Venous thromboembolism in patients with COVID-19 (SARS-CoV-2 infection) - a position paper of the German Society of Angiology (DGA).

As observed in other infections with a systemic inflammatory response, severe COVID-19 is associated with hypercoagulability and a prothrombotic state. Currently, there is growing evidence that pulmonary embolism and thrombosis contribute to adverse outcomes and increased mortality in critically ill patients with COVID-19. The optimal thromboprophylactic regimen for patients with COVID-19 is not known. Whereas pharmacologic thromboprophylaxis is generally recommended for all hospitalized COVID-19 patients, adequate dosing of anticoagulants remains a controversial issue. Therefore, we summarize current evidence from the available literature and, on behalf of the German Society of Angiology (DGA), we aim to provide advice to establish an improved and more uniform strategy for thromboprophylaxis in patients with COVID-19.

Opposing effects of ATP and adenosine on barrier function of rat coronary microvasculature.

ATP can differentially affect the micro- and macrovascular endothelial barrier. It has been shown that it can both increase and/or decrease macromolecule permeability of microvascular endothelial cells and microvessels, in vivo. We hypothesised that the barrier stabilising effect is mediated by ATP itself via P2 receptors, while barrier-disrupting effect is mediated by its metabolite adenosine via adenosine receptors. The effects of ATP, ADP, AMP and adenosine on barrier function were studied in cultured rat coronary microvascular endothelial monolayers (RCEC) in vitro, as well as in rat mesentery vessels, and in rat hearts in vivo. ATP and ADP showed a biphasic effect on permeability of RCEC monolayers with a reduction followed by a later increase in albumin permeability. The permeability decreasing effect of ATP was enhanced by ecto-nucleotidase inhibitor ARL67156 while permeability increasing effect was enhanced by apyrase, an extracellular ecto-nucleotidase. Moreover, the permeability increasing effect was abrogated by adenosine receptor antagonists, 8-phenyltheophylline (8-PT) and DMPX. Adenosine and adenosine receptor agonists 5'-(N-ethylcarboxamido)-adenosine (NECA), CGS21680, and R-PIA enhanced albumin permeability which was antagonised by 8-PT, A(1), and A(2) but not by A(3) receptor antagonists. Likewise, immunofluorescence microscopy of VE-cadherin and actin showed that NECA induces a disturbance of intercellular junctions. Pre-incubation of ATP antagonised the effects of NECA on permeability, actin cytoskeleton and intercellular junctions. Similar effects of the applied substances were observed in rat mesentery artery by determining the vascular leakage using intravital microscopy as well as in rat hearts by assessing myocardial water contents in vivo. In conclusion, the study demonstrates that in RCEC, ATP, ADP, and its metabolite adenosine play opposing roles on endothelial barrier function.

High frequency of silent pulmonary embolism in patients with cryptogenic stroke and patent foramen ovale.

BACKGROUND AND PURPOSE: Deep vein thrombosis and pulmonary embolism (PE) prove venous embolic activity and enforce the suspicion of paradoxical embolism in patients with stroke with patent foramen ovale. Because it has implications in secondary prevention, we investigated the frequency of silent PE in such a cohort of patients. METHODS: Patients with cryptogenic stroke or transient ischemic attack and patent foramen ovale who underwent a ventilation perfusion scintigraphy were identified from a stroke registry. Blinded from clinical data, ventilation perfusion scintigraphy scans were re-evaluated independently by 2 experts. Patients showing at least a subsegmental defect were considered as having silent PE. Factors potentially associated with PE were analyzed. RESULTS: The evaluation included 151 patients. Median age was 55.2 years and 59.9% were male. In 56 (37%) patients, silent PE was found; a deep vein thrombosis was evident in 11 (7%) patients. Atrial septal aneurysm was identified in 39 patients and hypermobile atrial septum in 37 patients. Atrial septal aneurysm and hypermobile atrial septum were independently associated with PE. In females, intake of oral contraceptives showed certain association with PE (6 of 25 versus 3 of 40; P=0.07). CONCLUSIONS: Silent PE frequently occurs in patients with cryptogenic stroke and patent foramen ovale, particularly when atrial septal aneurysm or hypermobile atrial septum are present.

