Logeart D , Isnard R , Damy T , Salvat M , Eicher J C , Roubille F , Tribouilloy C , Bauer F , Picard F , Trochu J N , Roul G 
Published: October 2019

Abstract

Background
Cardiac resynchronization (CRT) as well as implantable cardiac defibrillator (ICD) in primary prevention should be considered in patients with heart failure and reduced ejection fraction (HFrEF) only when pharmacological treatment has been optimized.

Purpose
we sought to analyze pharmacological treatments according to the presence or not of CRT-P, CRT-D or ICD in real life HFrEF patients by using a multicenter survey.

Methods
the survey (NCT01956539) was carried out between 2015 and 2018 in 32 hospitals and included 2735 patients with HF who gave their consent during consultation or hospitalization. In this study, we analyzed only outpatients with chronic HFrEF treated for more than 6 months.

Results
among 1061 patients studied, 138 had CRT-P or CRT-D and 215 had ICD for primary prevention. The main clinical characteristics were: age 65±13 years, ischemic heart disease in, NYHA classes 1, 2, 3 and 4 in 15%, 52%, 23% and 10% cases respectively, systolic blood pressure 115mmHg [IQR 104–129], heart rate 70bpm [IQR 60–80], eGFR 64ml/min/1.73m2 [IQR 46–83]and LVEF was 30% [IQR 24–34]. The table shows the rate of use of evidence-based drugs and the dose for ACEi/ARB and betablockers, according to the presence of ICD or CRT.
HFrEF CRT-P or D ICD (primary prevention) n=1061 n=138 n=215 Loop diuretics 78.2% 79.7% 74.9% ACEi or ARB 65.2% 75.4% 67.3% Sacubitril/valsartan 5.9% 8.5% 9.5% Betablockers 72.3% 83.9% 76.8% Mineralocorticoid antagonists 45.7% 63.6% 60.2% ACEi/ARB mean % maxi dose 77 81 83 Beta-blockers mean % maxi dose 74 63 79

Conclusion
these results suggest that pharmacological treatment remains poorly optimized in a number of patients with HFrEF who received ICD or CRT
P1666Do beta-blockers increase the risk for hospitalizations in heart failure with preserved ejection fraction? A secondary analysis of beta-blocker use in the TOPCAT trial
Authors: Silverman D N , Plante T B , Infeld M I , Juraschek S P , Dougherty G , Meyer M F 
Published: October 2019

Abstract

Background
The use of beta-blockers for treatment of heart failure (HF) with a reduced ejection fraction (EF) is unequivocally beneficial, but their role in the treatment of preserved EF (HFpEF) remains unclear.

Purpose
In a contemporary HFpEF cohort, we sought to assess the association of HF hospitalizations and the use of beta-blockers in patients with an EF above and below 50%.

Methods
The TOPCAT trial tested spironolactone vs. placebo among patients with HFpEF, including some with mild reductions in EF between 45–50%. The primary outcome was a composite of cardiovascular (CV) mortality, aborted cardiac arrest, or HF hospitalizations. Medication use, including beta-blockers, was reported at each visit and hospitalization. In the 1,761 participants from the Americas, we compared the association of beta-blocker use (vs. no use) and HF hospitalization or CV mortality using Cox proportional hazards models adjusted for baseline demographics, history of myocardial infarction, atrial fibrillation, chronic obstructive pulmonary disease, asthma, and hypertension. The analyses were repeated in the EF strata ≥50% and <50%.

Results
Among patients included in the current analysis (mean age 72 years, 50% female, 78% white), 1,496/1,761 (85%) received beta-blockers and 1,566/1,761 (89%) had an EF ≥50%. HF hospitalizations and CV mortality occurred in 399/1,761 (23%) and 223/1,761 (13%) of participants, respectively. Beta-blocker use was associated with an increase in risk of HF hospitalization among patients with preserved EF ≥50% [HR 1.56, (95% CI 1.09–2.24), p=0.01] and was associated with a reduction in risk of hospitalization in patients with an EF <50% [HR 0.42, (95% CI 0.18- 0.99), p<0.05]. We found a significant interaction for EF threshold and beta-blocker use on incident HF hospitalizations (p=0.01). There were no differences in CV mortality.
Figure 1. Kaplan Meier incidence plots

Conclusions
Beta-blocker use was associated with an increase in HF hospitalizations in patients with HFpEF (EF≥50%) but did not affect CV mortality. Further research is needed to confirm these findings and elucidate causality.
P1672Late right heart failure predictors after left ventricular assist device implantation
Authors: Gonzalez Fernandez O , Bouzas Cruz N , Ferrera Duran C , Woods A , Robinson-Smith N , Tovey S , MacGowan G , Schueler S 
Published: October 2019

Abstract

Background
Right heart failure (RHF) after left ventricular assist device (LVAD) implantation is a significant cause of morbidity and mortality. While multiple predictors of early RHF have been described, information on late RHF is scarce. The aim of this study was to identify predictors of late RHF in LVAD patients.

