bluuebunny/crossref_metadata_2025 huggingface dataset:
P1599Sodium channel gene therapy with dual adeno-associated viral vectors
Authors: Boink G J J , Wang J , Klerk M , Christoffels V M , Tan H L , Geerts D
Published: October 2019

Background

Sodium channel gene therapy carries significant potential for treatment of acquired and inherited arrhythmias. However, delivery is challenging to the length of the transgene that exceeds the packaging capacity of Adeno-Associated Virus (AAV), the most advanced long-term gene therapy vector to date. To overcome this issue, we have developed dual AAV vectors for the delivery of the skeletal muscle sodium channel 1 (SkM1).

Purpose

To achieve cardiac delivery of SkM1 and other large therapeutic genes using dual AAV vectors.

Methods

Dual AAV vectors were constructed, containing SkM1 gene fragments that allow reconstruction in the target cells by trans-splicing and recombination. An oversized single AAV vector containing SkM1 served as a control. HEK293T cells and neonatal rat ventricular cardiomyocytes (NRVMs) were transduced with dual AAV vectors or oversized single AAV vector at an MOI of 50,000 per vector. Etoposide and Teniposide were added 2h before transduction to improve the efficiency. SkM1 mRNA and protein were isolated 3 days post transduction and the expression was detected by RT-qPCR and Western blot.

Results

Robust full-length SkM1 protein expression was detected in both HEK cells and NRVMs transduced by dual AAV vectors while no expression was detected in the control. Transduction with dual AAV vectors also showed significantly higher SkM1 mRNA expression in both cell types (4 to 29-fold) comparing to oversized single AAV vector. Moreover, a relatively high level of SkM1 mRNA expression was achieved in NRVM; 22-fold higher than the native cardiac sodium channel.

Conclusion

Efficient delivery and expression of SkM1 was successfully achieved in vitro by hybrid dual AAV vectors. This approach supports the application of SkM1 and other sodium channel antiarrhythmic gene therapies. In vivo validation and functional testing are currently in on-going.
P1605Increased irregularity and spectral complexity of the intrinsic pacemaker beat-to-beat variability correlates with increased metabolic syndrome components
Authors: Calvo C J , Lozano W M , Arias-Mutis O J , Such-Miquel L , Genoves P , Chorro-Gasco F J , Alberola A , Pandit S V , Zarzoso M
Published: October 2019

Background

Metabolic syndrome (MetS) is becoming one of the future potential leading risk factors for heart and cardiovascular disease. MetS relates to a condition associated with at least three metabolic risk factors raising risk for health diseases concomitantly such as diabetes, stroke, hypertension, obesity and dyslipidemia. This can lead to chest pain, heart attack, heart damage and overall higher prevalence of cardiovascular disease, atrial fibrillation and sudden cardiac death. One of the underlying mechanisms of the progressive remodeling in presence of MetS components could be altered automaticity, which would reflect modifications of sinus node activity. These phenomena can be evaluated analyzing the components of heart rate variability (HRV).

Purpose

Our aim was to examine the modifications of sinus node variability in an isolated heart model of diet-induced obesity and MetS.

Methods

Male NZW rabbits were randomly assigned to high-fat (HF, n=8), control (HF-C, n=7), high-fat, high-sucrose (HFHS, n=9), and control (HFHS-C, n=9) groups, fed with their respective diets during 18/28 weeks. After euthanasia their hearts were isolated in a Langendorff system. We recorded 10–15 minutes of spontaneous activity. Short RR time series were analyzed, and standard HRV parameters were determined with special interest in the time-course of spectral, time-frequency and non-linear components. One-way ANOVA, Kruskal-Wallis test and bivariate correlations were used for statistical analysis (p<0.05).

Results

We did find an increase in the complexity and irregularity of intrinsic pacemaker activity as shown by modifications of entropy (ApEn: p=0.011 vs HF, p=0.002 vs HF-C, p=0.019 vs HFHS-C) and the complexity index (CI: p=0.006 vs HF, p=0.047 vs HF-C, p=0.027 vs HFHS-C) in HFHS animals (Figure). Higher dispersion on RR differences distributions was observed in the HFHS group. Time-frequency spectral heterogeneity increased in HFHS group (p=0.002 vs HF, p=0.050 vs HF-X, p=0.027 vs HFHS-C) even though no differences were found in standard time and frequency-domain analyses. High-band and low-band spectral concentration ratios showed decreased organization in HFHS when compared to HF (p=0.002) and controls HFHS-C (p=0.027) and HF-C (p=0.050). Interestingly, animal weight and glucose intolerance were highly correlated with the modifications of intrinsic pacemaker variability.

