Genetic determinants of Von Willebrand factor and the risk of cardiovascular disease

Normal haemostasis requires a delicate balance between procoagulant and anticoagulant factors. Disruption of this balance may lead to bleeding disorders, such as hemophilia, or thrombotic disorders, including deep vein thrombosis of the leg. As Virchow already reported in 1877, properties of the blood vessel wall, the blood flow and blood constituents contribute to the formation of thrombi in either veins or arteries. However, through contemporary research the complexity of this process leading to thrombus formation has become more apparent. An important player in thrombus formation is von Willebrand Factor (VWF), a large multifunctional glycoprotein. VWF initiates adherence of platelets to the injured vessel wall and subsequent platelet aggregation leading inevitably to the formation of thrombi. In addition, VWF is a carrier protein of coagulation factor VIII (FVIII), thereby protecting it from clearance. In healthy subjects normal plasma VWF levels range from 0.60 – 1.40 IU/mL and are characterized by a large variation. This can be partly attributed to a number of lifestyle and environmental factors, but most importantly to genetic factors. The necessity of maintaining normal VWF levels in the circulation is illustrated by two clinical manifestations that may occur when VWF exceeds its normal range. Low levels of VWF may lead to bleeding, which is known as von Willebrand Disease (VWD), the most common inherited bleeding disorder in humans. To the contrary, high VWF antigen (VWF:Ag) levels are associated with an increased risk of venous thrombosis and arterial thrombosis, including myocardial infarction (MI) and ischemic stroke

Prognostic markers in young patients with premature coronary heart disease

AbstractObjectivesTo evaluate the survival and prognostic implications of cardiovascular, inflammatory and prothrombotic risk factors in young patients with premature coronary heart disease (CHD).MethodsFollow-up data were obtained from 353 young patients with a first cardiac event (men ≤45 years and women ≤55 years). Baseline characteristics on traditional risk factors were collected at the time of the first event, and plasma levels of C-reactive protein (CRP), von Willebrand Factor (VWF), and fibrinogen were measured one to three months after the first event to exclude an acute phase response. We performed age and sex adjusted Cox regression analyses to assess the relationship between these factors and recurrent events with three different endpoints: all cause mortality, recurrent cardiac event (myocardial infarction or revascularisation procedure), and any recurrent event (cardiac event, cerebrovascular event or all cause mortality).ResultsDuring a total follow-up time of 1483 person years (mean 4.2 years), 11 patients died (3%), 42 patients had a recurrent cardiac event (12%), and 53 patients had any recurrent event (15%). CRP was associated with an increased risk of any recurrent event (HR 1.28[95% CI = 1.02–1.59] per unit increase in lnCRP). Also, both CRP (5.00[1.04–24.04]) and fibrinogen (5.04[1.05–24.23]) were associated with all cause mortality when levels were above the 50th percentile.ConclusionsFifteen percent of young patients with a first cardiac event have a recurrent event or die within a median follow-up of 4.2 years. In these young patients we have shown that, independently of cardiovascular risk factors, high CRP levels contribute to the risk of recurrent events, including all cause mortality, and high fibrinogen levels are associated with all cause mortality

Antithrombin levels are associated with the risk of first and recurrent arterial thromboembolism at a young age

Background and aims: It is as yet unknown whether antithrombin levels are associated with arterial thromboembolism (ATE) at a young age. To investigate the association between antithrombin levels and premature and recurrent ATE, we performed a case-control study and a subsequent nested cohort study of p

Effect of genetic variation in STXBP5 and STX2 on von willebrand factor and bleeding phenotype in type 1 von willebrand disease patients