Methods
A retrospective analysis of all adult patients who underwent HeartWare-VAD implantation for ischemic heart disease or non-ischemic dilated cardiomyopathy in a single centre was performed. Late RHF was defined as RHF requiring hospitalization and medical treatment after 30 days of LVAD implantation.

Results
A total of 16 (10.3%) patients from 156 implantations developed late RHF. Patients developing late RHF were older at time of surgery, 56.7±6.9 vs 49.5±12.5 years; p<0.01. A significantly higher rate of moderate or severe tricuspid regurgitation before implantation was found in patients presenting with late RHF, 81.2% vs 33.5%; p<0.001. Several echocardiographic parameters at discharge post-implant, such as mitral regurgitation, demonstrated a strong association with late RHF. A multivariate Cox proportional-hazards regression analysis (table 1) revealed that significant pre-operative tricuspid regurgitation (moderate or severe) was the strongest predictor of late RHF development after LVAD surgery (HR 5.50, 95% CI [1.34–22.58]; p=0.02). Significant mitral regurgitation post-implantation and older age also predicted late RHF development.
Multivariate Cox proportional-hazards analysis for late right heart failure Variable Hazard ratio 95% confidence interval P-value Tricuspid regurgitation- moderate or severe 5.50 1.34–22.58 0.02 Mitral regurgitation (discharge)- moderate or severe 3.54 1.14–11.02 0.03 Age 1.07 1.01–1.14 0.03 Right ventricular basal diameter 1.14 0.43–3.03 0.79 Right ventricular fractional area change 0.98 0.87–1.10 0.79 Multivariate analysis showing predictors of late right heart failure according to a multivariate model.
Late RHF according to TR severity

Conclusions
Pre-operative significant tricuspid regurgitation and mitral regurgitation after implantation predict the occurrence of late RHF. Prospective studies are needed to determine whether tricuspid valve interventions may reduce late RHF.
P1682Triglycerides are related to left ventricular mass in hypertensive patients, independently of other cardiometabolic risk factors: The effect of gender
Authors: Pietri P , Georgiopoulos G , Kordalis A , Tsiachris D , Vlachopoulos C , Vyssoulis G , Stefanadis C 
Published: October 2019

Abstract

Introduction
LDL cholesterol (LDL-C) is a strong cardiovascular risk factor and the main goal of treatment for both primary and secondary prevention. However, triglycerides (TGs) also convey a significant prognostic role. Left ventricular hypertrophy (LVH) increases cardiovascular risk in hypertensive patients. The purpose of the present study was to investigate the association of left ventricular mass (LVM) with TGs in never treated hypertensive patients.

Methods
We studied 760 never treated, non diabetic, hypertensive patients. Participants were subjected to transthoracic echocardiography and LVM was calculated according to the Devereux formula, indexed to body surface area (LVMI). Lipid variables including LDL-C, TGs, HDL-C, apolipoprotein A1 (ApoA1) and apolipoprotein B (ApoB) were measured in all patients.

Results
In multivariate regression analysis, LVMI was independently associated with TGs after adjustment for age, gender, smoking, SBP, glucose, LDL-C and ApoB/ApoA1 ratio (b=0.07, p=0.04). Gender-stratified analysis indicated that TGs were related to LVMI in men (b=0.15, p=0.001) but not in women (p=NS). In addition, TGs were associated with LVH in men increasing the odds by 7% to present LVMI over 115 g/m2 after controlling for age, smoking, SBP and glucose (OR: 1.07 per 10 mg/dl increase in TGs, 95% CI: 1.02–1.14, p=0.01).

Conclusion
TGs are strong determinants of LVMI in hypertensive patients, independently of other cardiometabolic risk factors, including LDL-C. The gender discrepancy may suggest a gender-specific effect of TGs on LV structure. Future studies need to clarify whether lowering TGs may induce regression of LVH, thus improving cardiovascular risk in hypertensive patients.