Modifications of intrinsic IHRV.

Conclusions

Modifications of intrinsic HRV seemed to be reliant on the number of components of MetS present, given that only HFHS group showed significant changes towards an increased complexity and irregularity of intrinsic pacemaker variability.

Acknowledgement/Funding

This work was partially supported by: GV2015-062, CB16/11/00486.
P1615HECT-Type Ubiquitin E3 Ligase ITCH attenuates cardiac hypertrophy by suppressing Wnt signaling pathway
Authors: Goto J , Otaki Y , Watanabe T , Aono T , Watanabe K , Toshima T , Kato S , Tamura H , Nishiyama S , Arimoto T , Takahashi H , Shishido T , Kubota I , Watanabe M
Published: October 2019

Background

The homologous to the E6-AP carboxyl terminus (HECT)–type ubiquitin E3 ligase ITCH is an enzyme that plays an important role in ubiquitin proteasomal protein degradation. Dishevelled proteins (Dvl1, Dvl2 and Dvl3), which are involved in canonical Wnt/β catenin signaling pathway, play a role in cardiac hypertrophy.

Purpose

The aim of this study was to examine whether ITCH interacts with Dvls and prevents cardiac hypertrophy induced by pressure overload.

Methods and results

We confirmed the protein interaction between ITCH and Dvls in cardiomyocytes. Overexpression of ITCH decreased protein expression levels of Dvls, phospho-GSK3β and β-catenin. Conversely, knockdown of ITCH using small interfering RNA augmented canonical Wnt/β catenin signaling pathway. Thoracic transverse aortic constriction (TAC) was performed in transgenic mice with cardiac-specific overexpression of ITCH (ITCH-Tg) and wild-type (WT) mice. The canonical Wnt/β catenin signaling pathway was inhibited and cardiac hypertrophy was attenuated in ITCH-Tg mice compared with WT mice after TAC.

Overexpression of ITCH in cardiomyocytes

Conclusion

We demonstrated that ITCH targets Dvls for ubiquitin-proteasome degradation in cardiomyocytes and ameliorates cardiac hypertrophy by suppressing canonical Wnt/β catenin signaling pathway.
P1624Blockade of protease activated receptor-1 signaling attenuates cardiac hypertrophy and fibrosis in renin-overexpressing hypertensive mice
Authors: Yokono Y , Narita M , Kawamura Y , Kato T , Kudo N , Tsushima M , Toyama Y , Hanada K , Shimada M , Makoto T , Osanai T , Tomita H
Published: October 2019

Introduction

Recent evidences have demonstrated that coagulation pathway is involved in cardiovascular remodeling induced by renin-angiotensin system (RAS), which finally leads to heart failure. Protease activated receptor-1 (PAR-1) is widely expressed in the vasculature and the heart, and plays important roles in pro-inflammatory process in the cardiovascular system. Recently, we demonstrated that the activity of factor Xa (FXa), which functions not only as a coagulation factor but as an agonist for PAR-1, was enhanced in renin-overexpressing hypertensive mice (Ren-Tg).

Purpose

The purpose of this study was to investigate whether inhibition of PAR-1 signaling has protective effects on the progression of heart failure induced by chronic RAS activation in Ren-Tg.

Methods and results

We treated 12–16 weeks-old male wild type mice (WT) and Ren-Tg with continuous subcutaneous infusion of PAR-1 antagonist SCH79797 (25mg/kg/day) or vehicle for 4 weeks. After treatment period, left ventricular (LV) wall thickness calculated as interventricular septum plus posterior wall thickness measured by echocardiography was greater in Ren-Tg than in WT (0.25±0.003 versus 0.18±0.002 mm), and SCH79797 attenuated the increase to 0.22±0.01 mm in Ren-Tg (both p<0.05, respectively). The ratio of heart weight to body weight was greater in Ren-Tg than in WT (6.1±0.4 versus 4.6±0.7 mg/g), and SCH79797 attenuated the increase to 5.2±0.1 mg/g (both p<0.05). The area of cardiac fibrosis evaluated by Masson-trichrome staining was greater in Ren-Tg than in WT (2.6±0.2 versus 1.4±0.3%), and SCH79797 attenuated it to 1.6±0.3% in Ren-Tg (both p<0.05). Cardiac mRNA expressions of tumor necrosis factor-α, transforming growth factor-β1, and β-myosin heavy chain were all greater in Ren-Tg than in WT, and SCH79797 attenuated the increases in Ren-Tg (all p<0.05).

