Long-term effectiveness and safety of edoxaban in patients with atrial fibrillation: 4-year data from the ETNA-AF-Europe study.

BACKGROUND: To assess long-term effectiveness and safety of edoxaban in Europe. METHODS AND RESULTS: ETNA-AF-Europe, a prospective, multinational, multi-centre, post-authorisation, observational study was conducted in agreement with the European Medicines Agency. The primary and secondary objectives assessed real-world safety (including bleeding and deaths) and effectiveness (including stroke, systemic embolic events and clinical edoxaban use), respectively. Median (interquartile range) age of the 13,164 patients was 75.0 (68.0-80.0) years; CHA2DS2-VASc and HAS-BLED scores were 3.0 (2.0-4.0) and 2.0 (1.0-2.0), respectively. Follow-up duration was 3.98 (3.21-4.05) years. Patients on edoxaban 30 mg (n = 3042) at baseline were older (80.0 vs 73.0 years), more likely assessed as frail by investigators (27.0% vs 6.6%) and had more comorbidities than those on edoxaban 60 mg (n = 9617; missing dosing information for n = 505). Annualised event rates of all-cause and cardiovascular death in the overall population, edoxaban 60 mg and edoxaban 30 mg groups were 4.1%, 2.8% and 8.4%, and 1.0%, 0.7% and 2.0%, respectively. Annualised rates of stroke were relatively constant throughout the follow-up, transient ischaemic attack and systemic embolism were < 1% in the overall population. Rates of any major and major gastrointestinal bleeding were low, with slightly higher rates for edoxaban 30 vs 60 mg group. Intracranial haemorrhage was uncommon (0.2%). CONCLUSIONS: In European patients with AF, long-term therapy with edoxaban is associated with low and relatively constant annualised rates of stroke and major bleeding. Differences in outcomes between the two approved doses are attributable to differences in clinical characteristics.

ACC/AHA and ESC/EACTS Guidelines for the Management of Valvular Heart Diseases: JACC Guideline Comparison.

Valvular heart disease (VHD) is common and poses important challenges from the standpoints of diagnosis and therapeutic management. Clinical practice guidelines have been developed to help health care professionals to overcome these challenges and provide optimal management to patients with VHD. The American College of Cardiology, in collaboration with the American Heart Association, and the European Society of Cardiology, in collaboration with the European Association for Cardio-Thoracic Surgery, recently updated their guidelines on the management of VHD. Although these 2 sets of guidelines are generally concordant, there are some substantial differences between these guidelines, which may have significant implications for clinical practice. This review prepared on behalf of the EuroValve Consortium describes the consistencies and discrepancies between the guidelines and highlights the gaps in these guidelines and the future research perspectives to fill these gaps.

The Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitor Empagliflozin Reverses Hyperglycemia-Induced Monocyte and Endothelial Dysfunction Primarily through Glucose Transport-Independent but Redox-Dependent Mechanisms.

