bluuebunny/crossref_metadata_2025_split huggingface dataset:
P4756Stroke and bleeding in low, intermediate and high risk patients with atrial fibrillation treated with edoxaban: Results of the ETNA-AF Europe registry
Authors: De Groot J R , De Caterina R , Kelly P , Monteiro P , Deharo J C , De Asmundis C , Lopez De Sa E , Weiss T W , Waltenberger J , Steffel J , Levy P , Bakhai A , Kirchhof P 
Published: October 2019

Abstract

Background
Edoxaban, a direct FXa inhibitor, has been proven non-inferior in efficacy and safer compared to warfarin in the ENGAGE AF-TIMI 48 trial. In routine care, the safety of edoxaban has not been formally established. ETNA-AF-Europe is a multinational, multi-centre, post-authorisation, observational study (NCT02944019) conducted in 825 sites in 10 European countries. Here 13,980 edoxaban-treated patients with AF were enrolled between November 2016 and February 2018, and will be followed-up for 4 years.

Methods
7,672 patients (73.4±9.26 years, 57.5% male) enrolled in the ETNA-AF Europe registry completed the one-year follow-up and were stratified into low-, intermediate- and high-risk for stroke and bleeding using the CHA2DS2-VASc and HASBLED score, respectively. We here analysed the occurrence of stroke, bleeding, intracranial haemorrhage and mortality in such categories.

Results
The mean CHA2DS2-VASc score at baseline was 3.1±1.38 and the mean HAS-BLED score was 2.5±1.1. Not surprisingly, patients at higher risk were older, had a lower body weight, more comorbidities, and a lower creatinine clearance. A higher proportion of patients at high risk received the reduced 30 mg edoxaban dose. Overall, the yearly event rates of stroke, intracranial haemorrhage, major bleeding and death were low. However, these rates increased consistently in patients with higher stroke and bleeding risks. Residual stroke risk on anticoagulation was comparable to the risk of major bleeding (Table 1).
Outcomes by stroke and bleeding risk CHA2DS2-VASc: mean 3.1±1.38 HAS-BLED: mean 2.5±1.1 All patients Low risk (0, 1 if female) Intermediate risk (1, 2 if female) High risk (≥2, 3 if female) Low risk (0, 1) Intermediate risk (2, 3) High risk (≥4) Patients, N 233 1,133 6,304 1,224 4,932 1,516 7,672 First occurrence of outcomes, n (%/year)   All-cause mortality 2 (0.92%) 12 (1.11%) 242 (4.09%) 14 (1.21%) 161 (3.47%) 82 (5.78%) 257 (3.56%)   Intracranial haemorrhage 0 (0.00%) 1 (0.09%) 19 (0.32%) 2 (0.17%) 10 (0.22%) 8 (0.56%) 20 (0.28%)   Major bleeding 0 (0.00%) 6 (0.56%) 62 (1.05%) 2 (0.17%) 43 (0.93%) 23 (1.63%) 68 (0.95%)   Stroke/SEE 0 (0.00%) 4 (0.37%) 59 (1.00%) 3 (0.26%) 41 (0.89%) 19 (1.34%) 63 (0.88%) SEE, systemic embolic event.

Conclusions
In this unselected cohort of patients with AF anticoagulated with edoxaban, high CHA2DS2-VASc and HAS-BLED scores were associated with higher risks of stroke, bleeding and death. Indirectly compared with the expected rates in non-anticoagulated patients, our data underpin the value of anticoagulants such as edoxaban in patients at high risk of stroke and bleeding.