Conclusions

Inhibition of PAR-1 signaling attenuates cardiac hypertrophy and fibrosis in Ren-Tg via inhibition of inflammatory cytokines production. These results support the involvement of PAR signaling in the development of heart failure induced by RAS, and may provide novel therapeutic insights for the treatment of hypertensive heart failure.
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

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

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

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

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

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

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

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

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

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.
P1696Clinical value of QRS spatial dispersion in non-ST elevation myocardial infarction
Authors: Ibrahim I M , Frere A , Alcekelly M M
Published: October 2019

Background

More than 40% of patients with non-ST Elevation Myocardial Infarction (NSTEMI) have multi-vessel disease with the rate of in-hospital emergent bypass surgery ranging from 11–13%. So, rapid scoring is critical for optimum management even before P2Y12 loading.

Purpose

We aimed to determine the role of QRS dispersion at emergency department, as a simple and rapid sign, in predicting coronary anatomy complexity and in-hospital outcome.

Methods

192 (126 males, age 57.4±6.8 years) patients with NSTEMI and QRS duration <120 ms who underwent coronary angiography were included. QRS dispersion was automatically measured.

Results

Using Spearman's rank correlation, SYNTAX score was found to be positively correlated with admission HR (r 0.54, p value <0.001), maximum HsTnT level (r 0.523, p value <0.001), age (r 0.262, p value 0.015), male gender (r 0.286, p value 0.005), QRS dispersion (r 0.248, p value 0.015), QTc dispersion (r 0.289, p value 0.01), and Grace score (r 0.247, p value 0.015). ROC curve analyses for prediction of SYNTAX score >33 were done for variables with significant correlation. By multivariate logistic regression, male gender (OR 5.042, 95% CI 1.633 –15.567, p value 0.005), admission HR >80 bpm (OR 1.088, 95% CI 1.024 –1.157, p value 0.017) and QRS dispersion >20ms (OR 1.020, 95% CI 1.003 –1.037, p value 0.02) were independent predictors of SYNTAX score >33 (table). Patients with QRS dispersion >20 ms had in-hospital higher Killip class (P<0.001), recurrent ischemia (P 0.003), serious ventricular arrhythmias (P 0.01) and higher GRACE score (P<0.001).

Binary logistic regression for prediction of SYNTAX score >33 Variables Univariate analysis Multivariate analysis OR (95% CI) P value OR (95% CI) P value Age >61 (years) 1.337 (1.019–4.392) 0.015 0.953 (0.878–1.033) 0.242 Male gender 4.851 (2.014–5.301) 0.001 5.042 (1.633–15.567) 0.005 HR >80 (bpm) 3.945 (1.706–6.953) 0.002 1.088 (1.024–1.157) 0.017 QRS dispersion >20 (ms) 2.911 (0.617–13.738) 0.013 1.020 (1.003–1.037) 0.02 QTc dispersion >53 (ms) 6.101 (1.926–19.323) 0.002 2.378 (1.890–2.561) 0.043 Maximum HsTnT >1105 (ng/L) 3.837 (0.236–8.965) 0.004 2.785 (2.501–3.012) 0.034 Grace Score >112 (points) 7.122 (0.632–12.216) <0.001 2.912 (2.703–3.309) 0.030

Conclusion

In NSTEMI, QRS dispersion was positively correlated with SYNTAX score and a cut-off value of 20 ms independently predicted SYNTAX score >33. Regarding in-hospital outcome, QRS dispersion >20 ms was associated with in-hospital higher Killip class, recurrent ischemia, serious ventricular arrhythmias and higher GRACE score
P1701Sex-related difference in receiving bystander cardiopulmonary resuscitation and clinical outcome among out-of-hospital cardiac arrest patients
Authors: Ichihara S , Hirayama A , Tahara Y , Yasuda S , Noguchi T , Nishimura K , Yonemoto N , Nonogi H , Nagao K , Ikeda T , Sato N , Tsutsui H
Published: October 2019

Background

Early studies from US and Europe have reported that female out-of-hospital cardiac arrest (OHCA) patients were less likely to receive bystander cardiopulmonary resuscitation (CPR). However, little is known about sex-related difference in receiving CPR and clinical outcome among adult OHCA patients in Japan.

