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Background: Von Willebrand factor (VWF) and its cleaving protease a disintegrin-like and metalloprotease with thrombospondin type I repeats 13 (ADAMTS13) are pivotal mediators of thrombosis and are associated with the progression of atherosclerosis. We investigated the impact of VWF, ADAMTS13 and VWF/ADAMTS13 on long-term major adverse cardiovascular outcomes (MACE) in patients undergoing percutaneous coronary intervention (PCI)., Methods: We analysed 701 patients undergoing PCI between 2003 and 2006. VWF and ADAMTS13 antigen levels were measured before PCI. As primary endpoint, we investigated MACE, a composite of all-cause mortality, myocardial infarction or ischemic stroke during 8 years of follow-up. As secondary endpoint, we investigated all-cause mortality., Results: Mean age was 63.8 years, 496 (70.8%) were male. Acute coronary syndrome (ACS) was diagnosed in 347 (49.5%) patients, stable coronary artery disease (SCAD) in 354 (50.5%). During follow-up 228 (32.5%) patients experienced MACE, and 161 (23.0%) died. In ACS patients, VWF was significantly associated with MACE (HR 1.402 (95%CI 1.003-1.959), p = 0.048), whereas ADAMTS13 and VWF/ADAMTS13 had no predictive value. In SCAD, neither VWF, ADAMTS13, nor VWF/ADAMTS13 correlated with MACE. VWF was significantly associated with all-cause death in ACS patients (HR 1.841 (95%CI 1.187-2.856), p = 0.006), but not in SCAD (1.394 (95%CI 0.856-2.269), p = 0.181). ADAMTS13 and VWF/ADAMTS13 were not correlated with ACS and SCAD, respectively., Conclusion: VWF but not ADAMTS13 and VWF/ADAMTS13 was associated with MACE and mortality in patients with ACS but not SCAD. This finding highlights the importance of VWF as an essential marker of risk in patients with ACS., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Several genes are expressed in aspirated coronary thrombi in acute myocardial infarction (AMI), exhibiting dynamic changes along ischemic time. Whether soluble biomarkers reflect the local gene environment and ischemic time is unclear. We explored whether circulating biomarkers were associated with corresponding coronary thrombi genes and total ischemic time., Material and Methods: In 33 AMI patients undergoing percutaneous coronary intervention (PCI), blood samples were collected within 6-24h for markers related to plaque rupture (metalloproteinase 9, tissue inhibitor of metalloproteinases 1), platelet and endothelial cell activation (P-selectin, CD40 ligand, PAR-1), hemostasis (tissue factor, tissue plasminogen activator, plasminogen activator inhibitor 1, free and total tissue factor pathway inhibitor, D-dimer, prothrombin fragment 1+2), inflammation (interleukin 8 and 18, fractalkine, monocyte chemoattractant protein 1 (MCP-1), CXCL1, pentraxin 3, myeloperoxidase) and galectin 3, caspase 8 and epidermal growth factor (EGF). Laboratory analyses were performed by Proximity Extension Assay (Proseek Multiplex CVD I(96 × 96)), ELISAs and RT-PCR., Results: Only circulating P-selectin correlated to the corresponding P-selectin gene expression in thrombi (r=0.530, p=0.002). Plasma galectin 3, fractalkine, MCP-1 and caspase 8 correlated inversely to ischemic time (r=-0.38-0.50, all p <0.05), while plasma MCP-1, galectin 3 and EGF were higher at short (≤ 4 h) vs. long (>4h) ischemic time (all p <0.05)., Conclusions: The dynamic changes in circulating mediators along ischemic time were not reflected in the profile of locally expressed genes. These observations indicate a locally confined milieu within the site of atherothrombosis, which may be important for selective therapy., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Plasminogen activator inhibitor-1 (PAI-1) has been shown to increase after percutaneous coronary intervention (PCI). Whether activated platelets, local trauma with activation of resident vascular cells or the acute phase response is the source of this PAI-1 increase is not well defined. Therefore we examined whether intensive platelet inhibition may modulate PAI-1 levels or whether the PAI-1 increase is associated with the acute phase protein C-reactive protein (CRP)., Methods: We included 51 patients with stable angina who underwent elective PCI with stent implantation. At the time of study, routine pretreatment with clopidogrel before PCI was not standard of care, but left to the discretion of the referring cardiologist. We matched 17 patients with stable angina that were not pretreated with clopidogrel but received a loading dose of 300 mg immediately after stent implantation according age, sex and smoking with 34 patients that received clopidogrel at least 12 to 24 hours before PCI. Blood samples for measurement of PAI-1, t-PA and CRP were taken directly before and 24 hours after the procedure., Results: PAI-1 and t-PA active antigen plasma levels before PCI were not different in patients with and without clopidogrel pretreatment. Whereas PCI induced a significant increase of PAI-1 levels in patients without pretreatment (p<0.05), the procedure had no effect on PAI-1 active antigen in patients pretreated with clopidogrel. This resulted in significant lower PAI-1 plasma levels 24 hours after PCI in patients with pretreatment (p<0.05). CRP was not associated with pre- or postprocedural PAI-1 levels., Conclusion: Clopidogrel pretreatment completely abolishes the increase of PAI-1 active antigen after coronary stent implantation. This suggests that peri-procedural platelet activation might play a major role for the increase of PAI-1 after PCI thus increasing the risk of acute and subacute thrombus formation based on a reduced endogenous fibrinolytic system.

