BACKGROUND:Whether anticoagulation alone is an adequate treatment for acute, intermediate-risk pulmonary embolism is uncertain. METHODS:We conducted a multinational, adaptive-design trial with blinded outcome adjudication. Patients with intermediate-risk pulmonary embolism (with a ratio of right ventricular end-diastolic diameter to left ventricular end-diastolic diameter of ≥1.0 and an elevated troponin level) were eligible if they had at least two indicators of cardiorespiratory distress (systolic blood pressure of ≤110 mm Hg, a heart rate of ≥100 beats per minute, or a respiratory rate of >20 breaths per minute). Patients were randomly assigned to undergo ultrasound-facilitated, catheter-directed fibrinolysis with alteplase plus anticoagulation (the intervention group) or anticoagulation alone (the control group) according to prespecified treatment protocols. The primary outcome was a composite of pulmonary embolism-related death, cardiorespiratory decompensation or collapse, or symptomatic recurrence of pulmonary embolism within 7 days. RESULTS:The intention-to-treat population comprised 544 patients: 273 in the intervention group and 271 in the control group. The mean (±SD) age was 58.2±13.5 years, and 42.6% of the patients were women. A primary-outcome event occurred in 11 patients (4.0%; 95% confidence interval [CI], 2.3 to 7.1) in the intervention group and 28 (10.3%; 95% CI, 7.2 to 14.5) in the control group (relative risk, 0.39; 95% CI, 0.20 to 0.77; P = 0.005). The effect was driven primarily by a lower risk of cardiorespiratory decompensation or collapse in the intervention group. Major bleeding occurred within 7 days after randomization in 11 patients (4.1%) in the intervention group and 6 (2.2%) in the control group (P = 0.32); major bleeding occurred within 30 days in 11 patients (4.1%) and 8 patients (3.0%), respectively (P = 0.64). No substantial between-group differences in the incidence of other serious adverse events were observed up to 30 days after randomization; no intracranial hemorrhage occurred. CONCLUSIONS:In patients with acute, intermediate-risk pulmonary embolism, ultrasound-facilitated, catheter-directed fibrinolysis plus anticoagulation led to a lower risk of the composite of pulmonary embolism-related death, cardiopulmonary decompensation or collapse, or symptomatic recurrence of pulmonary embolism within 7 days than anticoagulation alone. (Funded by Boston Scientific; HI-PEITHO ClinicalTrials.gov number, NCT04790370.).

Chronic venous disease (CVD) is a common disease, affecting up to 20% of the general population. In later clinical stages of venous refluxive disease dwelling oedema, skin changes and leg ulcers can occur. Therapeutic options comprise compression therapy and several minimal-invasive as well as open surgery treatments. Venous leg ulcers, as well as mixed arterial-venous leg ulcers inflict high socioeconomic and health care system burden. Despite both the high prevalence as well as the high cost, timely and effective treatment are often delayed. Thus, this review summarizes all of these mentioned aspects of CVD.

Background: Cardiovascular disease remains the leading cause of mortality worldwide. In recent years, several non-invasive imaging techniques have been introduced to improve the assessment of atherosclerotic burden and cardiovascular risk, including computed tomography and vascular ultrasound. Three-dimensional ultrasound has emerged as a promising method for the non-invasive quantification of plaque volume in peripheral arteries. Methods: In this prospective single-centre study, 63 patients with low to moderate cardiovascular risk (6-20% according to the Framingham Risk Score) were included. All participants underwent baseline examinations, and 38 patients completed follow-up after a mean period of 2 years. The assessment included coronary artery calcium scoring (CACS) by computed tomography and three-dimensional ultrasound to measure peripheral plaque volume in carotid and femoral arteries. Baseline values and progression of coronary and peripheral atherosclerosis were analysed using Spearman's correlation. Results: Sixty-three patients were included in the final analysis. A significant correlation was observed between baseline CACS and peripheral plaque volume (r = 0.32; p = 0.010). In addition, the progression of coronary calcium scores was significantly associated with the progression of peripheral plaque volume (r = 0.34; p = 0.037). Conclusions: Coronary artery calcium is significantly associated with peripheral plaque burden, both at baseline and over time. The parallel progression of coronary and peripheral atherosclerosis suggests that peripheral plaque volume assessed by 3D ultrasound may serve as a surrogate marker for coronary disease progression.