Methods

This study was a nation-wide, population-based observational study of OHCA in Japan from 2011 to 2015. We included all adult cardiogenic OHCA patients. We excluded patients witnessed by emergency medical services (EMS) from the present analysis. To account for the age-related difference, we stratified by age category: 18–39, 40–64, 65–79, and ≥80. To examine the association between patient sex and neurological outcome at 30-day, we fitted multivariable logistic regression model with adjustment for age, bystander CPR status, first document rhythm, dispatcher instruction and EMS response time.

Results

There were 339,317 adult cardiogenic, not EMS-witnessed OHCA patients (median age, 80; female, 43.5%) in Japan from 2011 to 2015. Overall, 171,122 (50.4%) received CPR by citizen, 34,283 (10.1%) had initial shockable rhythm, and 11,421 (3.4%) had favorable neurological status at 30-day. Female patients were more likely to receive bystander CPR (vs. male; 53.8% vs. 47.8%), and were less likely to have initial shockable rhythm (5.2% vs. 13.9%) and favorable neurological status at 30-day (1.8% vs. 4.6%) (all; p<0.001). With stratification by age category, elderly female patients (aged ≥65) were more likely to received bystander CPR (P<0.001), whereas male patients were more likely to received bystander CPR among patients aged <40. Multivariable logistic regression analysis showed that female patients had a lower rate of favorable neurological status at 30-day, compared to male patients in all age categories (all; P<0.05).

Sex difference in bystander CPR Overall Male (n=191,672) Female (n=147,645) p-value All (n=339,317) 50.4% 47.8% 53.8% <0.001 Aged 18–39 (n=6,216) 56.0% 56.9% 53.5% 0.02 Aged 40–64 (n=50,320) 48.5% 48.5% 48.3% 0.69 Aged 65–80 (n=105,141) 46.5% 45.5% 48.3% <0.001 Aged ≥80 (n=177,640) 53.2% 49.0% 56.7% <0.001

OR for neurological outcome at 30-day

Conclusion

Unlike the situation in Europe and US, female OHCA patients, especially elderly female, were more likely to receive bystander CPR in Japan. However, female patients had worse clinical outcome after OHCA. Further investigations including in-hospital treatment are needed to clarify the sex-difference in clinical outcome after OHCA.

Acknowledgement/Funding

None
P1721Determination of a predictive score of cardiogenic shock in acute coronary syndrome
Authors: Menezes Fernandes R , Mota T , Bispo J , Azevedo P , Guedes J , Silva D , Bento D , Marques N , Santos W , Mimoso J , Jesus I
Published: October 2019

Introduction

Cardiogenic shock is one of the leading causes of death in patients with acute coronary syndrome (ACS), reaching in-hospital mortality rates of 50%.

Purpose

To identify a predictive score of cardiogenic shock in patients with ACS.

Methods

We performed a retrospective, descriptive and correlational study encompassing patients admitted with ACS in a Cardiology service from 1st October 2010 to 1st October 2018. Demographic factors, risk factors, antecedents and clinical characteristics were analyzed. The correlation between the categorical variables was performed by the Chi-square test, while the T-Student test was applied to the continuous variables, with a significance level of 95%. Independent predictors of cardiogenic shock were identified through a binary logistic regression analysis, considering p=0,05. Then, a discriminatory function was applied using the Wilks lambda test to determine the discriminant score of the analized groups. Statistical analysis was conducted with SPSS 24.0.