PURPOSE: Hyperglycaemia-induced oxidative stress and inflammation contribute to vascular cell dysfunction and subsequent cardiovascular events in T2DM. Selective sodium-glucose co-transporter-2 (SGLT-2) inhibitor empagliflozin significantly improves cardiovascular mortality in T2DM patients (EMPA-REG trial). Since SGLT-2 is known to be expressed on cells other than the kidney cells, we investigated the potential ability of empagliflozin to regulate glucose transport and alleviate hyperglycaemia-induced dysfunction of these cells. METHODS: Primary human monocytes were isolated from the peripheral blood of T2DM patients and healthy individuals. Primary human umbilical vein endothelial cells (HUVECs) and primary human coronary artery endothelial cells (HCAECs), and fetoplacental endothelial cells (HPECs) were used as the EC model cells. Cells were exposed to hyperglycaemic conditions in vitro in 40 ng/mL or 100 ng/mL empagliflozin. The expression levels of the relevant molecules were analysed by RT-qPCR and confirmed by FACS. Glucose uptake assays were carried out with a fluorescent derivative of glucose, 2-NBDG. Reactive oxygen species (ROS) accumulation was measured using the H2DFFDA method. Monocyte and endothelial cell chemotaxis were measured using modified Boyden chamber assays. RESULTS: Both primary human monocytes and endothelial cells express SGLT-2. Hyperglycaemic conditions did not significantly alter the SGLT-2 levels in monocytes and ECs in vitro or in T2DM conditions. Glucose uptake assays carried out in the presence of GLUT inhibitors revealed that SGLT-2 inhibition very mildly, but not significantly, suppressed glucose uptake by monocytes and endothelial cells. However, we detected the significant suppression of hyperglycaemia-induced ROS accumulation in monocytes and ECs when empagliflozin was used to inhibit SGLT-2 function. Hyperglycaemic monocytes and endothelial cells readily exhibited impaired chemotaxis behaviour. The co-treatment with empagliflozin reversed the PlGF-1 resistance phenotype of hyperglycaemic monocytes. Similarly, the blunted VEGF-A responses of hyperglycaemic ECs were also restored by empagliflozin, which could be attributed to the restoration of the VEGFR-2 receptor levels on the EC surface. The induction of oxidative stress completely recapitulated most of the aberrant phenotypes exhibited by hyperglycaemic monocytes and endothelial cells, and a general antioxidant N-acetyl-L-cysteine (NAC) was able to mimic the effects of empagliflozin. CONCLUSIONS: This study provides data indicating the beneficial role of empagliflozin in reversing hyperglycaemia-induced vascular cell dysfunction. Even though both monocytes and endothelial cells express functional SGLT-2, SGLT-2 is not the primary glucose transporter in these cells. Therefore, it seems likely that empagliflozin does not directly prevent hyperglycaemia-mediated enhanced glucotoxicity in these cells by inhibiting glucose uptake. We identified the reduction of oxidative stress by empagliflozin as a primary reason for the improved function of monocytes and endothelial cells in hyperglycaemic conditions. In conclusion, empagliflozin reverses vascular cell dysfunction independent of glucose transport but could partially contribute to its beneficial cardiovascular effects.

JAG1-NOTCH4 mechanosensing drives atherosclerosis.

Endothelial cell (EC) sensing of disturbed blood flow triggers atherosclerosis, a disease of arteries that causes heart attack and stroke, through poorly defined mechanisms. The Notch pathway plays a central role in blood vessel growth and homeostasis, but its potential role in sensing of disturbed flow has not been previously studied. Here, we show using porcine and murine arteries and cultured human coronary artery EC that disturbed flow activates the JAG1-NOTCH4 signaling pathway. Light-sheet imaging revealed enrichment of JAG1 and NOTCH4 in EC of atherosclerotic plaques, and EC-specific genetic deletion of Jag1 (Jag1ECKO) demonstrated that Jag1 promotes atherosclerosis at sites of disturbed flow. Mechanistically, single-cell RNA sequencing in Jag1ECKO mice demonstrated that Jag1 suppresses subsets of ECs that proliferate and migrate. We conclude that JAG1-NOTCH4 sensing of disturbed flow enhances atherosclerosis susceptibility by regulating EC heterogeneity and that therapeutic targeting of this pathway may treat atherosclerosis.

From novel discovery tools and biomarkers to precision medicine-basic cardiovascular science highlights of 2021/22.

Here, we review the highlights of cardiovascular basic science published in 2021 and early 2022 on behalf of the European Society of Cardiology Council for Basic Cardiovascular Science. We begin with non-coding RNAs which have emerged as central regulators cardiovascular biology, and then discuss how technological developments in single-cell 'omics are providing new insights into cardiovascular development, inflammation, and disease. We also review recent discoveries on the biology of extracellular vesicles in driving either protective or pathogenic responses. The Nobel Prize in Physiology or Medicine 2021 recognized the importance of the molecular basis of mechanosensing and here we review breakthroughs in cardiovascular sensing of mechanical force. We also summarize discoveries in the field of atherosclerosis including the role of clonal haematopoiesis of indeterminate potential, and new mechanisms of crosstalk between hyperglycaemia, lipid mediators, and inflammation. The past 12 months also witnessed major advances in the field of cardiac arrhythmia including new mechanisms of fibrillation. We also focus on inducible pluripotent stem cell technology which has demonstrated disease causality for several genetic polymorphisms in long-QT syndrome and aortic valve disease, paving the way for personalized medicine approaches. Finally, the cardiovascular community has continued to better understand COVID-19 with significant advancement in our knowledge of cardiovascular tropism, molecular markers, the mechanism of vaccine-induced thrombotic complications and new anti-viral therapies that protect the cardiovascular system.