OBJECTIVE:Perioperative stroke associated with coronary artery bypass grafting (CABG) is a catastrophic event. Identification of patients at risk and reduction of its incidence remains of high importance. The aim of this study was to analyse the association of different degrees of asymptomatic carotid artery stenosis (CAS) with the perioperative outcome in a consecutive series of CABG patients and to identify predictors for CABG associated ischaemic stroke. METHODS:In total, 2727 patients undergoing isolated CABG procedure at the Medical University of Innsbruck between 2010 and 2020 were included in this study. Sonography data included the severity of carotid stenosis for left and right internal carotid artery individually. The primary outcome was the 30-day stroke and mortality rate, and the secondary outcome was 5-year mortality. A Cox regression model was performed after adjustment for EuroSCORE II. RESULTS:Left CAS>50% was present in 177 patients (7%) and right CAS>50% in 197 patients (7.8%). In total, 1.6% (40 patients) of the patients died within 30 days after surgery, and 1.0% (24 patients) experienced a postoperative stroke within 30 days. Patients with a carotid stenosis>90% had a higher 30-day mortality (p<0.001) and higher incidence of postoperative stroke within 30 days (p=0.005). Patients with a history of a prior stroke were at higher risk of experiencing another stroke within 30-days after surgery, with an HR of 6.829 (2.811-16.589) (p<0.001). CONCLUSIONS:Asymptomatic CAS>90% and history of stroke are both independent risk factors for perioperative stroke and 30-day mortality.

The number of endovascular interventional procedures for catheter-based therapy (CBT) of acute venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), has been increasing over the past years. The development of more efficient thrombectomy systems for CBT of VTE has potentially enhanced the efficacy of interventional treatment of VTE. Nevertheless, indications for CBT of VTE, i.e. catheter-directed thrombolysis (CDT) or catheter-based mechanical thrombus removal, need to be established based on existing data and expert consensus. Vascular experts should be involved in the decision-making process on CBTs in patients with acute VTE, and thrombus removal procedures should be performed in centers with experience in interventional treatment of VTE. This guideline document of the European Society of Vascular Medicine (ESVM) provides recommendations on indications and management of CBT in acute VTE and is endorsed by the European national societies of Vascular Medicine.

Background: Hepatocyte growth factor (HGF) is a pleiotropic cytokine mainly produced by mesenchymal cells. After endothelial damage by oxidized low-density lipoprotein (LDL), HGF is produced and released into the circulation in response. Due to this mechanism HGF has been proposed as possible clinical biomarker for clinical as well as subclinical atherosclerosis. Patients and methods: The conducted study is an observational, single centre, cohort study, including 171 patients with at least one cardiovascular risk factor or already established cardiovascular disease (CVD). Each patient underwent 3D plaque volumetry of the carotid and femoral arteries as well as physical examination and record of the medical history. Additionally, plasma HGF and further laboratory parameters like high sensitivity C-reactive protein and LDL-cholesterol were determined. Results: 169 patients were available for statistical analysis. In bivariate correlation, HGF showed a highly significant correlation with total plaque volume (TPV, r=0.48; p<0.001). In receiver operating characteristic (ROC) analysis for high TPV, HGF showed an area under the curve (AUC) of 0.68 (CI 95%: 0.59-0.77, p<0.001) with a sensitivity of 78% and a specificity of 52% to predict high TPV at a cut-off of 959 ng/ml. In the ROC-analysis for the presence of CVD, HGF demonstrated an AUC of 0.65 (95% CI 0.55-0.73; p=0.01) with a sensitivity of 77% and a specificity of 52%. Conclusions: Higher plasma levels of HGF are associated with higher atherosclerotic plaque volume as measured by 3D-ultrasound.