Background: Elevated homocysteine (Hcy) levels have been associated with increased risk for cardiovascular disease and it has been shown that hyperhomocysteinemia is associated with increased levels of t-PA antigen in individuals without evidence for coronary artery disease (CAD). The aim of this study was to examine if Hcy plasma levels are associated with plasma levels of fibrinolytic factors in patients with CAD and a history of acute myocardial infarction., Methods: We measured in 56 patients with CAD, 1 month after their first ST-elevation myocardial infarction, plasma levels of Hcy, the fibrinolytic parameters tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-type-1 (PAI-1), and t-PA-PAI-1 complexes., Results: Hcy plasma levels inversely correlated with t-PA activity (r=-0.303, p<0.05). Patients with mild hyperhomocysteinemia (Hcy>15 micromol/L, n=8) showed significantly lower plasma levels of t-PA activity (p<0.05). Regression analysis revealed that out of cardiovascular risk factors and medical treatment only Hcy was significantly associated with t-PA activity., Conclusions: Patients with CAD after a first myocardial infarction and hyperhomocysteinemia show a reduced t-PA activity independently from cardiovascular risk factors and medical treatment. Homocysteine lowering therapies may increase fibrinolytic activity and thereby may help to avoid atherothrombotic events in patients with CAD after a first myocardial infarction.

Introduction: Statins were previously shown to suppress cellular tissue factor (TF) in vitro. Here, we investigated the effect of atorvastatin on the TF-pathway and thrombin generation after coronary angioplasty and stenting in vivo., Materials and Methods: A cohort of 30 patients with coronary artery disease (CAD) was randomised to treatment with either none (n=10), 10 mg (n=10) or 80 mg (n=10) atorvastatin per day for the postinterventional period of 6 months starting the day before percutaneous coronary intervention (PCI). Fasting blood samples were collected on admission and after 6 weeks and 6 months of statin therapy to determine sTF, free tissue factor pathway inhibitor (TFPI) and prothrombin fragment F1.2 by immunoassay., Results: Soluble TF (sTF) significantly correlated with thrombin generation as measured by prothrombin fragment F1.2 at baseline. This correlation was lost 6 weeks and 6 months after initiation of statin therapy. In vivo, F1.2 was significantly lowered after 6 months of statin therapy by both, low dose (0 vs. 10 mg: 1.3+/-0.3 vs. 0.7+/-0.2 ng/ml; P<0.05) and high dose (0 vs. 80 mg: 1.2+/-0.3 vs. 0.6+/-0.2 ng/ml; P=0.01) atorvastatin compared to control. However, sTF and free TFPI did not change significantly with atorvastatin therapy when compared to baseline or control., Conclusions: Our results demonstrate reduced in vivo generation of thrombin six months after percutaneous coronary intervention and statin therapy independent of sTF and free TFPI.