Acknowledgement/Funding
The ETNA-AF Registry was funded by Daiichi Sankyo Europe GmbH, Munich, Germany.
P4766Edoxaban Treatment in routiNe clinical prActice for patients with atrial fibrillation (AF) in Europe (ETNA-AF-Europe): 1-year follow-up according to body mass index
Authors: Weiss T , De Caterina R , Kelly P , Monteiro P , Deharo J C , De Asmundis C , Lopez-De-Sa E , Waltenberger J , Steffel J , De Groot J R , Levy P , Bakhai A , Kirchhof P 
Published: October 2019

Abstract

Background
Non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) have substantially improved anticoagulation therapy for prevention of stroke and systemic embolism in patients with atrial fibrillation (AF), and available routine care data have so far broadly confirmed the safety of different NOACs in routine practice. However, such data for edoxaban are scarce, especially in extremely low and high body weight (BW). These extreme BWs may affect the bioavailability, distribution, and half-life of NOACs and, consequently, outcomes of treatment.

Methods
We analysed outcomes in normal-weight (BMI 18.5–25) vs overweight (BMI 25–30) and obese (BMI >30) patients enrolled into the ETNA-AF-Europe observational study (NCT02944019) collecting information on patients treated with edoxaban in 825 sites in 10 European countries. This snapshot analysis set includes data of 7,672 patients (56.3% of all enrolled patients) which have completed their 1-year follow-up visit (mean follow-up: 343.5 days).

Results
Median patient age was 74 years for all patients, 76 years for patients with a BMI 18.5–25 (group 1), 75 years for patients with BMI 25–30 (group 2), and 72 for patients with a BMI >30 (group 3). CrCl was 64 mL/min for patients with a BMI 18.5–25, 68 mL/min for patients with BMI 25–30, and 72 mL/min for patients with a BMI >30. The CHA2DS2-VASc (mean 3.1±1.38) and HAS-BLED (mean 2.5±1.10) score did not differ significantly between groups. As expected, diabetes and hypertension were significantly less prevalent in leaner patients and - accordingly - inversely correlated to age.
There was no correlation between body weight and life-threatening bleeding (group 1: 0.28%; group 2: 0.40%; group 3: 0.14%). Also, stroke rates (group 1: 0.74%; group 2: 0.81%; group 3: 0.76%) did not differ between groups.

Conclusion
BMI, within the range here assessed, does not affect 1-year outcomes in European AF patients treated with edoxaban.

Acknowledgement/Funding
Daiichi Sankyo Europe GmbH, Munich, Germany
P4767VTE-BLEED score predicts major bleeding in patients with atrial fibrillation
Authors: Klok F A , Chu K G , Valerio L , Van Der Wall S J , Barco S , Konstantinides S , Huisman M V 
Published: October 2019

Abstract

Background
Bleeding risk scores in atrial fibrillation (AF) are used to identify risk factors for bleeding but not to determine anticoagulant therapy since high bleeding risk strongly correlates to high risk of stroke. VTE-BLEED is a simple bleeding risk score (Klok FA Eur Respir J 2016) that predicts major bleeding (MB) in patients with venous thromboembolism, but has never been evaluated in AF.

Aims
To evaluate VTE-BLEED in AF and whether dabigatran dose reduction in VTE-BLEED high-risk patients would result in a lower incidence of MB and the composite endpoint of MB plus stroke/systemic embolism.

Methods
Assessment of VTE-BLEED in 18040 patients of the RE-LY trial (Connolly SJ NEJM 2009) that compared dabigatran (both 150mg BID and 110mg BID) to warfarin. The score was calibrated to fit the AF population. Hazard ratios (HR) were obtained for the VTE-BLEED high-risk patients randomized to dabigatran. The risk ratios for MB and the composite outcome of MB plus stroke/systemic embolism between dabigatran 150mg and 110mg were calculated for the VTE-BLEED high-risk group.

