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Abstract Background Lower extremity peripheral artery disease frequently presents with calcifications which reduces the accuracy of computed tomography (CT) angiography, especially below-the-knee. Photon-counting detector (PCD)-CT offers improved spatial resolution and less calcium blooming. We aimed to identify the optimal reconstruction parameters for PCD-CT angiography of the lower legs. Methods Tubes with different diameters (1–5 mm) were filled with different iodine concentrations and scanned in a water container. Images were reconstructed with 0.4 mm isotropic resolution using a quantitative kernel at all available sharpness levels (Qr36 to Qr76) and using different levels of quantum iterative reconstruction (QIR-2–4). Noise and image sharpness were determined for all reconstructions. Additionally, CT angiograms of 20 patients, reconstructed with a medium (Qr44), sharp (Qr60), and ultrasharp (Qr72) kernel at QIR-2-4, were evaluated by three readers assessing noise, delineation of plaques and vessel walls, and overall quality. Results In the phantom study, increased kernel sharpness led to higher image noise (e.g., 16, 38, 77 HU for Qr44, Qr60, Qr72, and QIR-3). Image sharpness increased with increasing kernel sharpness, reaching a plateau at the medium-high level 60. Higher QIR levels decreased image noise (e.g., 51, 38, 25 HU at QIR-2–4 and Qr60) without reducing vessel sharpness. The qualitative in vivo results confirmed these findings: the sharp kernel (Qr60) with the highest QIR yielded the best overall quality. Conclusion The combination of a sharpness level optimized reconstruction kernel (Qr60) and the highest QIR level yield the best image quality for PCD-CT angiography of the lower legs when reconstructed at 0.4-mm resolution. Relevance statement Using high-resolution PCD-CT angiography with optimized reconstruction parameters might improve diagnostic accuracy and confidence in peripheral artery disease of the lower legs. Key Points Effective exploitation of the potential of PCD-CT angiography requires optimized reconstruction parameters. Too soft or too sharp reconstruction kernels reduce image quality. The highest level of quantum iterative reconstruction provides the best image quality. Graphical Abstract

Background: Although pulmonary embolism (PE) and sarcopenia are common diseases, only a few studies have assessed the impact of sarcopenia in PE on usage of reperfusion treatments in PE. Methods: All hospitalizations of PE patients aged ≥75 years 2005–2020 in Germany were included in this study and stratified for sarcopenia. Impact of sarcopenia on treatment procedures and adverse in-hospital events were investigated. Results: Overall, 576,364 hospitalizations of PE patients aged ≥75 years (median age 81.0 [78.0–85.0] years; 63.3 % females) were diagnosed in Germany during the observational period 2005–2020. Among these, 2357 (0.4 %) were coded with sarcopenia. PE patients with sarcopenia were in median 2 years older (83.0 [79.0–87.0] vs. 81.0 [78.0–85.0] years, P