Insulin stabilizes microvascular endothelial barrier function via phosphatidylinositol 3-kinase/Akt-mediated Rac1 activation.

OBJECTIVE: Insulin is a key regulator of metabolism, but it also confers protective effects on the cardiovascular system. Here, we analyze the mechanism by which insulin stabilizes endothelial barrier function. METHODS AND RESULTS: Insulin reduced basal and antagonized tumor necrosis factor-alpha-induced macromolecule permeability of rat coronary microvascular endothelial monolayers. It also abolished reperfusion-induced vascular leakage in isolated-perfused rat hearts. Insulin induced dephosphorylation of the regulatory myosin light chains, as well as translocation of actin and vascular endothelial (VE)-cadherin to cell borders, indicating a reduction in contractile activation and stabilization of cell adhesion structures. These protective effects were blocked by genistein or Hydroxy-2-naphthalenylmethylphosphonic acid tris acetoxymethyl ester (HNMPA-[AM](3)), a pan-tyrosine-kinase or specific insulin-receptor-kinase inhibitor, respectively. Insulin stimulated the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and NO production, and it activated Rac1. Inhibition of PI3K/Akt abrogated Rac1 activation and insulin-induced barrier protection, whereas inhibition of the endothelial nitric oxide synthase/soluble guanylyl cyclase pathway partially inhibited them. Inhibition of Rac1 abrogated the assembly of actin at cell borders. Accordingly, it abolished the protective effect of insulin on barrier function of the cultured endothelial monolayer, as well as the intact coronary system of ischemic-reperfused hearts. CONCLUSIONS: Insulin stabilizes endothelial barrier via inactivation of the endothelial contractile machinery and enhancement of cell-cell adhesions. These effects are mediated via PI3K/Akt- and NO/cGMP-induced Rac1 activation.

Factors associated with shunt dynamic in patients with cryptogenic stroke and patent foramen ovale: an observational cohort study.

BACKGROUND: As previously reported there is evidence for a reduction in right to left shunt (RLS) in stroke patients with patent foramen ovale (PFO). This occurs predominantly in patients with cryptogenic stroke (CS). We therefore analysed factors associated with a shunt reduction on follow-up in stroke patients suffering of CS. METHODS: On index event PFO and RLS were proven by transesophageal echocardiography and contrast-enhanced transcranial Doppler-sonography (ce-TCD). Silent PE was proved by ventilation perfusion scintigraphy (V/Q) within the stroke work-up on index event; all scans were re-evaluated in a blinded manner by two experts. The RLS was re-assessed on follow-up by ce-TCD. A reduction in shunt volume was defined as a difference of ≥20 microembolic signals (MES) or the lack of evidence of RLS on follow-up. For subsequent analyses patients with CS were considered; parameters such as deep vein thrombosis (DVT) and silent pulmonary embolism (PE) were analysed. RESULTS: In 39 PFO patients suffering of a CS the RLS was re-assessed on follow-up. In all patients (n = 39) with CS a V/Q was performed; the median age was 40 years, 24 (61.5%) patients were female. In 27 patients a reduction in RLS was evident. Silent PE was evident in 18/39 patients (46.2%). Factors such as atrial septum aneurysm, DVT or even silent PE were not associated with RLS dynamics. A greater time delay from index event to follow-up assessment was associated with a decrease in shunt volume (median 12 vs. 6 months, p = 0.013). CONCLUSIONS: In patients with CS a reduction in RLS is not associated with the presence of a venous embolic event such as DVT or silent PE. A greater time delay between the initial and the follow-up investigation increases the likelihood for the detection of a reduction in RLS.

Decrease in shunt volume in patients with cryptogenic stroke and patent foramen ovale.