Results
The adapted VTE-BLEED score classified 4060 patients (22.5%) as high-risk. A high score indeed predicted MB in patients treated with dabigatran 150mg BID or 110mg BID, for HRs of 2.48 (95% CI 1.96–3.13) and 2.61 (95% CI 2.04–3.33), respectively. In VTE-BLEED high-risk patients, the risk ratio between the two dabigatran doses was 0.53 (95% CI 0.35–0.78) for MB and 0.55 (95% CI 0.38–0.79) for the composite outcome, both in favor of dabigatran 110mg BID (Figure 1). Compared to the current European label of dabigatran, application of VTE-BLEED to determine dabigatran dosing would result in a different dose for 21% of patients.
Figure 1

Conclusions
VTE-BLEED was validated for AF. Our data suggest that dabigatran dose reduction in VTE-BLEED bleed high-risk patients -in addition to targeting individual modifiable risk factors for bleeding- may lower the risk of MB and improve patient outcome. This finding could have important clinical implications but should be confirmed in future studies.
P4781Comparative effcomparative effectiveness and safety of factor-xa inhibitors vs phenprocoumon in patients with non-valvular atrial fibrillation and malignant diseases, insights from the RELOADED study
Authors: Bonnemeier H , Kreutz R , Enders D , Schmedt N , Haeckl D , Vaitsiakhovich T , Kloss S 
Published: October 2019

Abstract

Background
Data on safety and effectiveness of Factor-Xa inhibitors and phenprocoumon in patients with non-valvular atrial fibrillation (NVAF) and malignant diseases is scarce. Among others, our study aimed to investigate the safety and effectiveness in new users of Factor-Xa inhibitors vs. phenprocoumon, the vitamin-K antagonist (VKA) of choice in Germany.

Methods
We conducted a new user cohort study (one year washout period) in patients with NVAF and malignant diseases. German claims data between January 1st, 2013 and June 30th, 2017 were utilized and a multiple Cox-regression was performed to calculate confounder-adjusted hazard ratios (HRs) for the risk of ischemic stroke (IS)/systemic embolism (SE), intracranial haemorrhage (ICH) as well as renal function worsening, defined by end stage renal disease (ESRD) or dialysis and acute kidney injury (AKI) in Factor-Xa inhibitors and phenprocoumon initiators. Diagnoses of malignant diseases were assessed over the one-year baseline period.

Results
The population comprised 3,779 phenprocoumon initiators, 3,386 rivaroxaban initiators, 2,697 apixaban initiators and 434 edoxaban initiators. In the confounder-adjusted analysis, no difference related to the risk of IS/SE was found for rivaroxaban and edoxaban vs. phenprocoumon, where apixaban showed a numerically increased risk for stroke (figure 1). Point estimates related to the risk of ICH showed the expected beneficial effects for both, rivaroxaban and apixaban. A strong beneficial effect was observed for rivaroxaban when assessing the risk of renal function worsening. Hazard ratios related to the risk of ESRD/dialysis and AKI were 0.27 (0.10; 0.69) and 0.64 (0.38; 1.06), respectively. For apixaban, only the ESRD/dialysis showed a reduction in risk when compared to phenprocoumon, HR 0.42 (0.19; 0.94).

Conclusion
This retrospective database study conducted in Germany adds evidence on the effectiveness and safety profile of Factor-Xa inhibitors over VKA in patients with NVAF and malignant diseases, a critical subgroup of patients where anticoagulation is challenging. However, apixaban showed a numerically increased risk for IS/SE compared to phenprocoumon. Both, rivaroxaban and apixaban showed a risk reduction for renal function worsening within the study period of 63% and 48%, respectively compared to phenprocoumon. Only rivaroxaban showed a risk reduction of 36% for AKI.

Acknowledgement/Funding
The study was funded by Bayer AG
P4798Stereotactic radiotherapy for atrial fibrillation in three cancer patients
Authors: Shoji M , Inaba K , Itami J , Iwasa T , Yoshida M , Matsuyama T , Kumagai K , Hirao K , Qian P , Gardner E , Zei P 
Published: October 2019

Abstract

Background
Although catheter ablation is an effective therapy for atrial fibrillation (AF), risks remain and improved efficacy is desired. Stereotactic radiotherapy is a well-established therapy used to noninvasively treat malignancies with precision.

Objective
We sought to evaluate stereotactic arrhythmia radioablation (STAR) as a therapeutic option for treating AF.