Background: The evolving technique of carotid stenting (CS) requires optimal antithrombotic strategies to reduce periinterventional thromboembolic risk. In animal models of balloon injury, tissue factor (TF) was shown to be the major procoagulant of the atherosclerotic plaque mediating prolonged procoagulant activity., Methods: We analyzed TF and TF-dependent hemostatic markers before and 2, 6 and 24 h after CS with two antithrombotic drug regimens. Group A (n=20) received prolonged unfractionated heparin (UFH) for 18-20 h starting at intervention next to aspirin and thienopyridine. In group B (n=16), single bolus UFH was administered next to combined antiplatelet therapy. Natural anticoagulants were determined at baseline., Results: Patients with symptomatic and asymptomatic cerebrovascular disease did not differ in plasma TF levels. Furthermore, no statistically significant difference for TF, TFPI/Xa-complex and prothrombin fragment F1.2 was observed between bolus and prolonged heparin treatment. No significant change was found in time course for these parameters. Two patients (5.5%; one in each treatment group) suffered periinterventional minor stroke associated with increased levels of F1.2 and TFPI/Xa-complex. Both were resistant to activated protein C (APC ratio<1.9) due to heterozygous factor V Leiden mutation., Conclusions: No significant activation of the TF pathway was seen with both antithrombotic regimens suggesting that single bolus UFH combined with antiplatelet therapy is generally sufficient to control TF-dependent procoagulant activity after CS. However, patients with resistance to activated protein C may be at increased periinterventional stroke risk.

Aim/hypothesis: E-selectin is thought to play a key role in the early stages of vascular disease by facilitating the attachment of leukocytes to the endothelium. Recently, a polymorphism in the E-selectin gene (S128R) has been associated with higher E-selectin levels in patients with diabetes mellitus and with premature coronary artery disease. The impact of the S128R polymorphism on the development of diabetic coronary artery disease has not been investigated yet., Patients and Methods: A total of 254 patients recruited from the Division of Cardiology, University of Vienna with diabetes mellitus type 2 was assessed for the E-selectin S128R polymorphism by a novel mutagenic separated PCR, allowing fast and reliable genotyping without restriction enzyme digest. Ninety-five patients had a history of myocardial infarction, 90 were admitted with stable coronary artery disease whereas in 69 the presence of CAD could be excluded., Results: Of all 254 individuals tested, 197 (77.6%) exhibited wildtype E-selectin 128S genotype, 54 (21.3%) were heterozygous S128R and 3 (1.1%) were homozygous for the 128R allele. In all groups the genotype frequencies did not differ significantly. No associations were found between E-selectin genotype and coronary artery disease or myocardial infarction., Conclusion/interpretation: In subjects suffering from diabetes mellitus type 2 the E-selectin S128R polymorphism is not associated with coronary artery disease nor with an increased risk for myocardial infarction. Thus, screening for this polymorphism is not indicated for risk assessment of CAD in patients with diabetes mellitus.

Background: Current data suggest that pretreatment with clopidogrel (in addition to aspirin) prior to elective percutaneous coronary intervention (PCI) might be associated with a reduced incidence of subsequent adverse ischemic events. The aim of this placebo-controlled study was to find out whether an extended pretreatment period with clopidogrel before an elective PCI might confer a superior inhibition of the platelet activation and aggregation than clopidogrel given not until PCI., Methods: Twenty patients with stable angina being already on aspirin were randomly assigned to receive the loading dose of 300 mg clopidogrel, either 24 h before or immediately after stent implantation. At several time points before and after PCI, the activation of both the platelet and the coagulation system was determined by measuring beta-thromboglobulin (beta-TG) and prothrombin fragment f1.2 (f1.2), respectively, in venous blood and in blood emerging from a microvascular injury (shed blood)., Results: Pretreatment with clopidogrel before PCI exhibited a slight reduction of beta-TG (from 178 to 139 ng/ml, p=0.085) and of f1.2 (from 0.81 to 0.75 nmol/l, p=0.045) in venous blood. Heparin administration (at the beginning of PCI) resulted in a 65% inhibition of ss-TG (from 10,590 to 2833 ng/ml) and 90% inhibition of f1.2 formation (from 38.7 to 4.2 nmol/l) in shed blood of patients with clopidogrel pretreatment. The extent of inhibition was, however, comparable to that observed in patients without clopidogrel pretreatment (beta-TG: from 8025 to 2812 ng/ml, 76% inhibition, p=0.47; f1.2: from 34.9 to 3.8 nmol/l, 86% inhibition, p=0.80). After PTT normalisation (6 h after PCI), levels of beta-TG and f1.2 both in venous blood and in shed blood did not differ between the two treatment regimens up to 48 h after PCI., Conclusion: Pretreatment with clopidogrel did not result in a pronounced inhibition of the platelet and coagulation system activation in patients on aspirin undergoing elective coronary stent implantation.