Edoxaban for stroke prevention in atrial fibrillation and age-adjusted predictors of clinical outcomes in routine clinical care.

AIMS: Patients with atrial fibrillation (AF) treated with oral anticoagulation still suffer from cardiovascular complications including cardiovascular death, stroke, and major bleeding. To identify risk factors for predicting stroke and bleeding outcomes in anticoagulated patients, we assessed 2-year outcomes in patients with AF treated with edoxaban in routine care. We also report the age-adjusted risk predictors of clinical outcomes. METHODS AND RESULTS: The Edoxaban Treatment in Routine Clinical Practice for Patients With Non-Valvular Atrial Fibrillation (ETNA-AF) Europe (NCT02944019) is a prospective, multi-centre, post-authorisation, observational study with an overall 4-year follow-up conducted in 825 centres enrolling edoxaban-treated patients in 10 European countries. Of the 13 133 patients with AF (mean age: 73.6 ± 9.5 years), 5682 (43.3%) were female. At the 2-year follow-up, 9017/13 133 patients were still on edoxaban; 1830 discontinued treatment including 937 who died (annualised event rate of all-cause death was 3.87%). 518 (2.14%) patients died of cardiovascular causes; 234 (0.97%) experienced major bleeding and 168 (0.70%) experienced stroke or systemic embolic events (SEE). Intracranial haemorrhage was noted in 49 patients (0.20%). History of transient ischaemic attack (TIA) at baseline was the strongest predictor of ischaemic stroke or SEE (Wald χ2: 73.63; P < 0.0001). Low kidney function at baseline was the strongest predictor of major bleeding (Wald χ2: 30.68; P < 0.0001). History of heart failure (HF) was the strongest predictor of all-cause (Wald χ2: 146.99; P < 0.0001) and cardiovascular death (Wald χ2: 100.38; P < 0.0001). CONCLUSION: Patients treated with edoxaban in ETNA-AF-Europe reported low 2-year event rates in unselected AF patients. Prior stroke, reduced kidney function, and HF identify patients at high risk of stroke, bleeding and all-cause/cardiovascular death, respectively.

The orphan receptor GPRC5B activates pro-inflammatory signaling in the vascular wall via Fyn and NFκB.

BACKGROUND AND AIMS: Atherosclerosis is driven by an inflammatory process of the vascular wall. The novel orphan G-protein coupled receptor 5B of family C (GPRC5B) is involved in drosophila sugar and lipid metabolism as well as mice adipose tissue inflammation. Here, we investigated the role of GPRC5B in the pro-atherogenic mechanisms of hyperglycemia and vascular inflammation. METHODS: Immortalized and primary endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) were used for stimulation with high glucose or different cytokines. Adenoviral- or plasmid-driven GPRC5B overexpression and siRNA-mediated knockdown were performed in these cells to analyze functional and mechanistic pathways of GPRC5B. RESULTS: In ECs and VSMCs, stimulation with high glucose, TNFα or LPS induced a significant upregulation of endogenous GPRC5B mRNA and protein levels. GPRC5B overexpression and knockdown increased and attenuated, respectively, the expression of the pro-inflammatory cytokines TNFα, IL-1ß, IL-6 as well as the pro-atherogenic vascular adhesion molecules ICAM-1 and VCAM-1. Furthermore, the expression and activity of the metalloproteinase MMP-9, a component of atherosclerotic plaque stabilization, were significantly enhanced by GPRC5B overexpression. Mechanistically, GPRC5B increased the phosphorylation of ERK1/2 and activated NFκB through a direct interaction with the tyrosine kinase Fyn. CONCLUSIONS: Our findings demonstrate that GPRC5B is upregulated in response to high glucose and pro-inflammatory signaling. GPRC5B functionally modulates the inflammatory activity in cells of the vascular wall, suggesting a pro-atherogenic GPRC5B-dependent positive feedback loop via Fyn and NFκB. Thus, GPRC5B warrants further attention as a novel pharmacological target for the treatment of vascular inflammation and possibly atherogenesis.