Background: In type 1 von Willebrand Disease (VWD) patients, von Willebrand Factor (VWF) levels and bleeding symptoms are highly variable. Recently, the association between genetic variations in STXBP5 and STX2 with VWF levels has been discovered in the general population. We assessed the relationship between genetic variations in STXBP5 and STX2, VWF levels, and bleeding phenotype in type 1 VWD patients. Methods: In 158 patients diagnosed with type 1 VWD according to the current ISTH guidelines, we genotyped three tagging-SNPs in STXBP5 and STX2 and analyzed their relationship with VWF:Ag levels and the severity of the bleeding phenotype, as assessed by the Tosetto bleeding score. Results: In STX2, rs7978987 was significantly associated with VWF:Ag levels (bèta-coefficient (β) = -0.04 IU/mL per allele, [95%CI -0.07;-0.001], p = 0.04) and VWF:CB activity (β = -0.12 IU/mL per allele, [95%CI -0.17;-0.06], p<0.0001). For rs1039084 in STXBP5 a similar trend with VWF:Ag levels was observed: (β = -0.03 IU/mL per allele [95% CI -0.06;0.003], p = 0.07). In women, homozygous carriers of the minor alleles of both SNPs in STXBP5 had a significantly higher bleeding score than homozygous carriers of the major alleles. (Rs1039084 p = 0.01 and rs9399599 p = 0.02). Conclusions: Genetic variation in STX2 is associated with VWF:Ag levels in patients diagnosed with type 1 VWD. In addition, genetic variation in STXBP5 is associated with bleeding phenotype in female VWD patients. Our findings may partly explain the variable VWF levels and bleeding phenotype in type 1 VWD patients

The effect of bioresorbable vascular scaffold implantation on distal coronary endothelial function in dyslipidemic swine with and without diabetes

Background: We studied the effect of bioresorbable vascular scaffold (BVS) implantation on distal coronary endothelial function, in swine on a high fat diet without (HFD) or with diabetes (DM + HFD). Methods: Five DM + HFD and five HFD swine underwent BVS implantation on top of coronary plaques, and were studied six months later. Conduit artery segments >. 5. mm proximal and distal to the scaffold and corresponding control segments of non-scaffolded coronary arteries, as well as segments of small arteries within the flow-territories of scaffolded and non-scaffolded arteries were harvested for in vitro vasoreactivity studies. Results: Conduit segments proximal and distal to the BVS edges showed reduced endothelium-dependent vasodilation as compared to control vessels (p <. 0.01), with distal segments being most prominently affected (p <. 0.01). Endothelial dysfunction was only observed in DM + HFD swine and was principally due to a loss of NO. Endothelium-independent vasodilation and vasoconstriction were unaffected. Surprisingly, segments from the microcirculation distal to the BVS showed enhanced endothelium-dependent vasodilation (p <. 0.01), whereas endothelium-independent vasodilation and vasoconstriction were unaltered. This enhanced vasorelaxation was only observed in DM + HFD swine, and did not appear to be either NO- or EDHF-mediated. Conclusions: Six months of BVS implantation in DM + HFD swine causes NO-mediated endothelial dysfunction in nearby coronary segments, which is accompanied by a, possibly compensatory, increase in endothelial function of the distal microcirculation. Endothelial dysfunction extending into coronary conduit segments beyond the implantation-site, is in agreement with recent reports expressing concern for late scaffold thrombosis and of early BVS failure in diabetic patients

Performance related factors are the main determinants of the von Willebrand factor response to exhaustive physical exercise

Background: Physical stress triggers the endothelium to release von Willebrand Factor (VWF) from the Weibel Palade bodies. Since VWF is a risk factor for arterial thrombosis, it is of great interest to discover determinants of VWF response to physical stress. We aimed to determine the main mediators of the VWF increase by exhaustive physical exercise. Methods: 105 healthy individuals (18-35 years) were included in this study. Each participant performed an incremental exhaustive exercise test on a cycle ergometer. Respiratory gas exchange measurements were obtained while cardiac function was continuously monitored. Blood was collected at baseline and directly after exhaustion. VWF antigen (VWF:Ag) levels, VWF collagen binding (VWF:CB) levels, ADAMTS13 activity and common variations in Syntaxin Binding Protein-5 (STXBP5, rs1039084 and rs9399599), Syntaxin-2 (STX2, rs7978987) and VWF (promoter, rs7965413) were determined. Results: The median VWF:Ag level at baseline was 0.94 IU/mL [IQR 0.8-1.1] and increased with 47% [IQR 25-73] after exhaustive exercise to a median maximum VWF:Ag of 1.38 IU/mL [IQR 1.1-1.8] (p<0.0001). VWF:CB levels and ADAMTS13 activity both also increased after exhaustive exercise (median increase 43% and 12%, both p<0.0001). The strongest determinants of the VWF:Ag level increase are performance related (p<0.0001). We observed a gender difference in VWF:Ag response to exercise (females 1.2 IU/mL; males 1.7 IU/mL, p = 0.001), which was associated by a difference in performance. Genetic variations in STXBP5, STX2 and the VWF promoter were not associated with VWF:Ag levels at baseline nor with the VWF:Ag increase. Conclusions: VWF:Ag levels strongly increase upon exhaustive exercise and this increase is strongly determined by physical fitness level and the intensity of the exercise, while there is no clear effect of genetic variation in STXBP5, STX2 and the VWF promoter