Background: Pulmonary embolism (PE) is a potentially life-threatening condition. Admission and treatment in the intensive care unit (ICU) is an important element in critically ill PE patients. Objectives: We aimed to identify risk factors for ICU admission and differences in patient profiles regarding risk factors and comorbidities between PE patients who had to be admitted to an ICU and those who were treated in a normal ward without ICU. Methods: We used the German nationwide inpatient sample to analyze all hospitalizations of PE patients in Germany from 2016 to 2020 stratified for ICU admission. Results: Overall, 484,859 hospitalized PE patients were treated in German hospitals from 2016 to 2020. Among these, 92,313 (19.0%) were admitted to ICU. Patients treated in ICU were younger (69.0 [IQR, 58.0-78.0] vs 72.0 [IQR, 60.0-80.0] years; P < .001) and had higher prevalence of cardiovascular risk factors and comorbidities. In-hospital case fatality rate was elevated in PE patients treated in ICU (22.7% vs 10.7%; P < .001), and ICU admission was independently associated with increased in-hospital case fatality (odds ratio [OR], 2.54; 95% CI, 2.49-2.59; P < .001). Independent risk factors for ICU admission comprised PE with imminent or present decompensation (OR, 3.30; 95% CI, 3.25-3.35; P < .001), hemodynamic instability (OR, 4.49; 95% CI, 4.39-4.59; P < .001), arterial hypertension (OR, 1.20; 95% CI, 1.18-1.22; P < .001), diabetes mellitus (OR, 1.16; 95% CI, 1.14-1.18; P < .001), obesity (OR, 1.300; 95% CI, 1.27-1.33; P < .001), surgery (OR, 2.55; 95% CI, 2.50-2.59; P < .001), stroke (OR, 2.86; 95% CI, 2.76-2.96; P < .001), pregnancy (OR, 1.45; 95% CI, 1.21-1.74; P < .001), heart failure (OR, 1.74; 95% CI, 1.71-1.77; P < .001), atrial fibrillation/flutter (OR, 1.69; 95% CI, 1.66-1.73; P < .001), chronic obstructive pulmonary disease (OR, 1.21; 95% CI, 1.18-1.24; P < .001), and renal failure (OR, 1.92; 95% CI, 1.88-1.95; P < .001). Conclusion: ICU treatment is an important element in the treatment of PE patients. Besides hemodynamic compromise, cardiovascular risk factors, stroke, pregnancy, and cardiopulmonary as well as renal comorbidities were independent predictors of ICU admission. Necessity of ICU admission was afflicted by increased case fatality.

Abstract Background Pulmonary embolism (PE) is a life‐threatening acute disease accompanied by high morbidity and mortality. Regarding hospitalizations of patients with PE, risk stratification of these patients is crucial. Thus, risk stratification tools like risk scores are of key interest. Methods The nationwide German inpatient sample of the years 2005–2018 was used for this present analysis. Hospitalized PE patients were stratified according to Mansoor's Self‐Report Tool for Cardiovascular Risk Assessment class, and the performance of this score was evaluated to predict adverse in‐hospital events. Results Overall, 1 174 196 hospitalizations of PE patients (53.5% females; 56.4% ≥70 years) were registered in Germany between 2005 and 2018. According to the Mansoor's self‐report tool for cardiovascular risk assessment, 346 126 (29.5%) PE patients were classified as high risk. Higher Mansoor's Self‐Report Tool for Cardiovascular Risk Assessment class was predictive for in‐hospital death (OR 1.129 [95%CI 1.117–1.141], P

Abstract Introduction In patients with peripheral artery disease (PAD) the presence of diabetes mellitus (DM) is associated with higher morbidity and mortality. Because huge efforts are made to improve medical care of patients with DM including chronic disease programs, the aim of the present study was to investigate temporal trends regarding the clinical burden of DM on PAD patients within a 15‐year observational period. Methods We analyzed all patients hospitalized because of PAD between 2005 and 2019 in Germany stratified regarding DM. Results Overall, 2 654 871 hospitalizations of PAD patients (865 823 with DM) were included. Hospitalizations based on PAD inclined from 142 778 in 2005 to 190 135 in 2019 (β 3956 per year; 95% confidence interval [CI] 3034–4878, p

Abstract Animal experiments and early phase human trials suggest that inhibition of factor XIa (FXIa) safely prevents venous thromboembolism (VTE), and specific murine models of sepsis have shown potential efficacy in alleviating cytokine storm. These latter findings support the role of FXI beyond coagulation. Here, we combine targeted proteomics, machine learning and bioinformatics, to discover associations between FXI activity (FXI:C) and the plasma protein profile of patients with VTE. FXI:C was measured with a modified activated partial prothrombin time (APTT) clotting time assay. Proximity extension assay-based protein profiling was performed on plasma collected from subjects from the Genotyping and Molecular Phenotyping of Venous Thromboembolism (GMP-VTE) Project, collected during an acute VTE event (n = 549) and 12-months after (n = 187). Among 444 proteins investigated, N = 21 and N = 66 were associated with FXI:C during the acute VTE event and at 12 months follow-up, respectively. Seven proteins were identified as FXI:C-associated at both time points. These FXI-related proteins were enriched in immune pathways related to causes of thrombo-inflammation, extracellular matrix interaction, lipid metabolism, and apoptosis. The results of this study offer important new avenues for future research into the multiple properties of FXI, which are of high clinical interest given the current development of FXI inhibitors.