BACKGROUND: In patients with patent foramen ovale (PFO) there is evidence supporting the hypothesis of a change in right-to-left shunt (RLS) over time. Proven, this could have implications for the care of patients with PFO and a history of stroke. The following study addressed this hypothesis in a cohort of patients with stroke and PFO. METHODS: The RLS volume assessed during hospitalisation for stroke (index event/T0) was compared with the RLS volume on follow-up (T1) (median time between T0 and T1 was 10 months). In 102 patients with a history of stroke and PFO the RLS volume was re-assessed on follow-up using contrast-enhanced transcranial Doppler/duplex (ce-TCD) ultrasound. A change in RLS volume was defined as a difference of ≥20 microembolic signals (MES) or no evidence of RLS during ce-TCD ultrasound on follow-up. RESULTS: There was evidence of a marked reduction in RLS volume in 31/102 patients; in 14/31 patients a PFO was no longer detectable. An index event classified as cryptogenic stroke (P < 0.001; OD = 39.2, 95% confidence interval 6.0 to 258.2) and the time interval to the follow-up visit (P = 0.03) were independently associated with a change in RLS volume over time. CONCLUSIONS: RLS volume across a PFO decreases over time, especially in patients with cryptogenic stroke. These may determine the development of new strategies for the management in the secondary stroke prevention.

Anemia as a risk factor for cerebral venous thrombosis? An old hypothesis revisited. Results of a prospective study.

BACKGROUND: Several case reports have linked iron deficiency anemia with the occurrence of cerebral venous thrombosis (CVT) or stroke, yet, it is unclear whether this is a chance association. METHODS: In a case-control design data of whole blood count and screening for thrombophilic coagulation abnormalities of 121 prospectively identified patients with CVT and 120 healthy controls were compared. Anemia was defined as a hemoglobin (Hb) concentration of <120 g/l in females, and <130 g/l in males, severe anemia as a Hb <90 g/l. Adjusted odds ratios (OR) were calculated based on a logistic regression model treating variables with a level of significance of p < or = 0.2 on univariate analysis as potential confounders. RESULTS: Thrombophilia (OR 1.22, 95% CI 1.07-1.76, p < 0.01), severe anemia (OR 1.10, 95% CI 1.01-2.22, p < 0.05), and hypercholesterinemia (OR 1.21, 95% CI 1.04-2.57, p < 0.05) were the only independent variables associated with CVT on multivariate analysis. CONCLUSION: Severe anemia is significantly and independently associated with CVT.

[Obstructive sleep apnea-related cardiovascular disease]. / Vaskuläre Folgeerkrankungen bei obstruktiver Schlafapnoe.

The clinical spectrum of obstructive sleep apnea-(OSA-)related cardiovascular disease (CVD) comprises systemic arterial hypertension (prevalence: 40-60%), pulmonary hypertension (20-30%), coronary artery disease (20-30%), congestive heart failure (5-10%), and stroke (5-10%). During sleep, heart rhythm disorders such as atrioventricular blocks, sinus arrests and atrial fibrillation can be induced by OSA. OSA-related CVD mainly affects those patients with an apnea-hypopnea index > 30/h and, if left untreated, is linked to increased mortality. Epidemiologic data have clearly shown that cardiovascular risk is increased in OSA independent of confounding factors such as obesity and concomitant metabolic disease. In recent years, the pathophysiology of OSA-related CVD has been further elucidated showing that apart from the well-known sympathetic activation, increased oxidative stress and pro-inflammatory changes seem to play major roles. Furthermore, studies using high resolution ultrasonography have demonstrated endothelial dysfunction and enhanced atherosclerosis in these patients. Finally, animal models of OSA have delineated that daytime arterial hypertension is the consequence of the OSA-associated chronic intermittent hypoxia. Therapy of OSA by continuous positive airway pressure (CPAP) ventilation exerts cardioprotective effects. It has been shown to rectify the vascular micromilieu, restore endothelium-dependent vasodilation, lower 24-h blood pressure, eliminate nocturnal heart rhythm disorders, and improve left ventricular function. Furthermore, long-term CPAP therapy leads to a reduction in important clinical endpoints such as the rates of myocardial infarction and stroke.

Tako-tsubo cardiomyopathy in a 92-year old woman.

Tako-Tsubo cardiomyopathy (TTC) is an acute reversible cause of segmental myocardial dysfunction that is poorly understood and cannot be explained by the occlusion of a single coronary vessel. Its clinical presentation is similar to that of acute coronary syndrome and is often precipitated by a severe psychological or physical stress.