Methods
Three cancer patients with drug refractory AF were enrolled. Planning software using 3-D CT of the left atrium was used to design a desired ablation volume encompassing antral circumferential pulmonary vein isolation, a roof line, and a floor line to create a “BOX” lesion set. Target dose to the treatment volume was 25 Gy, with exposure to the esophagus excluded. After planning, patients were treated in the radioablation suite.

Results
STAR was able to deliver the intended radiation dose to target without complication in 3 patients. No acute complications were seen for up to 6 months. One patient with paroxysmal AF died of deterioration of cancer. The autopsy revealed evidence of fibroblasts and fibrogenesis at the regions of atrial tissues targeted with radioablation. Two patients with longstanding persistent AF remained in AF at 6 months. In one patient, atrial electrograms were recorded at the atrial posterior wall from the esophagus before STAR, and it was absent at 3 months after STAR, indicating electrical isolation.
BOX isolation created by STAR

Conclusions
Although STAR may be safe, further evaluation is warranted regarding effectiveness. For longstanding persistent AF, AF may be difficult to terminate only with a BOX lesion set without electrical cardioversion.
4878Different relationships between blood pressures and clinical events in SPRINT and ACCORD-BP trial
Authors: Shin D.-H , Ahn C M , Kim J S , Kim B K , Ko Y G , Park S H , Choi D H , Hong M K , Jang Y S , Roe M T 
Published: October 2019

Abstract

Introduction
SPRINT showed that intensive control of systolic blood pressure (SBP) <120mmHg was beneficial when compared to the standard treatment (SBP <140mmHg). In contrast, ACCORD-BP trial failed to prove the benefit of intensive SBP lowering in diabetic patients. J-curve phenomenon might be the key to help understanding the different results of two trials.

Methods
SPRINT and ACCORD-BP databases were obtained via BioLINCC. Since BP changes along with the time, timing at which BP became stable after treatment were chosen at 9 months for SPRINT and 1 year for ACCORD BP. The final analytic datasets consisted of 8,787 and 4,306 event-free patients at the time of stable BP, respectively. Clinical events were defined at the primary composite endpoint for each trial. The effects of BP on clinical events were modeled using natural cubic splines in Cox regression models. Degrees of freedom of splines curves were chosen using Akaike Information Criterion.

Results
Analyzing SPRINT database, the spline-based hazard ratio (HR) curve showed a J-curve, which means lowering DBP below 77mmHg could be harmful, while SBP had a linear relationship (HR 1.13 per 10mmHg increase, 95% confidence interval [CI] 1.06∼1.20, p<0.0001; Figure). In ACCORD-BP trial, no J-curve phenomenon was observed. The effect of SBP was linear and almost the same to the result of SPRINT with HR 1.13 (95% CI 1.06∼1.20, p=0.0003). The relationship between DBP and clinical events was non-significant with a negative trend, which means the lower, the worse (HR 0.91, 95% CI 0.82∼1.01 p=0.071).

Conclusions
Despite the different results regarding the benefit of intensive BP control, the effects of SBP on clinical events were quite similar in SPRINT and ACCORD-BP trial. Instead,differences existed in the relationships between DBP and clinical events. Understanding the meaning of different patterns of relationships including J-curve might be the key to determine the optimal BP control.
4965Non-transcriptional disruption of Ca2+i homeostasis and Cx43 function in the right ventricle precedes overt arrhythmogenic cardiomyopathy in PKP2-deficient mice
Authors: Kim J C , Perez-Hernandez M , Alvarado F J , Maurya S R , Montnach J , Yin Y , Zhang M , Lin X , Heguy A , Rothenberg E , Lundby A , Valdivia H H , Cerrone M , Delmar M 
Published: October 2019

Abstract

Background
Plakophilin-2 (PKP2) is classically defined as a protein of the desmosome, an intercellular adhesion structure that also acts as a signaling hub to maintain structural and electrical homeostasis. Mutations in PKP2 associate with most cases of gene-positive arrhythmogenic right ventricular cardiomyopathy (ARVC). A better understanding of PKP2 cardiac biology can help elucidate the mechanisms underlying arrhythmic and cardiomyopathic events that occur consequent to its mutation. Here we sought to captureearly molecular/cellular events that can act as nascent substrates for subsequent arrhythmic/cardiomyopathic phenotypes.

