Optimal long-term anticoagulation after acute pulmonary embolism: current state of the art and a look into the near future.

PURPOSE OF REVIEW: This review aims to summarize the current state of the art and future directions in optimal long-term anticoagulation following acute pulmonary embolism (PE). RECENT FINDINGS: Actual studies and guidelines underscore the preference for direct oral anticoagulants (DOAC) in standard therapeutic doses for maintenance therapy post-PE, while considering patient-specific factors and dose-reduction criteria. Risk stratification should always include the assessment of concomitant trigger- or risk factors regarding their strength and persistence. The use of tools like specific scores can facilitate the identification of optimal candidates for long-term therapy, emphasizing once more personalized approaches and strategies. Special patient groups, such as cancer associated thrombosis, chronic thromboembolic pulmonary hypertension or antiphospholipid syndrome require even more tailored therapy approaches. SUMMARY: Optimal long-term anticoagulation post-PE should be guided by straightforward and individual risk assessment strategies. The array of indications for DOACs has gotten wider in last years, also within special patient groups. Still, chronic thromboembolic pulmonary hypertension and antiphospholipid syndrome remains domain of vitamin K agonists.

Impact of familiarity with the format of the exam on performance in the OSCE of undergraduate medical students - an interventional study.

BACKGROUND: Assessments, such as summative structured examinations, aim to verify whether students have acquired the necessary competencies. It is important to familiarize students with the examination format prior to the assessment to ensure that true competency is measured. However, it is unclear whether students can demonstrate their true potential or possibly perform less effectively due to the unfamiliar examination format. Hence, we questioned whether a 10-min active familiarization in the form of simulation improved medical students´ OSCE performance. Next, we wanted to elucidate whether the effect depends on whether the familiarization procedure is active or passive. METHODS: We implemented an intervention consisting of a 10-min active simulation to prepare the students for the OSCE setting. We compared the impact of this intervention on performance to no intervention in 5th-year medical students (n = 1284) from 2018 until 2022. Recently, a passive lecture, in which the OSCE setting is explained without active participation of the students, was introduced as a comparator group. Students who participated in neither the intervention nor the passive lecture group formed the control group. The OSCE performance between the groups and the impact of gender was assessed using X2, nonparametric tests and regression analysis (total n = 362). RESULTS: We found that active familiarization of students (n = 188) yields significantly better performance compared to the passive comparator (Cohen´s d = 0.857, p < 0.001, n = 52) and control group (Cohen´s d = 0.473, p < 0.001, n = 122). In multivariate regression analysis, active intervention remained the only significant variable with a 2.945-fold increase in the probability of passing the exam (p = 0.018). CONCLUSIONS: A short 10-min active intervention to familiarize students with the OSCE setting significantly improved student performance. We suggest that curricula should include simulations on the exam setting in addition to courses that increase knowledge or skills to mitigate the negative effect of nonfamiliarity with the OSCE exam setting on the students.

Hepatocyte growth factor as indicator for subclinical atherosclerosis.

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.

Increasing Soluble P-Selectin Levels Predict Higher Peripheral Atherosclerotic Plaque Progression.

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.

The angiogenic neuropeptide catestatin exerts beneficial effects on human coronary vascular cells and cardiomyocytes.

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.

Inverse Correlation of Cholesterol Efflux Capacity with Peripheral Plaque Volume Measured by 3D Ultrasound.

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.

Effect of chronic kidney disease and sex on carotid and femoral plaque volume as measured by three-dimensional ultrasound.

INTRODUCTION: Previously, we reported the association between cardiovascular risk factors (CVRFs) and the presence of cardiovascular disease with peripheral atherosclerosis. In this paper, we specifically aimed to investigate the association of chronic kidney disease (CKD) and sex with carotid and femoral plaque volume. MATERIALS AND METHODS: 404 patients (median age 64; 57% men) with at least 1 CVRF or established cardiovascular disease where included into the study. 3D ultrasonography evaluated with an automated software was used to measure peripheral plaque volume. Statistical analyses were performed using SPSS Statistic. RESULTS: CKD was diagnosed in 56 patients (13.9%), with most patients in stage 3a. Total atherosclerotic plaque volume was significantly higher in patients with CKD (p < 0.001) compared to those without CKD and in men compared to women in all vascular territories (p < 0.001). CONCLUSION: Our data show that we need to be even more vigilant about the presence of atherosclerotic plaques and cardiovascular disease in these patients. Already in patients with CKD stage 3a, efficient CVRF reduction and intensive treatment is warranted.