Interpretation and actionability of genetic variants in cardiomyopathies: a position statement from the European Society of Cardiology Council on cardiovascular genomics.

This document describes the contribution of clinical criteria to the interpretation of genetic variants using heritable Mendelian cardiomyopathies as an example. The aim is to assist cardiologists in defining the clinical contribution to a genetic diagnosis and the interpretation of molecular genetic reports. The identification of a genetic variant of unknown or uncertain significance is a limitation of genetic testing, but current guidelines for the interpretation of genetic variants include essential contributions from clinical family screening that can establish a de novo assignment of the variant or its segregation with the phenotype in the family. A partnership between clinicians and patients helps to solve major uncertainties and provides reliable and clinically actionable information.

Progress in cardiac research: from rebooting cardiac regeneration to a complete cell atlas of the heart.

We review some of the important discoveries and advances made in basic and translational cardiac research in 2020. For example, in the field of myocardial infarction (MI), new aspects of autophagy and the importance of eosinophils were described. Novel approaches, such as a glycocalyx mimetic, were used to improve cardiac recovery following MI. The strategy of 3D bio-printing was shown to allow the fabrication of a chambered cardiac organoid. The benefit of combining tissue engineering with paracrine therapy to heal injured myocardium is discussed. We highlight the importance of cell-to-cell communication, in particular, the relevance of extracellular vesicles, such as exosomes, which transport proteins, lipids, non-coding RNAs, and mRNAs and actively contribute to angiogenesis and myocardial regeneration. In this rapidly growing field, new strategies were developed to stimulate the release of reparative exosomes in ischaemic myocardium. Single-cell sequencing technology is causing a revolution in the study of transcriptional expression at cellular resolution, revealing unanticipated heterogeneity within cardiomyocytes, pericytes and fibroblasts, and revealing a unique subpopulation of cardiac fibroblasts. Several studies demonstrated that exosome- and non-coding RNA-mediated approaches can enhance human induced pluripotent stem cell (iPSC) viability and differentiation into mature cardiomyocytes. Important details of the mitochondrial Ca2+ uniporter and its relevance were elucidated. Novel aspects of cancer therapeutic-induced cardiotoxicity were described, such as the novel circular RNA circITCH, which may lead to novel treatments. Finally, we provide some insights into the effects of SARS-CoV-2 on the heart.

Transforming growth factor-ß1 signalling triggers vascular endothelial growth factor resistance and monocyte dysfunction in type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) leads to monocyte dysfunction associated with atherogenesis and defective arteriogenesis. Transforming growth factor (TGF)-ß1, placenta growth factor (PlGF)-1 and vascular endothelial growth factor (VEGF)A play important roles in atherogenesis and arteriogenesis. VEGF-receptor (VEGFR)-mediated monocyte migration is inhibited in T2DM (VEGFA resistance), while TGF-ß1-induced monocyte migration is fully functional. Therefore, we hypothesize that TGF-ß antagonises the VEGFA responses in human monocytes. We demonstrate that monocytes from T2DM patients have an increased migratory response towards low concentrations of TGF-ß1, while PlGF-1/VEGFA responses are mitigated. Mechanistically, this is due to increased expression of type II TGF-ß receptor in monocytes under high-glucose conditions and increased expression of soluble (s)VEGFR1, which is known to interfere with VEGFA signalling. VEGFA resistance in monocytes from T2DM patients can be rescued by either experimental down-regulation of TGF-ß receptor expression in vitro or by functional blocking of TGF-ß signalling using either a TGF-ß receptor kinase inhibitor or a TGF-ß neutralizing antibody. Our data demonstrate that both T2DM and high-glucose potentiate the TGF-ß pathway. TGF-ß signalling impairs VEGFR-mediated responses in T2DM monocytes and in this way contributes to mononuclear cell dysfunction, provide novel insights into T2DM vascular dysfunction.

The year in basic vascular biology research: from mechanoreceptors and neutrophil extracellular traps to smartphone data and omics.