Background and Aims In chronic ischaemic heart failure, revascularisation strategies control symptoms but are less effective in improving left ventricular ejection fraction (LVEF). The aim of this trial is to investigate the safety of cardiac shockwave therapy (SWT) as a novel treatment option and its efficacy in increasing cardiac function by inducing angiogenesis and regeneration in hibernating myocardium.Methods In this single-blind, parallel-group, sham-controlled trial (cardiac shockwave therapy for ischemic heart failure, CAST-HF; NCT03859466) patients with LVEF <= 40% requiring surgical revascularisation were enrolled. Patients were randomly assigned to undergo direct cardiac SWT or sham treatment in addition to coronary bypass surgery. The primary efficacy endpoint was the improvement in LVEF measured by cardiac magnetic resonance imaging from baseline to 360 days.Results Overall, 63 patients were randomized, out of which 30 patients of the SWT group and 28 patients of the Sham group attained 1-year follow-up of the primary endpoint. Greater improvement in LVEF was observed in the SWT group (Delta from baseline to 360 days: SWT 11.3%, SD 8.8; Sham 6.3%, SD 7.4, P = .0146). Secondary endpoints included the 6-minute walking test, where patients randomized in the SWT group showed a greater Delta from baseline to 360 days (127.5 m, SD 110.6) than patients in the Sham group (43.6 m, SD 172.1) (P = .028) and Minnesota Living with Heart Failure Questionnaire score on day 360, which was 11.0 points (SD 19.1) for the SWT group and 17.3 points (SD 15.1) for the Sham group (P = .15). Two patients in the treatment group died for non-device-related reasons.Conclusions In conclusion, the CAST-HF trial indicates that direct cardiac SWT, in addition to coronary bypass surgery improves LVEF and physical capacity in patients with ischaemic heart failure. Structured Graphical Abstract Direct cardiac shockwave therapy (SWT) in addition to coronary artery bypass graft (CABG) surgery improves left ventricular ejection fraction (LVEF), physical capacity and quality of life in patients with ischaemic heart failure. 6MWT, 6-min walking test; FUP, follow-up; GDMT, guideline-directed medical therapy; NYHA, New York Heart Association; iCMP, ischaemic cardiomyopathy

Introduction: Myocardial infarction (MI) induces irreversible tissue damage, eventually leading to heart failure. Exogenous induction of angiogenesis positively influences ventricular remodeling after MI. Recently, we could show that therapeutic angiogenesis by the neuropeptide catestatin (CST) restores perfusion in the mouse hind limb ischemia model by the induction of angio-, arterio-and vasculogenesis. Thus, we assumed that CST might exert beneficial effects on cardiac cells.Methods/results: To test the effect of CST on cardiac angiogenesis in-vitro matrigel assays with human coronary artery endothelial cells (HCAEC) were performed. CST significantly mediated capillary like tube formation comparable to vascular endothelial growth factor (VEGF), which was used as positive control. Interestingly, blockade of bFGF resulted in abrogation of observed effects. Moreover, CST induced proliferation of HCAEC and human coronary artery smooth muscle cells (HCASMC) as determined by BrdU-incorporation. Similar to the matrigel assay blockade of bFGF attenuated the effect. Consistent with these findings western blot assays revealed a bFGF-dependent phosphorylation of extracellular-signal regulated kinase (ERK) 1/2 by CST in these cell lines. Finally, CST protected human cardiomyocytes in-vitro from apoptosis. Conclusion: CST might qualify as potential candidate for therapeutic angiogenesis in MI.

INTRODUCTION:Cardiovascular disease (CVD) is a systemic multifocal illness called atherosclerosis that causes artery constriction and blockage. By causing cholesterol to build up in the artery wall, hypercholesterolemia is a major factor in the pathophysiology of atherosclerotic plaque development. Reverse cholesterol transport is the process of transporting cholesterol from the periphery back to the liver through cholesterol efflux mediated by high-density lipoprotein (HDL). It was suggested that the cholesterol efflux capacity (CEC), which is inversely linked with cardiovascular risk, can serve as a stand-in measure for reverse cholesterol transport. In this work, we sought to investigate a potential link between the peripheral plaque volume (PV) and CEC.METHODS:Since lipid-lowering therapy interferes with CEC, we performed a cross-sectional study of 176 patients (48.9% females) with one cardiovascular risk factor or known CVD that did not currently take lipid-lowering medication. CEC was determined using cAMP-treated 3H-cholesterol-labeled J774 cells. Cholesterol ester transfer protein (CETP)-mediated cholesterol ester transfer was measured by quantifying the transfer of cholesterol ester from radiolabeled exogenous HDL cholesterol to Apolipoprotein B-containing lipoproteins. PV in the carotid and the femoral artery, defined as the total PV, was measured using a 3D ultrasound system equipped with semi-automatic software.RESULTS:In our patients, we discovered an inverse relationship between high total PV and CEC (p = 0.027). However, there was no connection between total PV and low-density lipoprotein cholesterol, lipoprotein (a), or CETP-mediated cholesterol ester transfer.CONCLUSION:In patients not receiving lipid-lowering treatment, CEC inversely correlates with peripheral atherosclerosis, supporting its role in the pathophysiology of atherosclerosis.