BackgroundIntensive care units (ICU) capacities are one of the most critical determinants in health-care management of the COVID-19 pandemic. Therefore, we aimed to analyze the ICU-admission and case-fatality rate as well as characteristics and outcomes of patient admitted to ICU in order to identify predictors and associated conditions for worsening and case-fatality in this critical ill patient-group.MethodsWe used the German nationwide inpatient sample to analyze all hospitalized patients with confirmed COVID-19 diagnosis in Germany between January and December 2020. All hospitalized patients with confirmed COVID-19 infection during the year 2020 were included in the present study and were stratified according ICU-admission.ResultsOverall, 176,137 hospitalizations of patients with COVID-19-infection (52.3% males; 53.6% aged ≥70 years) were reported in Germany during 2020. Among them, 27,053 (15.4%) were treated in ICU. COVID-19-patients treated on ICU were younger [70.0 (interquartile range (IQR) 59.0–79.0) vs. 72.0 (IQR 55.0–82.0) years, P < 0.001], more often males (66.3 vs. 48.8%, P < 0.001), had more frequently cardiovascular diseases (CVD) and cardiovascular risk-factors with increased in-hospital case-fatality (38.4 vs. 14.2%, P < 0.001). ICU-admission was independently associated with in-hospital death [OR 5.49 (95% CI 5.30–5.68), P < 0.001]. Male sex [OR 1.96 (95% CI 1.90–2.01), P < 0.001], obesity [OR 2.20 (95% CI 2.10–2.31), P < 0.001], diabetes mellitus [OR 1.48 (95% CI 1.44–1.53), P < 0.001], atrial fibrillation/flutter [OR 1.57 (95% CI 1.51–1.62), P < 0.001], and heart failure [OR 1.72 (95% CI 1.66–1.78), P < 0.001] were independently associated with ICU-admission.ConclusionDuring 2020, 15.4% of the hospitalized COVID-19-patients were treated on ICUs with high case-fatality. Male sex, CVD and cardiovascular risk-factors were independent risk-factors for ICU admission.

(1) Background: Endothelial dysfunction initiates cardiovascular pathologies, including peripheral artery disease (PAD). The pathophysiology of impaired new vessel formation in the presence of angiogenic stimuli, such as ischemia and inflammation, is unknown. We have recently shown in mice that reduced endothelial protein C receptor (EPCR) expression results in defective angiogenesis following experimental hindlimb ischemia. (2) Purpose: To determine soluble (s)EPCR levels in the plasma of patients with PAD and to compare them with the protein C activity and biomarkers of endothelial function, inflammation, and angiogenesis. (3) Methods and Results: Clinical tests of vascular function and immunoassays of plasma from patients with PAD stage II were compared to age- and sex-matched individuals with and without cardiovascular risk factors or PAD stage III/IV patients. sEPCR levels were significantly lower in PAD stage II patients compared to subjects with risk factors, but no PAD, and further decreased in PAD stage III/IV patients. Plasma protein C activity or levels of ADAM17, a mediator of EPCR shedding, did not differ. Significant associations between sEPCR and the ankle-brachial index (p = 0.0359), age (p = 0.0488), body mass index (p = 0.0110), and plasma sE-selectin levels (p = 0.0327) were observed. High-sensitive CRP levels and white blood cell counts were significantly elevated in PAD patients and associated with serum glucose levels, but not sEPCR. In contrast, plasma TNFα or IL1β levels did not differ. Circulating levels of VEGF were significantly elevated in PAD stage II patients (p = 0.0198), but not associated with molecular (sE-selectin) or functional (ankle-brachial index) markers of vascular health. (4) Conclusions: Our findings suggest that circulating sEPCR levels may be useful as biomarkers of endothelial dysfunction, including angiogenesis, in persons older than 35 years and that progressive loss of endothelial protein C receptors might be involved in the development and progression of PAD.