Methods
We used multiple quantitative imaging modalities, as well as biochemical and high-resolution mass spectrometry methods to study the functional/structural properties of cells/tissues derived from cardiomyocyte-specific, tamoxifen-activated, PKP2 knockout mice (“PKP2cKO”). Studies were carried out 14 days post-tamoxifen injection, a time point preceding an overt electrical or structural phenotype.Myocytes from right or left ventricular free wall were studied separately, to detect functional/structural asymmetries.

Results
Most properties of PKP2cKO left ventricular (LV) myocytes were not different from control; in contrast, PKP2cKO right ventricular (RV) myocytes showed increased amplitude and duration of Ca2+transients, increased frequency of spontaneous Ca2+release events, increased [Ca2+] in the cytoplasm and sarcoplasmic reticulum compartments, and dynamic Ca2+accumulation in mitochondria. In addition, RyR2 in RV presented enhanced sensitivity to Ca2+and preferential phosphorylation in a domain known to modulate Ca2+gating. RNAseq at 14 days post-TAM showed no relevant difference in transcript abundance between RV and LV, neither in control nor in PKP2cKO cells, suggesting that in the earliest stage, [Ca2+]i dysfunction is not transcriptional. Rather, we found an RV-predominant increase in membrane permeability that can permit Ca2+entry into the cell. Cx43 ablation mitigated the increase in membrane permeability, the accumulation of cytoplasmic Ca2+and the early stages of RV dysfunction.

Conclusions
Loss of PKP2 creates an RV-predominant arrhythmogenic substrate (Ca2+ dysregulation) that precedes the cardiomyopathy and that is, at least in part, mediated by a Cx43-dependent membrane conduit. Given that asymmetric Ca2+ dysregulation precedes the cardiomyopathic stage, we speculate that abnormal Ca2+ handling in RV myocytes can be a trigger for gross structural changes observed at a later stage.
4968Increased Gao expression underlies cardiac dysfunction and lethal arrhythmias accompanied with abnormal Ca2+ handling
Authors: Inazumi H , Kuwahara K , Kuwabara Y , Nakagawa Y , Kinoshita H , Moriuchi K , Yanagisawa H , Nishikimi T , Oya M , Yamada M , Kashihara T , Kurebayashi N , Sugihara M , Nakao K , Kimura T 
Published: October 2019

Abstract

Background
We previously demonstrated that a transcriptional repressor, neuron restrictive silencer factor (NRSF), maintains normal cardiac function and electrical stability. Transgenic mice expressing a dominant-negative mutant of NRSF in their hearts (dnNRSF-Tg) exhibit systolic dysfunction with cardiac dilation and premature death due to lethal arrhythmias like human dilated cardiomyopathy (DCM). Underlining mechanisms remain to be elucidated, however.

Purpose
We studied underling mechanisms by which NRSF maintains normal cardiac function to identify novel therapeutic targets for heart failure.

Methods and results
We generated cardiac-specific NRSF knockout mice (NRSFcKO) and confirmed that cardiac phenotypes of NRSFcKO are similar to those of dnNRSF-Tg.
cDNA microarray analysis revealed that cardiac gene expression of GNAO1 that encodes Gαo, a member of inhibitory G protein Gαi family, is increased in both dnNRSF-Tg and NRSFcKO ventricles.
We confirmed that GNAO1 is a direct target of NRSF through ChIP-seq analysis, reporter assay and electrophoretic mobility shift assay.
In dnNRSF-Tg, pharmacological inhibition of Gαo with pertussis toxin improved systolic dysfunction and knockdown of Gαo by crossing with GNAO1 knockout mice improved not only systolic function but also frequency of ventricular arrhythmias and survival rates.
Electrophysiological and biochemical analysis in ventricular myocytes obtained from dnNRSF-Tg demonstrated that genetic reduction of Gαo ameliorated abnormalities in Ca2+ handling, which include increased current density in surface sarcolemmal L-type Ca2+ channel, reduced content of sarcoplasmic reticulum Ca2+ and lowered peak of Ca2+ transient. Furthermore, genetic reduction of Gαo attenuated increased phosphorylation levels of CAMKII in dnNRSF-Tg ventricles, which presumably underlies the improvement in Ca2+ handling. In addition, we identified increased Gαo expression in ventricles of heart failure model mice induced by transverse aortic constriction and cardiac troponin T mutant DCM model mice, in both of which, genetic reduction of Gαo ameliorated cardiac dysfunction.
Figure 1