Background: Toll-like receptors (TLRs) play a pivotal role in the immunologic response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Exaggerated inflammatory response of innate immune cells, however, may drive morbidity and death in Coronavirus disease 19 (COVID-19). Objective: We investigated the engagement of SARS-CoV-2 with TLR4 in order to better understand how to tackle hyperinflammation in COVID-19. Methods: We combined RNA-sequencing data of human lung tissue and of bronchoalveolar lavage fluid cells derived from COVID-19 patients with functional studies in human macrophages using SARS-CoV-2 spike proteins and viable SARS-CoV-2. Pharmacological inhibitors as well as gene editing with CRISPR/Cas9 were used to delineate the signalling pathways involved. Results: We found TLR4 to be the most abundantly upregulated TLR in human lung tissue irrespective of the underlying pathology. Accordingly, bronchoalveolar lavage fluid cells from patients with severe COVID-19 showed an NF-κB-pathway dominated immune response, whereas they were mostly defined by type I interferon signalling in moderate COVID-19. Mechanistically, we found the Spike ectodomain, but not receptor binding domain monomer to induce TLR4-dependent inflammation in human macrophages. By using pharmacological inhibitors as well as CRISPR/Cas9 deleted macrophages, we identify SARS-CoV-2 to engage canonical TLR4-MyD88 signalling. Importantly, we demonstrate that TLR4 blockage prevents exaggerated inflammatory responses in human macrophages infected with different SARS-CoV-2 variants, including immune escape variants B.1.1.7.-E484K and B.1.1.529 (omicron). Conclusion: Our study critically extends the current knowledge on TLR-mediated hyperinflammatory responses to SARS-CoV-2 in human macrophages, paving the way for novel approaches to tackle severe COVID-19. Take-home message: Our study combining human lung transcriptomics with functional studies in human macrophages clearly supports the design and development of TLR4 - directed therapeutics to mitigate hyperinflammation in severe COVID-19.

Background and aims: The adhesion molecule P-selectin is expressed by endothelial cells and platelets. It is involved in platelet activation and leukocyte adhesion, both important processes in the pathogenesis of atherosclerosis. Our study was designed to assess the predictive value of soluble P-selectin (sP-selectin) on the progression of peripheral atherosclerosis. Methods: This is an observational, single-center, cohort study that included 443 patients with established cardiovascular disease (CVD) or at least one cardiovascular risk factor. Over a period of 4 years, each patient underwent three-dimensional (3D) ultrasound to assess the plaque volume of the carotid and femoral arteries once per year. In addition, plasma sP-selectin levels were measured at each visit. The association between changes in sP-selectin and peripheral atherosclerotic plaque progression was assessed using growth curve models. Results: 338 patients were available for statistical analysis. Each standard deviation increase in sP-selectin was significantly (p < 0.001) associated with a 46.09 mm3 higher plaque volume. In ROC-analysis, changes in sP-selectin over time showed an optimal cut-off value around Δ 0.0 µg/mL sP-selectin and significantly improved the predictive value of the ESC-SCORE (AUC for the combination of both parameters was 0.75 (95% CI 0.68–0.81, p < 0.001). Patients with increasing sP-selectin showed a significantly higher plaque progression compared to patients with decreasing or stable sP-selectin levels (202 mm3 vs. 110 mm3, p < 0.001). Conclusions: Increasing sP-selectin levels can predict higher atherosclerotic plaque progression as measured by 3D ultrasound. We suggest serial measurements of sP-selectin as an easily measurable biomarker for peripheral atherosclerotic plaque progression.