High baseline fetuin-A levels are associated with lower atherosclerotic plaque progression as measured by 3D ultrasound.

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 µg/ml. In patients with high fetuin A levels (>712 µg/ml), a significantly lower plaque progression was observed compared to the group with low fetuin-A levels <712 µg/ml (high fetuin-A 197 mm3 vs. low fetuin-A 279 mm3; p = 0.01). Conclusions: Higher fetuin-A levels appear to predict lower atherosclerotic plaque progression in patients with or at risk of cardiovascular disease.

Association of Food and Alcohol Consumption with Peripheral Atherosclerotic Plaque Volume as Measured by 3D-Ultrasound.

BACKGROUND: Food patterns and alcohol consumption influence the risk for cardiovascular diseases (CVD) and a healthy nutrition is essential for the prevention of CVD. The aim of this study was to determine the influence of nutrition and alcohol consumption on peripheral atherosclerotic plaque volume (PV) using an innovative 3D ultrasound approach. METHODS: In this prospective, single centre study we included 342 patients with at least one cardiovascular risk factor or established CVD. PV in the carotid and femoral artery was measured using a semi-automatic software. Information on food and alcohol consumption of the participants was collected using an internationally acknowledged standardized questionnaire (DEGS1). RESULTS: Patients with low total PV consumed significantly more vegetables (p = 0.004) and vegetable juice (p = 0.019) per week compared to patients with high total PV. In contrast, patients with high total PV reported a higher alcohol consumption compared to patients with low total PV (p = 0.026). Patients without vascular disease, in particular cerebrovascular disease (p = 0.001) and peripheral arterial disease (p = 0.012), reported a significantly higher fish consumption per week. In the multivariate model, we found a significant negative association for vegetable consumption (p = 0.034) and female gender (p = 0.018) but a significant positive association for alcohol (p = 0.001), age (p < 0.001) the presence of vascular disease (p < 0.001) and cardiovascular risk factors (p < 0.001) with total PV. CONCLUSION: In this study we were able to show an association of food and alcohol consumption with peripheral atherosclerotic PV measured by 3D-ultrasonography. Following a healthy nutritional lifestyle (vegetable consumption, no excessive alcohol consumption) and regular fish consumption appears to be associated with less peripheral atherosclerosis and decreased prevalence of vascular diseases, respectively.

NGAL Correlates with Femoral and Carotid Plaque Volume Assessed by Sonographic 3D Plaque Volumetry.

BACKGROUND/OBJECTIVES: Inflammation represents a cornerstone in the development of atherosclerosis and early detection is essential to avoid cardiovascular events. Biomarkers like interleukin-1 beta, interleukin-6, or high sensitivity CRP (hs-CRP) have been investigated intensively in this field. Since they have several limitations, additional biomarkers are needed for cardiovascular risk stratification. The acute phase protein, neutrophil gelatinase-associated lipocalin (NGAL), modulates inflammation and is elevated in cardiovascular disease (CVD). Moreover, it contributes to plaque destabilization. METHODS: In this prospective, single-center study, we included 323 asymptomatic patients with at least one cardiovascular risk factor or established CVD. NGAL levels were measured in plasma samples using a commercially available ELISA. Carotid, femoral, and total atherosclerotic plaque volumes (PV) were measured using a 3D ultrasound system (Philips iU22). Patients were separated into a low (n = 243) and high (n = 80) total PV group. RESULTS: NGAL was significantly higher in patients with high total PV versus patients with low total PV. The NGAL amplitude for the prediction of high total PV was significantly higher when compared with hs-CRP. A high predictive value could also be observed for patients without established CVD. CONCLUSION: NGAL seems to be a promising biomarker for the identification of asymptomatic patients with atherosclerotic disease.

Early onset of menopause is associated with increased peripheral atherosclerotic plaque volume and progression.

BACKGROUND AND AIMS: Cardiovascular disease (CVD) is the leading cause of death in western countries. One risk factor unique to women is the menopausal status. The aim of this study was to analyse the influence of the onset of menopause (MP) on the extent and progression of atherosclerotic plaque volume (PV). METHODS: Postmenopausal women with at least one cardiovascular risk factor (CVRF) but without established CVD were included. Quantification of PV was performed in peripheral arteries using a three - dimensional (3D) ultrasound (US) technique. Follow-up examination to assess PV progression was performed after 19 (±8) months. RESULTS: 110 consecutive postmenopausal women (mean age 65.5) were included. Females with an earlier onset of MP (<45 years) had a significantly higher PV than those with an intermediate (45-52 years) or later onset of menopause (>52 years), irrespective of other CVRF (244 mm³ vs. 193 mm³ vs. 73 mm³, respectively, p = 0.023). In addition, women with an earlier onset of MP had a higher PV progression compared to women with an intermediate or late onset (40 mm³ vs. 35 mm³ vs. 8.5 mm³; p = 0.002, respectively). Moreover, these results were confirmed in multivariate regression, where only onset of MP (OR 0.88; 95%CI 0.81-0.96; p = 0.004) and age (OR 1.06; 95%CI 1.08-1.13; p = 0.025) were significant predictors for a higher atherosclerotic progression. CONCLUSIONS: An earlier onset of MP was associated with an increase in atherosclerotic PV and accelerated progression, independent of other CVRF.