In the present study, we sought to investigate whether elevated serum levels of homocysteine (Hcy), predisposing to endothelial dysfunction during progression of atherosclerosis, were paralleled by increased Hcy concentrations in human coronary arteries. Paraffin sections of coronary arteries were obtained from explanted hearts of cardiac transplant recipients suffering from coronary artery disease (CAD, n=32, mean age=56.6+/-6.8), and from heart donors where transplantation was not performed due to organization-related circumstances (Co, n=6, mean age 25.0+/-10.6), and characterized immunohistochemically for Hcy, CD68, and smooth muscle alpha-actin. Although the CAD group presented with high serum Hcy levels (27.7+/-12.8 micromol/l), the media and intimal layers containing the endothelium showed the lowest enrichment of Hcy (media: 20.8+/-4.4%; intima: 6.1+/-2.3%). Surprisingly, the control group revealed an extensive Hcy enrichment, co-localizing with vascular smooth cells (media: 32.3+/-14.0%; intima: 7.0+/-2.0%). In conclusion, we have provided evidence for a reverse relation between Hcy serum concentration and enrichment of Hcy in coronary arteries of patients with severe CAD, suggesting that Hcy is not likely to be involved directly in atheromatosis development of coronary arteries.

Objective: Vascular inflammation is a hallmark in the development of abdominal aortic aneurysms (AAA). Heme oxygenase-1 (HO-1) is a novel vascular anti-inflammatory factor. A (GT)(n) dinucleotide repeat in the HO-1 gene promoter shows a length polymorphism that modulates the level of gene transcription. Short (< 25 GT) repeats are associated with an increased HO-1 upregulation in response to inflammatory stimuli than are longer repeats. We hypothesised that patients with AAA had less frequently short repeats in the HO-1 gene promoter compared to patients with coronary (CAD) or peripheral artery disease (PAD), or healthy controls., Methods: 70 consecutive patients with atherosclerotic AAA, each 70 age- and sex-matched patients with CAD and PAD as well as 61 unmatched healthy atherosclerosis-free controls for a total of 271 individuals were studied. The frequency of carriers of short repeats in the HO-1 gene promoter was determined and compared between the groups., Results: In the AAA group, 29 patients (41%) were carriers of short (GT)(n) repeats compared to 47 patients (67%) in the CAD group, 44 patients (63%) in the PAD group and 35 healthy controls (59%). Patients with AAA were less frequently carriers of short repeats compared to age- and sex-matched patients with CAD (OR = 0.38, p = 0.006) and PAD (OR = 0.35, p = 0.01). Healthy controls exhibited short alleles more frequently than patients with AAA (p = 0.04), but comparable to CAD (p = 0.3) and PAD patients (p = 0.7)., Conclusion: Patients with AAA were less frequently carriers of short (< 25 GT) repeats in the HO-1 gene promoter than patients with atherosclerosis or healthy subjects. This suggests that short alleles, and thus, facilitated upregulation of HO-1, may be a protective anti-inflammatory factor against the development of AAA., (Copyright 2002 Elsevier Science Ltd.)

Activation markers of blood coagulation and fibrinolysis and several fibrinolytic parameters were determined in arteriosclerotic patients to investigate the relation between extension and main localization of vessel disease, risk factors and disturbances within the blood coagulation and the fibrinolytic system. Indications of an increased intravascular fibrin formation and subsequent fibrinolysis were found in peripheral artery disease (PAD) patients but not in coronary artery disease (CAD) patients. Compared with healthy controls PAD patients had elevated TAT (median: 3.2 ng/ml, 1.5-70 vs. 2.1, 1.2-4.7, p less than 0.005) and D-Dimer (median: 365 ng/ml, range 85-2000 vs. 185, 79-360; p less than 0.0001) plasma levels, whereas TAT (2.4, 1.2-13) and D-Dimer (190, 58-1000) levels of CAD patients were in the normal range. No associations were detected between risk factors of arteriosclerosis (hyperlipidemia, diabetes mellitus, cigarette smoking, hypertension) and the plasma levels of the activation markers TAT and D-Dimer. Independent from risk factors PAD and CAD patients had elevated plasma plasminogen activator inhibitor capacity (PAI cap). Our results provide evidence that 1) increased plasma levels of blood coagulation and fibrinolysis activation markers are not related to risk factors of arteriosclerosis but seem to be unspecifically caused by activation processes on arteriosclerotic vessel wall defects, 2) increased plasma PAI cap found in arteriosclerotic patients is a relatively unspecific phenomenon associated with arterial vessel disease.