Background: Based on the new data from the primary analysis of the OPTIC (Optimizing Ponatinib Treatment in CP-CML) trial on dose optimization of ponatinib in patients with chronic phase (CP)-CML, the German consensus paper on ponatinib published in 2020 (Saussele S et al., Acta Haematol. 2020) has been updated in this addendum. Summary: Focus is on the update of efficacy and safety of ponatinib, reflecting the new data set, as well as the update of the benefit-risk assessment and recommendations for ponatinib starting dose in CP-CML – provided that the decision to use ponatinib has already been made. Furthermore, based on OPTIC and additional empirical data, the expert panel collaborated to develop a decision tree for ponatinib dosing, specifically for intolerant and resistant patients. The recommendations on cardiovascular management have also been updated based on the most recent 2021 guidelines of the European Society of Cardiology (ESC) on cardiovascular disease prevention in clinical practice. Key Messages: The OPTIC data confirm the high efficacy of ponatinib in patients with CP-CML and provide the basis for individualized dose adjustment during the course of treatment.

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Österreichische Nationalbank Introduction Atherosclerosis is a systemic multifocal disease that can cause the narrowing and occlusion of arteries resulting in cardiovascular disease (CVD). Hypercholesterolemia plays a pivotal role in the pathogenesis of atherosclerotic plaques by the accumulation of cholesterol in the arterial wall. Cholesterol efflux mediated by HDL is capable of transporting cholesterol from the periphery back to the liver in a process called reverse cholesterol transport. Cholesterol efflux capacity (CEC) is inversely correlated with cardiovascular risk and proposed as a surrogate marker for reverse cholesterol transport. In this study, we set out to study a possible association between CEC and peripheral plaque volume. Methods Since lipid-lowering therapy interferes with CEC, we studied a subset of 176 patients (48.9% females) with a median age of 64 (IQR 57-70) without lipid-lowering medication that had been included in a study of 443 patients with at least one cardiovascular risk factor or established CVD. CETP-mediated cholesterol ester transfer was measured by quantifying the transfer of cholesterol ester from radiolabelled exogenous HDL to apoB-containing lipoproteins. CEC was determined using cAMP treated 3H-cholesterol-labeled J774 cells. Plaque volume in the carotid and the femoral artery was measured using a 3D ultrasound system equipped with semi-automatic software. Results We found a strong inverse correlation between CEC and high total plaque volume (p = 0.027) in patients without lipid-lowering therapy. On the other hand, there was no correlation between CETP-mediated cholesterol ester transfer (3h) and (16h), LDL- cholesterol, or lipoprotein(a) with total plaque volume. Conclusion CEC correlates inversely with peripheral atherosclerosis in patients not taking lipid-lowering therapy, further strengthening its role as a cardiovascular biomarker.

Background and aims: The glycoprotein fetuin-A has anti-inflammatory effects, increases insulin resistance and plays an important role in calcium metabolism. The aim of our study was to assess the predictive value of fetuin-A on atherosclerotic plaque progression in comparison to the established cardiovascular biomarker high sensitivity C-reactive protein (hsCRP). Methods: In this prospective, single center-, cohort study, we included 194 patients with at least one cardiovascular risk factor or established cardiovascular disease (CVD). Over a period of 4 years, each patient underwent 3D plaque volumetry of the carotid and femoral arteries on a yearly basis. To evaluate the predictive value of biomarkers in terms of plaque progression, the baseline values of fetuin-A and hsCRP were correlated with the plaque progression from baseline to the last follow up visit. Results: 171 patients were included in the final analysis. Baseline fetuin-A levels showed a significant negative correlation with plaque progression (r = -0.244; p = 0.001). In contrast, baseline hsCRP levels showed no correlation with plaque progression (r = 0.096, p = 0.20). In the ROC-analysis, fetuin-A had a significantly better predictive value than hsCRP (fetuin-A AUC 0.67; p = 0.001 vs hsCRP AUC 0.49; p = 0.88) with an optimal cut-off value at 712 mu g/ml. In patients with high fetuin A levels (>712 mu g/ml), a significantly lower plaque progression was observed compared to the group with low fetuin-A levels <712 mu g/ml (high fetuin-A 197 mm(3) vs. low fetuin-A 279 mm(3) ; p = 0.01) Conclusions: Higher fetuin-A levels appear to predict lower atherosclerotic plaque progression in patients with or at risk of cardiovascular disease. (C) 2021 The Authors. Published by Elsevier B.V.