バレイショ近縁種における種の分化 XIII. S.acaule X S.demissumより得た7倍雑種の染色体行動と両親ゲノムの類縁関係

中央アンデス産Acaulia群4倍種S. acaule (acl, 2n=48)とメキシコ産Demissa群6倍種S. demissum (dms, 2n=72)のゲノムの類縁関係を明らかにするために, 前者を母本として得た7倍雑種(2n=84)の還元分裂における染色体行動と稔性を調べた。以下その結果を要約する。両種間の交雑は極めて困難で, aclを母とした時のみ受粉花数当り0.02の低率で雑種が得られたにすぎない。得られた雑種は, 両親との形態的比較から, aclの非還元性卵とdmsの還元性花粉の受精に起因するものと推定された。この雑種の第1中期における染色体対合行動は甚だしく多様であったが, その対合型のモードは(12)_+(20)_+8_I, その平均対合頻度は(0.18)_V+(1.11)_+(11.73)_+(18.11)_+(7.26)_Iで, 著しく高頻度の3価形成を示す点が特徴的であった。このような対合行動はその後の染色体行動にも反映し, 第1後期では観察細胞のすべてに平均4.8の遅滞染色体がみられ, 第2中期では94%の細胞が分散染色体を示し, 数的平衡核板頻度は0.6%にすぎなかった。稔性は極めて低く, 調査花粉粒数の27%が一見正常であったが, 自殖及び戻交配のいずれにおいても全く種子を生じなかった。上記の観察結果, 特に高頻度で出現した3価染色体の成因を考察して次の知見を得た。すでにaclはAAA^aA^a, dmsはA^dA^dC_1C_1C_2C_2のゲノム型をもつことが知られているので, 当雑種のゲノム型はAAA^aA^aA^dC_1C_2となる。A^dゲノムは若干の構造的差異はもつもののAゲノム群に属することも知られている。したがって, 当雑種にみられる3価形成は, 主に, aclからのAAとdmsからのA^dの3ゲノム間の染色体対合に由来すると推論でき, 両種はこれらのゲノムの相同性によって相互に関係づけられているものと考えられる。 / Meiotic behavior and fertility were studied in a heptaploid F_1 hybrid (2n=84) obtained from crossing S. acaule (acl, 2n=48) with S. demissum (dms, 2n=72), with the aim of assessing a genomic relationship between the parent species. Crossability between the two species was very low, the number of hybrid plants per pollination being only 0.02. Morphological evidence indicated that the hybrid arose through the union of an unreduced egg of acl and a reduced pollen grain of dms. The hybrid had the mean pairing frequency of (0.18)_V+(1.11)_+(11.73)_+(18.11)_+(7.26)_I per cell at metaphase I, with (12)_+(20)_+8_I as the modal configuration. Its subsequent behaviors were extremely irregular, showing several laggards in all the cells and chromatid bridges in occasional cells at anaphase I and also scattered chromosomes in 94% of the cells at metaphase II. The hybrid gave only 27% stainable pollen and no seed either on selfing or on backcrossing with both parents. The pattern of chromosome pairing found in the hybrid was interpreted in terms of genomic relationship between both parent species. From this, it was suggested that one (A) of the two genomes (designated AA^a) which acl possess in its gametes seems to be closely similar to, but not identical with, one (A^d) of the three genomes (A^dC_1C_2) which dms possess in its gemetes

Vasopressors Do Not Influence Cerebral Critical Closing Pressure During Systemic Inflammation Evoked by Experimental Endotoxemia and Sepsis in Humans

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Regioscan Zoetwatermaatregelen fase 2 : hoofdrapport

Dit hoofdrapport bevat de achtergronden bij de tweede versie van de Regioscan Zoetwatermaatregelen. Met Regioscan Zoetwatermaatregelen 2.0 kan het effect van lokale maatregelen aan de zoetwateropgave nog beter in beeld worden gebracht en is nu landsdekkend toepasbaar. De kansrijkheid van maatregelen kan zo snel worden ingeschat en gebruikt worden om met zoetwatergebruikers het gesprek aan te gaan