2020 has been an extraordinary year. The emergence of COVID-19 has driven urgent research in pulmonary and cardiovascular science and other fields. It has also shaped the way that we work with many experimental laboratories shutting down for several months, while bioinformatics approaches and other large data projects have gained prominence. Despite these setbacks, vascular biology research is stronger than ever. On behalf of the European Society of Cardiology Council for Basic Cardiovascular Science (ESC CBCS), here we review some of the vascular biology research highlights for 2020. This review is not exhaustive and there are many outstanding vascular biology publications that we were unable to cite due to page limits. Notwithstanding this, we have provided a snapshot of vascular biology research excellence in 2020 and identify topics that are in the ascendency and likely to gain prominence in coming years.

Individual patient data analysis of the BIOFLOW study program comparing safety and efficacy of a bioresorbable polymer sirolimus eluting stent to a durable polymer everolimus eluting stent.

OBJECTIVES: This analysis of pooled individual patient data (IPD) aimed to evaluate the safety and efficacy of a bioresorbable polymer sirolimus eluting stent system (BP-SES; Orsiro) compared to a durable polymer everolimus eluting stent system (DP-EES; Xience) in the pooled population as well as in subgroups. METHODS: IPD with up to 12 months follow-up of the randomized controlled trials BIOFLOW-II (NCT01356888), -IV (NCT01939249), and -V (NCT02389946) as well as the all comers registry BIOFLOW-III (NCT01553526) were pooled. A total of 3,717 subjects (2,923 in BP-SES and 794 in DP-EES) with 5,328 lesions (4,225 lesions in BP-SES and 1,103 in DP-EES) were included in the IPD. The primary endpoint was target lesion failure (TLF) at 12 months follow-up. Subgroups analyzed included diabetes, age (≥65 years), gender, complex lesions (B2/C), small vessels (reference vessel diameter ≤2.75 mm), multivessel treatment, renal disease, and patients with acute coronary syndrome. RESULTS: Overall, TLF at 12 months was significantly lower with 5.2%in the BP-SES group versus 7.6% in the DP-EES group (p = .0098). Similarly, target vessel myocardial infarction (TV-MI) was 3.1 versus 5.7% (p = .0005). The rate of stent thrombosis was similar in both groups (0.004%). By regression analysis, an independent stent effect in favor of BP-SES was observed for TLF (p = .0043) and TV-MI (p = .0364) in small vessels. CONCLUSION: Results of this IPD analysis suggest that the BP-SES with ultrathin struts is as safe as and more efficacious than DP-EES in the overall cohort and especially in small vessels.

Endothelial function in cardiovascular medicine: a consensus paper of the European Society of Cardiology Working Groups on Atherosclerosis and Vascular Biology, Aorta and Peripheral Vascular Diseases, Coronary Pathophysiology and Microcirculation, and Thrombosis.

Endothelial cells (ECs) are sentinels of cardiovascular health. Their function is reduced by the presence of cardiovascular risk factors, and is regained once pathological stimuli are removed. In this European Society for Cardiology Position Paper, we describe endothelial dysfunction as a spectrum of phenotypic states and advocate further studies to determine the role of EC subtypes in cardiovascular disease. We conclude that there is no single ideal method for measurement of endothelial function. Techniques to measure coronary epicardial and micro-vascular function are well established but they are invasive, time-consuming, and expensive. Flow-mediated dilatation (FMD) of the brachial arteries provides a non-invasive alternative but is technically challenging and requires extensive training and standardization. We, therefore, propose that a consensus methodology for FMD is universally adopted to minimize technical variation between studies, and that reference FMD values are established for different populations of healthy individuals and patient groups. Newer techniques to measure endothelial function that are relatively easy to perform, such as finger plethysmography and the retinal flicker test, have the potential for increased clinical use provided a consensus is achieved on the measurement protocol used. We recommend further clinical studies to establish reference values for these techniques and to assess their ability to improve cardiovascular risk stratification. We advocate future studies to determine whether integration of endothelial function measurements with patient-specific epigenetic data and other biomarkers can enhance the stratification of patients for differential diagnosis, disease progression, and responses to therapy.