Abstract Background Failed myocardial tissue reperfusion due to microvascular injury despite successful culprit lesion percutaneous coronary intervention (PCI) is associated with poor clinical outcome in patients with ST-elevation myocardial infarction (STEMI). A possible influence of dysglycaemia on myocardial reperfusion injury is unclear. Objectives To investigate the association between glycaemic status and microvascular injury determined by magnetic resonance imaging in STEMI patients. Methods This prospective observational cohort study included 260 consecutive STEMI patients undergoing primary PCI between 2016 and 2019. Peripheral venous blood samples for glucose and HbA1c measurements were drawn on admission. Primary microvascular injury endpoint was defined as presence of intramyocardial haemorrhage (IMH) assessed by cardiac magnetic resonance T2* mapping at 4 (interquartile range [IQR]:2–5) days after PCI. Results HbA1c (odds ratio [OR]: 1.73 [95% CI: 1.24–2.40]; p=0.001), pre-diagnosis of diabetes (OR: 2.63 [95% CI: 1.18–5.90]; p=0.02) and glucose concentration (OR: 1.01 [95% CI: 1.00–1.01]; p=0.01) significantly predicted IMH, which was present in 90 (35%) patients. Of these three parameters, only HbA1c remained significantly associated with IMH (OR: 2.12 [95% CI: 1.12–3.99]; p=0.02) after adjusting for total ischemic time, culprit lesion location, pre- and post-interventional TIMI flow and peak biomarker concentrations (troponin, N-terminal pro-B-type natriuretic peptide and C-reactive protein). The rate of IMH was 24% in patients with HbA1c <5.7%, 43% in patients with HbA1c ≥5.7 to 6.4% and 59% in patients with HbA1c ≥6.5% (p<0.001). Conclusions In STEMI patients undergoing primary PCI, admission HbA1c was independently associated with reperfusion injury as determined by IMH. These findings suggest that IMH could represent the underlying pathophysiological link between dysglycaemia and adverse outcomes following STEMI. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): FWF - Austrian Science Fund; ÖKG - Austrian Society of Cardiology Figure 1. This figure illustrates the relation between HbA1c and IMH by two patient examples successfully treated with PCI (intervention with stent implantation schematically shown on the very left side). The first patient (upper line), representing the patient group with HbA1c <5.7% (associated IMH risk 24%), showed an anterior wall STEMI without IMH (T2* mapping on the very right, corresponding schematic picture of the infarct area without IMH next on the left). The second patient (lower line), representing the patients with HbA1c ≥5.7% (associated IMH risk 47%), showed an anterior wall STEMI with large IMH (arrows point to the hypo-intense core on the T2* mapping image and to the corresponding dark-red area in the schematic illustration). The zoomed view of one microvessel indicates the complex pathophysiology of IMH (including endothelial destruction, embolisation of thrombotic material and inflammation). (Created with BioRender)

In this review, we discuss spatiotemporal kinetics and inflammatory signatures of innate immune cells specifically found in response to SARS-CoV-2 compared to influenza virus infection. Importantly, we cover the current understanding on the mechanisms by which SARS-CoV-2 may fail to engage a coordinated type I response and instead may lead to exaggerated inflammation and death. This knowledge is central for the understanding of available data on specialized pro-resolving lipid mediators in severe SARS-CoV-2 infection pointing toward inhibited E-series resolvin synthesis in severe cases. By investigating a publicly available RNA-seq database of bronchoalveolar lavage cells from patients affected by COVID-19, we moreover offer insights into the regulation of key enzymes involved in lipid mediator synthesis, critically complementing the current knowledge about the mediator lipidome in severely affected patients. This review finally discusses different potential approaches to sustain the synthesis of 3-PUFA-derived pro-resolving lipid mediators, including resolvins and lipoxins, which may critically aid in the prevention of acute lung injury and death from COVID-19.