Dabigatran Added to Dual Antiplatelet Therapy to Treat a Left Ventricular Thrombus in an 87 Year Old Patient With Myocardial Infarction and Very High Bleeding Risk.

Background: A left ventricular (LV) thrombus is detected in approximately 5-10% of patients after myocardial infarction (MI). If left untreated, these LV thrombi carry a significant risk of complications including embolic stroke. According to current guidelines, anticoagulation with vitamin K antagonists (VKA) is recommended to treat a LV thrombus. Case presentation: An 87 year old patient was referred to our department with non ST-elevation MI. Five months before, he had been diagnosed with a subacute ST elevation MI, which had been treated conservatively. Recently, a rectal neoplasia had been diagnosed, but not operated yet. The patient underwent coronary angiography with implantation of two drug eluting stents (Cre8) requiring dual antiplatelet therapy. During ventriculography an apical LV thrombus of 16 mm diameter was detected. Due to the high bleeding risk in this patient, VKA therapy with potentially fluctuating international normalized ratio (INR) values was considered unsuitable. Therefore, dabigatran at a dose of 110 mg bid was chosen as anticoagulation therapy. After 4 weeks, cardiac computed tomography was performed, which failed to detect the LV thrombus described previously. Notably, triple therapy with dabigatran, clopidogrel, and aspirin was well tolerated without evidence for bleeding. The surgical resection of the rectal neoplasm was performed 2 months later without bleeding complications. Discussion: Anticoagulation is effective in patients with MI and a LV thrombus in reducing the risk of embolization and in dissolving the thrombus. Our case is complex due to the required triple therapy, very old age and significant bleeding risk of our patient due to the rectal neoplasia. Although only few reports are available for the use of non VKA oral anticoagulants (NOAC) in this indication, we chose dabigatran at a dose of 110 mg bid added to dual antiplatelet therapy for our patient. Besides the advantage of a predictable pharmacokinetic profile of NOAC in contrast to VKA, the effect of dabigatran can rapidly be reversed by idaruzicumab in the case of severe bleeding. Conclusion remarks: Physicians should carefully weigh the risk of thromboembolic events versus the risk of bleeding when combining antiplatelet with anticoagulation therapy.

Influence of Traditional Cardiovascular Risk Factors on Carotid and Femoral Atherosclerotic Plaque Volume as Measured by Three-Dimensional Ultrasound.

BACKGROUND: Atherosclerosis is a systemic multifocal disease with a preference for the branching points of the arteries. In this study, we quantitatively measured carotid and femoral plaque volume in subjects with cardiovascular risk factors (CVRF) and/or established atherosclerotic disease using a 3D ultrasound technique. METHODS: In this prospective, single-centre study, we included 404 patients (median age 64; 56.9% men) with at least one CVRF or established cardiovascular disease. Plaque volume was measured using 3D ultrasound equipped with an automated software. RESULTS: We found a strong correlation of plaque volume with CVRF and the number of vascular beds involved. The strongest associations with total and femoral plaque volume were noted for smoking, hypertension, age, as well as for the presence of peripheral arterial occlusive disease (p < 0.05). Carotid plaque volume was best predicted by hyperlipidaemia, hypertension, age, as well as the presence of cerebrovascular disease and coronary artery disease (p < 0.05). CONCLUSION: We conclude that smoking appears to be associated with total and femoral plaque volume, whereas hyperlipidaemia seems to be associated with carotid plaque volume. Measurement of 3D plaque volume is a practical and reproducible technique with the potential to become an additional screening tool in cardiovascular risk stratification.

Incidental finding of an absent left common carotid artery.

We describe a case of a young woman evaluated for Raynaud's phenomenon in whom an extremely rare variation, the absence of the left common carotid artery, was incidentally detected as an isolated finding. The detection of vascular anomalies may be important for future endovascular or surgical interventions.