Results

During this period, 4458 patients were admitted with ACS and 74 (1,7%) developed cardiogenic shock. In this subgroup, 59,5% were over 65 years of age, 63,5% were male and 93,2% presented with acute myocardial infarction with ST segment elevation. Also, 83,8% were in sinus rhythm at admission, 22,7% had creatinine>1,5 mg/dL and 17,9% had left ventricular ejection fraction (LVEF) <30%. The in-hospital mortality rate was 51,4%. LVEF <30% (p=0,018), creatinine>1,5 mg/dL (p=0,044) and absence of sinus rhythm at admission (p=0,041) were independent predictors of cardiogenic shock. A predictive score of this complication in patients with ACS was determined using the formula: 1,723 + 1,505 x (creatinine>1,5) + 4,483 x (LVEF <30%) – 2,094 x (sinus rhythm at admission). A cutoff of 0,58 was obtained with 44,4% sensitivity, 85,2% specificity and 85% discriminative power.

Conclusion

Cardiogenic shock occurred in 1,7% of patients admitted with ACS and was associated with a high mortality rate. We determined a predictive score of this complication with a good discriminative power, which included LVEF <30%, creatinine >1,5 mg/dL and the rhythm on admission's electrocardiogram. By taking into account clinical variables, this score can be used at a very early stage of admission, allowing risk stratification of developing cardiogenic shock in each patient. However, it needs validation to be applied in clinical practice.
P1722A new predictive score for mortality and cardiogenic shock in patients with ST-elevation myocardial infarction
Authors: Picarra B , Pais J A , Santos A R , Carrington M , Bras D , Carvalho J , Aguiar J
Published: October 2019

Introduction

Acute Myocardial Infarction with ST elevation (STEMI) presents a high rate of potentially fatal complications and in-hospital mortality.

Objective

To test the predictive capacity for Cardiogenic Shock (CS) and In-hospital Mortality (MIH) of a new risk score in patients (Pts) with STEMI.

Population and methods

Evaluated 5765 Pts with STEMI without CS at admission. The new score, was derived by previous studies in this population, and was calculated according to the following criteria: age ≥65 years (1 point), heart rate ≥100bpm (2 points), systolic blood pressure <100mmHg (2 points), blood glucose at admission above 180 mg/dL (1 point) and creatinine at admission >1.5mg/dL (2 points). The population was divided into three subgroups: group A low score (0–2 points), group B intermediate score (3–5 points) and group C score (6–8 points). The endpoints defined were CS during hospitalization, in-hospital mortality and combined end-point of MIH and CS. The relationship between each of the possible scores (from 0 to 8) and the various end-points was determined, and the sensitivity and specificity of the score as a predictor of MIH and CS was defined as the area under the ROC curve (ASC).

Results

After the application of the score, 3 subgroups were obtained: group A with 4819 Pts (83,6%), group B with 884 Pts (15,3%) and group C 62 Pts (1,1%). Patients of group C had a higher MIH (Group C: 45,2% vs B: 11,4% vs A: 2,0%, p<0,001), higher CS (C: 29,5% vs B: 12,0% vs A: 2,3%, p<0,001) and a higher combined end-point of MIH and CC (C: 53,2% vs B: 17,8% vs A: 3,4%, p<0,001) during hospitalization. The proposed score revealed a high predictive capacity of MIH (ASC 0,802, 95% CI 0,775–0,830, p=0,001), of CS (ASC 0,763, 95% CI 0,731–0,795, p=0,001) and for the combined endpoint (MIH and CC) ASC 0,781, 95% CI 0,756–0,806, p=0,001). The logistic regression models showed that Pts with a high score (group C) presented a 41-fold higher risk of MIH (OR 41,3; p<0,001) and 18-fold higher CS (OR 18,0; p<0.001) than patients with low score (group A). It was also found that the risk associated with an increase in one point score unit was 100% (OR 2,0 p<0.001) for MIH and 82% (OR 1,82, p<0,001) for CS.

Conclusion

This new score, with the use of practical and friendly variables, demonstrated a high predictive capacity of MIH and CS.
P1731High-sensitivity troponin with sex-specific thresholds in suspected acute coronary syndrome
Authors: Lee K K , Ferry A V , Anand A , Strachan F E , Chapman A R , Newby D B , Tuck C , Keerie C , Weir C J , Shah A S V , Mills N L
Published: October 2019

Background/Introduction

Major disparities between women and men in the diagnosis, management and outcome of acute coronary syndrome are well recognised. Whether sex-specific diagnostic thresholds for myocardial infarction will address these differences is uncertain.