Hyaluronan/Collagen Hydrogels with Sulfated Glycosaminoglycans Maintain VEGF165 Activity and Fine-Tune Endothelial Cell Response.

In order to restore the regeneration capacity of large-size vascularized tissue defects, innovative biomaterial concepts are required. Vascular endothelial growth factor (VEGF165) is a key factor of angiogenesis interacting with sulfated glycosaminoglycans (sGAG) within the extracellular matrix. As this interplay mainly controls and directs the biological activity of VEGF165, we used chemically modified sGAG derivatives to evaluate the structural requirements of sGAG for controlling and tuning VEGF165 function and to translate these findings into the design of biomaterials. The in-depth analysis of this interaction by surface plasmon resonance and ELISA studies in combination with molecular modeling stressed the relevance of the substitution position, degree of sulfation, and carbohydrate backbone of GAG. Acrylated hyaluronan (HA-AC)/collagen (coll)-based hydrogels containing cross-linked acrylated, sulfated hyaluronan (sHA-AC) derivatives with different substitution patterns or an acrylated chondroitin sulfate (CS-AC) derivative function as multivalent carbohydrate-based scaffolds for VEGF165 delivery with multiple tuning capacities. Depending on the substitution pattern of sGAG, the release of biologically active VEGF165 was retarded in a defined manner compared to pure HA/coll gels, which further controlled the VEGF165-induced stimulation of endothelial cell proliferation and extended morphology of cells. This indicates that sGAG can act as modulators of protein interaction profiles of HA/coll hydrogels. In addition, sHA-AC-containing gels with and even without VEGF165 strongly stimulate endothelial cell proliferation compared to gels containing only CS-AC or HA-AC. Thus, HA/coll-based hydrogels containing cross-linked sHA-AC are biomimetic materials able to directly influence endothelial cells in vitro, which might translate into an improved healing of injured vascularized tissues.

Brain-derived neurotrophic factor, depressive symptoms and somatic comorbidity in patients with coronary heart disease.

OBJECTIVE: Depression and coronary heart disease (CHD) are highly comorbid conditions. Brain-derived neurotrophic factor (BDNF) plays an important role in cardiovascular processes. Depressed patients typically show decreased BDNF concentrations. We analysed the relationship between BDNF and depression in a sample of patients with CHD and additionally distinguished between cognitive-affective and somatic depression symptoms. We also investigated whether BDNF was associated with somatic comorbidity burden, acute coronary syndrome (ACS) or congestive heart failure (CHF). METHODS: The following variables were assessed for 225 hospitalised patients with CHD: BDNF concentrations, depression [Patient Health Questionnaire-9 (PHQ-9)], somatic comorbidity (Charlson Comorbidity Index), CHF, ACS, platelet count, smoking status and antidepressant treatment. RESULTS: Regression models revealed that BDNF was not associated with severity of depression. Although depressed patients (PHQ-9 score >7) had significantly lower BDNF concentrations compared to non-depressed patients (p = 0.04), this was not statistically significant after controlling for confounders (p = 0.15). Cognitive-affective symptoms and somatic comorbidity burden each closely missed a statistically significant association with BDNF concentrations (p = 0.08, p = 0.06, respectively). BDNF was reduced in patients with CHF (p = 0.02). There was no covariate-adjusted, significant association between BDNF and ACS. CONCLUSION: Serum BDNF concentrations are associated with cardiovascular dysfunction. Somatic comorbidities should be considered when investigating the relationship between depression and BDNF.

Edoxaban for stroke prevention in atrial fibrillation in routine clinical care: 1-year follow-up of the prospective observational ETNA-AF-Europe study.