Conclusions
We found that increased expression of Gαo, induced by attenuation of NRSF-mediated repression, plays a crucial role in the progression of cardiac dysfunction and lethal arrhythmias by evoking Ca2+ handling abnormality. These data demonstrate that Gαo is a potential therapeutic target for heart failure.
5162Novel insights into desminopathy in the era of next generation sequencing
Authors: Kubanek M , Schimerova T , Piherova L , Krebsova A , Hansikova H , Zeman J , Palecek T , Houstek J , Zamecnik J , Macek Jr M , Ridzon P , Stranecky V , Kmoch S , Melenovsky V , Kautzner J 
Published: October 2019

Abstract

Aims
The pleomorphic clinical presentation makes the diagnosis of desminopathy difficult. This disease of intermediate filaments causes not only a contractile dysfunction in cardiomyopathy and skeletal myopathy, but also a secondary mitochondrial dysfunction. We aimed to describe prevalence, phenotypic expression and mitochondrial function in desmin mutation carriers identified in a large cohort of patients with unexplained cardiomyopathy.

Methods and results
A representative cohort of 327 Czech patients with unexplained cardiomyopathy underwent whole exome sequencing. The cohort consisted of cases with familial and sporadic dilated cardiomyopathy (81%), left ventricular noncompaction cardiomyopathy (LVNC) (13%), and less frequently of restrictive (3%) or arrhythmogenic cardiomyopathy (3%). Clinical and laboratory data of desmin mutation carriers were collected. Morphology, desmin expression and mitochondrial function were studied in available myocardial and skeletal muscle specimens.
Rare, conserved and possibly pathogenic desmin variants were identified in 6 (1.8%) probands. Two desmin mutations previously classified as variants of uncertain significance (p.K43E, p.S57L), one novel desmin variant (p.A210D) and two known pathogenic desmin mutations (p.R406W, p.R454W) were in affected individuals associated with characteristic pathological desmin aggregates in myocardial and/or skeletal biopsy samples. The individual with the novel desmin variant p.Q364H had decreased myocardial expression of desmin with absent desmin aggregates in myocardial/skeletal biopsy and presented with familial left ventricular non-compaction cardiomyopathy, a novel phenotype of desminopathy. Assessment of mitochondrial function in four carriers of desmin mutations with fresh-frozen skeletal and/or myocardial muscle specimens confirmed decreased metabolic capacity of mitochondrial respiratory chain complexes, which was in case of myocardial succinate respiration more profound than in end-stage heart failure of other etiologies. Genetic testing corrected an inappropriate clinical diagnosis in two probands previously diagnosed with mitochondrial disease and inflammatory cardiomyopathy. During a median follow-up of 56 months, 5 (83%) probands developed end-stage heart failure.

Conclusions
Desminopathy is a rare cause of cardiomyopathy and/or skeletal muscle myopathy with a pleomorphic clinical presentation and poor prognosis. The presence of desminopathy should be considered also in individuals with left ventricular non-compaction cardiomyopathy, and in the differential diagnosis of mitochondrial diseases and inflammatory cardiomyopathy.

Acknowledgement/Funding
Research grant of the Ministry of Health, Czech Republic [MZ 15-27682A], No. 00023001 (IKEM, Prague, CZ), the Czech Science Foundation [14-36804G].