Purpose

To evaluate the impact of implementing a high-sensitivity cardiac troponin I (hs-cTnI) assay with sex-specific diagnostic thresholds for myocardial infarction in women and men with suspected acute coronary syndrome.

Methods

In a stepped-wedge, cluster-randomized controlled trial across ten hospitals we evaluated the implementation of a hs-cTnI assay in 48,282 (47% women) consecutive patients with suspected acute coronary syndrome. During a validation phase the hs-cTnI assay results were suppressed and a contemporary cTnI assay with a single threshold was used to guide care. Myocardial injury was defined as any hs-cTnI concentration >99th centile of 16 ng/L in women and 34 ng/L in men. The primary outcome was myocardial infarction after the initial presentation or cardiovascular death at 1 year. In this prespecified analysis, we evaluated outcomes in men and women before and after implementation of the hs-cTnI assay.

Results

Use of the hs-cTnI assay with sex-specific thresholds increased myocardial injury in women by 42% (from 3,521 (16%) to 4,991 (22%)) and by 6% in men (from 5,068 (20%) to 5,369 (21%)). Whilst treatment increased in both sexes, women with myocardial injury remained less likely than men to undergo coronary revascularisation (15% versus34%), or to receive dual anti-platelet (26% versus43%), statin (16% versus26%) or other preventative therapies (P<0.001 for all). The primary outcome occurred in 18% (369/2,072) and 17% (488/2,919) of women with myocardial injury during the validation and implementation phase respectively (adjusted hazard ratio 1.11, 95% confidence interval 0.92 to 1.33), compared to 18% (370/2,044) and 15% (513/3,325) of men (adjusted hazard ratio 0.85, 95% confidence interval 0.71 to 1.01).

Patient management

Conclusion

Use of sex-specific thresholds identified five-times more additional women than men with myocardial injury, such that the proportion of women and men with myocardial injury is now similar. Despite this increase, women received approximately half the number of treatments for coronary artery disease as men and their outcomes were not improved.

Acknowledgement/Funding

The British Heart Foundation
P1744Patient prehospital delays in acute myocardial infarction. A nationwide patient survey. Heart attack-time is life campaign
Authors: Hudzik B , Korbel E , Popielarz B , Broja L , Botor B , Kozbial K , Piaseczna-Spitaleri E , Hawranek M , Przybylowski P , Gasior M
Published: October 2019

Introduction

A minimal delay from symptom onset to reperfusion therapy is essential in the management of acute myocardial infarction (AMI). The patient's response to initial symptoms (patient delay) substantially affects the delay. Nevertheless, predictors of patient-related delays are less clear. The aim of the study was to compare knowledge and awareness of heart attack symptoms and reactions to it in a general Polish population.

Methods

In this cross-sectional study, 1 376 persons aged 18 years or older enrolled in an Internet survey (computer assisted web interview, CAWI). Heart attack knowledge, self-efficacy for recognizing and responding to heart attack symptoms, and perceived risk for a future heart attack were measured. Primary exclusion criteria were: prior MI or family history of MI. The survey was carried out as a part of the nationwide “Heart attack – time is life” Campaign.

Results

Based on the Polish Registry on Acute Coronary Syndromes (PL-ACS) the median total ischemic time in Poland is 260 minutes, whereas the median patient delay is 142 minutes. The main factors associated with long time delays include interhospital transfers, symptoms presentation during the night, age >65 years, inhabitants of rural areas, diabetes mellitus, first-ever MI, female sex. The survey demonstrated that 73.8% of respondents recognize that chest pain may be associated with MI, but only 22.2% of them would call the emergency medical services. Age-, sex-, income-, and education-related responses are depicted in the Figure. Only 23% of these respondents would make the call immediately, whereas 31.7% would wait at least 3–4 hours (in some cases event until the next day). 66.4% of the surveyed population would ignore the chest pain main reason being “nothing serious” or “a result of extreme emotions”. Notwithstanding, the majority of the surveyed population is aware of the seriousness of the AMI-related complications (heart failure, disability, rehospitalizations, death).

Conclusions

These findings highlight the urgent need to develop effective, tailored campaigns to close the knowledge gap and, primarily, to educate the Polish society about the correct response to chest pain. Young age, higher education, and high income were not predictors of common sense and correct responses.