AIMS: Non-vitamin K oral anticoagulants are safe and effective for stroke prevention in patients with atrial fibrillation (AF). Data on the safety and efficacy of edoxaban in routine care are limited in Europe. We report 1-year outcomes in patients with AF treated with edoxaban in routine care. METHODS AND RESULTS: ETNA-AF-Europe is a prospective, multicentre, post-authorization, observational study enrolling patients treated with edoxaban in 10 European countries, the design of which was agreed with the European Medicines Agency as part of edoxaban's post-approval safety plan. Altogether 13 092 patients in 852 sites completed the 1-year follow-up [mean age: 73.6 ± 9.5 years; 57% male, mean follow-up: 352 ± 49 days (median: 366 days)]. Most patients had associated comorbidities (mean CHA2DS2-VASc score: 3.1 ± 1.4). Stroke or systemic embolism was reported in 103 patients (annualized event rate: 0.82%/year), and major bleeding events were reported in 132 patients (1.05%/year). Rates of intracranial haemorrhage were low [30 patients (0.24%/year)]. Death occurred in 442 patients (3.50%/year); cardiovascular (CV) death occurred in 206 patients (1.63%/year). The approved dosing of edoxaban was chosen in 83%. All-cause and CV mortality were higher in patients receiving edoxaban 30 mg vs. 60 mg, in line with the higher age and more frequent comorbidities of the 30 mg group. Major bleeding was also numerically more common in patients receiving edoxaban 30 mg vs. 60 mg. CONCLUSION: The rates of stroke, systemic embolism, and major bleeding are low in this large unselected cohort of high-risk AF patients routinely treated with edoxaban.

Association of 5-HTTLPR/rs25531 with depressive symptoms in patients with coronary heart disease: A prospective study.

BACKGROUND: 5-HTTLPR/rs25531 is suspected to be involved in the pathogenesis of both coronary heart disease (CHD)1 and depression. We aimed to investigate the role of 5-HTTLPR/rs25531 in the development of depressive symptoms among CHD patients in a longitudinal design. METHODS: N = 265 participants with CHD diagnosis were included while hospitalized in a department of cardiology and genotyped for the 5-HTTLPR/rs25531. Depressive symptoms were measured using the Patient Health Questionnaire (PHQ-9)7 at baseline and after 6 and 12 months. Binary logistic regression models were used to analyze the association of 5-HTTLPR/rs25531 with the prevalence of depressive symptoms at each time point as well as with the incidence and persistence of depressive symptoms at follow-up. RESULTS: "LALA" genotype was associated with a higher prevalence of depressive symptoms 12 months after study inclusion. "LALA" genotype was associated with a higher incidence of depressive symptoms 6 and 12 months after study inclusion. There was no association of 5-HTTLPR/rs25531 with the persistence of depressive symptoms. LIMITATIONS: Inclusion criteria did not demand a particular cardiac event at baseline, which aggravated the interpretation of the time-specific results. The majority of the participants was of male gender which could cause bias. The present study only vaguely differentiated between ethnical groups which might cause bias regarding nationality-dependent allele distributions. CONCLUSION: The present study suggests a time-dependent association of the "LALA" genotype with depressive symptoms in CHD patients. 5-HTTLPR/rs25531 might be an important marker to detect risk groups for later onset depressive symptoms among CHD patients.

Prediction Power on Cardiovascular Disease of Neuroimmune Guidance Cues Expression by Peripheral Blood Monocytes Determined by Machine-Learning Methods.

Atherosclerosis is the underlying pathology in a major part of cardiovascular disease, the leading cause of mortality in developed countries. The infiltration of monocytes into the vessel walls of large arteries is a key denominator of atherogenesis, making monocytes accountable for the development of atherosclerosis. With the development of high-throughput transcriptome profiling platforms and cytometric methods for circulating cells, it is now feasible to study in-depth the predicted functional change of circulating monocytes reflected by changes of gene expression in certain pathways and correlate the changes to disease outcome. Neuroimmune guidance cues comprise a group of circulating- and cell membrane-associated signaling proteins that are progressively involved in monocyte functions. Here, we employed the CIRCULATING CELLS study cohort to classify cardiovascular disease patients and healthy individuals in relation to their expression of neuroimmune guidance cues in circulating monocytes. To cope with the complexity of human datasets featured by noisy data, nonlinearity and multidimensionality, we assessed various machine-learning methods. Of these, the linear discriminant analysis, Naïve Bayesian model and stochastic gradient boost model yielded perfect or near-perfect sensibility and specificity and revealed that expression levels of the neuroimmune guidance cues SEMA6B, SEMA6D and EPHA2 in circulating monocytes were of predictive values for cardiovascular disease outcome.