Fibrinogen promotes early atherosclerotic changes of the carotid artery in young, healthy adults.

AIM: To determine whether high plasma levels or activities of different hemostatic proteins contribute to the development of early atherosclerotic vessel wall changes. Elevated levels of various hemostatic proteins and markers of inflammation have been linked to an increased risk of ischemic cardiovascular events; however, the mechanisms by which these molecules might contribute to this increased risk is not clear. METHODS: The intima-media thickness of the common carotid arteries (CCA-IMT) of 125 healthy young volunteers without known cardiovascular risk factors was measured by high-resolution ultrasound. Plasma concentrations of fibrinogen, thrombomodulin, protein Z and CRP were quantified, and the plasma activities of protein C, plasminogen and factor VIII were measured. Other established risk factors, such as body mass index (BMI) and plasma levels of cholesterol, triglycerides and homocysteine, were also determined. Furthermore, the carotid arteries were examined for the presence of plaques and stenoses. RESULTS: Univariate analysis showed a significant negative correlation between CCA-IMT and HDL cholesterol, and positive correlations with age, BMI, LDL cholesterol, triglycerides, homocysteine, fibrinogen and thrombomodulin, but not with total cholesterol, lipoprotein(a) and hsCRP. CCA-IMT was also statistically independent of the activities of protein C, factor VIII and plasminogen. Multivariate analysis revealed a significant correlation of CCA-IMT with age, BMI and fibrinogen. CONCLUSION: Our data suggest that fibrinogen levels correlate with early atherosclerotic changes of the carotid artery in a population with very low cardiovascular risk.

Antioxidant vitamin C improves endothelial function in obstructive sleep apnea.

RATIONALE: Obstructive sleep apnea (OSA) is associated with oxidative stress, endothelial dysfunction, and increased cardiovascular morbidity and mortality. OBJECTIVE: We tested the hypothesis that endothelial dysfunction in patients with OSA is linked to oxidative stress. METHODS: In the present study, we measured flow-mediated dilation (FMD) of the brachial artery by ultrasound in 10 otherwise healthy, untreated patients with OSA and 10 age-and sex-matched control subjects without sleep-disordered breathing before and after intravenous injection of the antioxidant vitamin C. The investigator performing the FMD measurements was blinded to the status of the patients. RESULTS: When compared with control subjects, baseline FMD was significantly reduced in the patients with OSA. After intravenous injection of 0.5 g vitamin C, vasoreactivity remained unchanged in the control subjects. In the patients with OSA, ascorbate led to an increase in FMD to a level comparable to that observed in the control group. CONCLUSION: The reduced endothelial-dependent vasodilation in untreated patients with OSA acutely improves by the free radical scavenger vitamin C. These results are in favor of oxidative stress being responsible for the endothelial dysfunction in OSA. Antioxidant strategies should be explored for the treatment of OSA-related cardiovascular disease.

Pharmacodynamics of two different dosing regimens of tirofiban in citrate or PPACK anticoagulated blood.

The primary objective of this study was to compare the inhibitory activity of tirofiban measured with the rapid platelet function assay (RPFA) and with light transmission aggregometry using two different anticoagulants (citrate versus PPACK). Twenty patients treated with tirofiban for percutaneous coronary intervention were studied at six time points during tirofiban treatment. Tirofiban was given with a bolus dose of 10 microg/kg and an infusion of 0.10 microg/kg per min (10 patients) or with a bolus dose of 15 microg/kg and an infusion of 0.15 microg/kg per min (10 patients). Inhibition of platelet function appeared highest using citrated blood and the RPFA-device and lowest when assessed by aggregometry in PPACK-anticoagulated blood. Only the higher dose of tirofiban achieved an inhibition of platelet aggregation of at least 80% in all test systems.

Use of gadobutrol in coronary angiography.

Gadobutrol was used in coronary angiography in three patients. All three patients had a substantially increased risk of developing renal complications with iodinated contrast agents. Gadobutrol was well tolerated in all three patients without any complications. The quality of the coronary angiograms was good.