BackgroundPatients with peripheral arterial disease (PAD) are at increased risk for major adverse cardiovascular events (MACE) such as cardiovascular death, myocardial infarction, and stroke as well as major adverse limb events (MALE) such as amputation and acute limb ischemia. Therefore, prevention of thrombotic events is crucial to improve the prognosis of PAD patients. This review article concludes current evidence and guideline recommendations about antithrombotic therapy in PAD patients.Antithrombotic therapy is highly effective to reduce MACE and MALE events in PAD patients. Recently, the concept of dual pathway inhibition (low-dose rivaroxaban plus acetylic salicylic acid (ASA) has been tested in the COMPASS and VOYAGER-PAD trial. Compared to ASA alone dual pathway inhibition was superior to prevent MACE and MALE. After peripheral revascularization, in particular the risk for acute limb ischemia was reduced. In contrast, the risk for major bleeding is increased. Therefore, current guidelines recommend the combination of low-dose rivaroxaban and ASA in PAD patients with low bleeding risk. In patients with high bleeding risk, a single antiplatelet drug (preferable clopidogrel) is indicated. In patients with atherosclerotic vascular disease and indication for oral anticoagulation, no additional antiplatelet drug is necessary, as this would increase the risk of bleeding without improving the prognosis.ConclusionAntithrombotic treatment reduces MACE and MALE and is recommended in all patients with PAD. Individual bleeding risk should always be considered based on the current data situation and an individual benefit-risk assessment must be carried out.

Background: Diabetes mellitus (DM) represents a relevant risk factor regarding morbidity and mortality worldwide. However, only limited data exist regarding the impact of DM on the clinical outcome of patients with COVID-19 infection. Methods: All hospitalized patients with confirmed COVID-19-infection (ICD-code U07.1) during the year 2020 in Germany were included in the present study. Patients were stratified regarding the co-prevalence of DM (ICD-codes E10-E14), and the impact of DM on in-hospital case fatality and in-hospital adverse events was analyzed. Results: Overall, 176,137 hospitalizations with confirmed COVID-19 infection were documented; of these, 45,232 (25.7%) patients had an additional diagnosis of DM. Diabetic patients with COVID-19 were more often of male sex and 7 years older (median 76.0 (IQR: 66.0–83.0) vs. 69.0 (52.0–81.0) years, p < 0.001). COVID-19 patients with DM demonstrated an aggravated comorbidity profile, as reflected by a higher Charlson comorbidity index (6.0 (IQR: 4.0–8.0) vs. 3.0 (1.0–5.0), p < 0.001). Risk for pneumonia (OR 1.38 (95% CI: 1.35–1.41), p < 0.001), acute respiratory distress syndrome (OR 1.53 (95% CI: 1.47–1.60), p < 0.001), and need for intensive care (21.3% vs. 13.3%, p < 0.001) were increased in DM patients. DM was an independent risk factor for acute kidney failure (OR 1.49 (95% CI: 1.44–1.53), p < 0.001), dialysis (OR 1.56 (95% CI: 1.47–1.66), p < 0.001), mechanical ventilation (OR: 1.49 (95% CI: 1.43–1.56), p < 0.001), extracorporeal membrane oxygenation (OR 1.44 (95% CI: 1.27–1.62), p < 0.001), major adverse cardiac and cerebrovascular events (OR: 1.24 (95% CI: 1.20–1.27), p < 0.001), and in-hospital mortality (OR: 1.26 (95% CI: 1.22–1.30), p < 0.001). Conclusions: In patients with COVID-19-infection, DM is a relevant risk factor for adverse events, including mortality. The vulnerable patient group of diabetics with COVID-19 requires intense medical care and monitoring during hospitalization.

Blood clot formation initiates ischemic events, but coagulation roles during postischemic tissue repair are poorly understood. The endothelial protein C receptor (EPCR) regulates coagulation, as well as immune and vascular signaling, by protease activated receptors (PARs). Here, we show that endothelial EPCR-PAR1 signaling supports reperfusion and neovascularization in hindlimb ischemia in mice. Whereas deletion of PAR2 or PAR4 did not impair angiogenesis, EPCR and PAR1 deficiency or PAR1 resistance to cleavage by activated protein C caused markedly reduced postischemic reperfusion in vivo and angiogenesis in vitro. These findings were corroborated by biased PAR1 agonism in isolated primary endothelial cells. Loss of EPCR-PAR1 signaling upregulated hemoglobin expression and reduced endothelial nitric oxide (NO) bioavailability. Defective angiogenic sprouting was rescued by the NO donor DETA-NO, whereas NO scavenging increased hemoglobin and mesenchymal marker expression in human and mouse endothelial cells. Vascular specimens from patients with ischemic peripheral artery disease exhibited increased hemoglobin expression, and soluble EPCR and NO levels were reduced in plasma. Our data implicate endothelial EPCR-PAR1 signaling in the hypoxic response of endothelial cells and identify suppression of hemoglobin expression as an unexpected link between coagulation signaling, preservation of endothelial cell NO bioavailability, support of neovascularization, and prevention of fibrosis.

Patients with peripheral arterial disease (PAD) benefit from combination therapy with acetylsalicylic acid (ASA, 100 mg, one time per day) plus low-dose rivaroxaban (2.5 mg, two times per day) compared to ASA monotherapy. In particular, major adverse cardiac and limb events were significantly reduced after peripheral endovascular revascularization (EVR). In this pilot study, the platelet activation status in vivo and platelet reactivity in vitro were longitudinally analyzed by flow cytometric assays and calibrated automated thrombography in platelet-rich plasma (PRP) from 10 patients with PAD receiving ASA (100 mg, one time per day) before EVR, ASA plus clopidogrel (75 mg, one time per day) after EVR, and ASA plus rivaroxaban (2.5 mg, two times per day) during a long-term follow-up. Platelet responsiveness to clopidogrel was compared to additional 10 patients with stable PAD and clopidogrel (75 mg, one time per day) monotherapy. ASA plus rivaroxaban treatment resulted in a significantly decreased thrombin peak in PRP for two triggers, namely, low concentration of tissue factor (TF) and thrombin, compared to ASA monotherapy. TF-controlled thrombin generation was additionally characterized by a significantly prolonged lag time in PRP and platelet-free plasma during ASA plus rivaroxaban combination therapy. In comparison, ASA plus clopidogrel treatment presented a significant reduction of the thrombin peak in PRP, which was less pronounced than during subsequent ASA plus rivaroxaban therapy. Platelet responsiveness to clopidogrel was observed for 60% of patients receiving ASA plus clopidogrel and clopidogrel monotherapy, respectively. Blocking of CD36 on the platelet surface further reduced the thrombin peak in PRP induced by TF for all three therapy regimes. Platelet activation in vivo and in response to the GPVI-agonist convulxin or thrombin in vitro was similar, whereas integrin αIIbβ3 activation and α-granule release induced by the PAR-1 activating peptide TRAP-6 were significantly diminished during ASA plus rivaroxaban treatment compared to ASA monotherapy. In conclusion, the data of this pilot study indicate an inhibitory effect of rivaroxaban on the thrombin propagation phase of CD36-sensitive platelet thrombin formation in patients with PAD treated with ASA plus rivaroxaban combination therapy, which is associated with decreased PAR-1 but not thrombin-mediated platelet activation.

BackgroundAn increasing level of evidence suggests that obesity not only is a major risk factor for cardiovascular diseases (CVDs) but also has adverse outcomes during COVID-19 infection.MethodsWe used the German nationwide inpatient sample to analyze all hospitalized patients with confirmed COVID-19 diagnosis in Germany from January to December 2020 and stratified them for diagnosed obesity. Obesity was defined as body mass index ≥30 kg/m2 according to the WHO. The impact of obesity on in-hospital case fatality and adverse in-hospital events comprising major adverse cardiovascular and cerebrovascular events (MACCE), acute respiratory distress syndrome (ARDS), venous thromboembolism (VTE), and others was analyzed.ResultsWe analyzed data of 176,137 hospitalizations of patients with confirmed COVID-19 infection; among them, 9,383 (5.3%) had an additional obesity diagnosis. Although COVID-19 patients without obesity were older (72.0 [interquartile range (IQR) 56.0/82.0] vs. 66.0 [54.0/76.0] years, p < 0.001), the CVD profile was less favorable in obese COVID-19 patients (Charlson comorbidity index 4.44 ± 3.01 vs. 4.08 ± 2.92, p < 0.001). Obesity was independently associated with increased in-hospital case fatality (OR 1.203 [95% CI 1.131–1.279], p < 0.001) and MACCE (OR 1.168 [95% CI 1.101–1.239], p < 0.001), ARDS (OR 2.605 [95% CI 2.449–2.772], p < 0.001), and VTE (OR 1.780 [95% CI 1.605–1.973], p < 0.001) and also associated with increased necessity of treatment on intensive care unit (OR 2.201 [95% CI 2.097–2.310], p < 0.001), mechanical ventilation (OR 2.277 [95% CI 2.140–2.422], p < 0.001), and extracorporeal membrane oxygenation (OR 3.485 [95% CI 3.023–4.017], p < 0.001).ConclusionsObesity independently affected case fatality, MACCE, ARDS development, VTE, and other adverse in-hospital events in patients with COVID-19 infection. Obesity should be taken into account regarding COVID-19 prevention strategies, risk stratification, and adequate healthcare planning. Maintaining a healthy weight is important not only to prevent cardiometabolic diseases but also for better individual outcomes during COVID-19 infection.

Introduction: Atherosclerosis and pulmonary embolism (PE) affect cardiovascular mortality substantially. We aimed to investigate the impact of atherosclerosis on the outcomes of patients with deep venous thrombosis (DVT) and to identify the differences in DVT patients with and without PE. Methods: Patients with DVT with and without symptomatic atherosclerosis (defined as coronary artery disease, myocardial infarction and/or peripheral artery disease) as well as with and without PE under oral anticoagulation were enrolled during January 2011–April 2013 and compared. The impact of symptomatic atherosclerosis on several outcomes was analyzed. Results: Overall, 509 DVT patients (70.0 [56.0–77.0] years, 51.9% females) were included in this study. Among them, 179 (36.3%) had symptomatic atherosclerosis and 204 (40.1%) a concomitant PE. DVT patients with symptomatic atherosclerosis were older (74.0 [IQR 65.0–80.0] vs. 63.0 [48.0–75.0] years, p < 0.0001), more often male (56.4% vs. 43.9%, p = 0.0087) and had a higher prevalence of classical CVRF and a higher Charlson comorbidity index (7.00 [5.00–8.00] vs. 4.00 [2.00–6.00], p < 0.001). Symptomatic atherosclerosis was associated with increased mortality (HR 1.98 [95%CI 1.12–3.49], p = 0.018) and hospitalizations (HR 1.64 [95%CI 1.21–2.21], p = 0.0012) and primary long-term outcome (HR 1.99 [95%CI 1.31–3.04], p = 0.0013) during the 2 years follow-up-period in DVT patients. DVT patients without PE had diabetes mellitus (28.2% vs. 16.3%, p < 0.01) and symptomatic atherosclerosis (42.9% vs. 26.4%, p < 0.001) more often compared to DVT patients with PE, and symptomatic atherosclerosis was associated with isolated DVT (without PE) (OR 2.01 [95%CI 1.28–3.16], p < 0.01). Conclusions: Atherosclerosis was associated with isolated DVT (without PE) and increased mortality in DVT patients under oral anticoagulation. The profile of CVRF and comorbidities differed between DVT patients with and without a concomitant PE. In the case of DVT or PE, patients should be screened for concomitant atherosclerotic disease. Clinical Trial Registration: at clinicaltrials with Unique identifier NCT01809015.