Claudia Marsik

Simvastatin Prevents Vascular Hyporeactivity During Inflammation

Background—There is growing evidence that statins exert anti-inflammatory and antioxidative vascular actions that are independent of lipid lowering. We tested whether hyporeactivity to the endothelium-dependent vasodilator acetylcholine (ACh) and the vasoconstrictor norepinephrine (NE) during acute experimental inflammation could be prevented by simvastatin. Methods and Results—In a randomized, placebo-controlled, parallel group study, forearm blood flow (FBF) responses to NE, ACh, and the endothelium-independent vasodilator nitroglycerin (NTG) were assessed at baseline, after 4 days of simvastatin 80 mg PO or placebo treatment, and during Escherichia coli endotoxin (lipopolysaccharide [LPS])–induced inflammation in 20 healthy volunteers. Additionally, markers of inflammation and neutrophil oxidative burst were assessed. Simvastatin and placebo had no effect on FBF or oxidative/inflammatory markers. LPS administration decreased the responses of FBF to NE by 43% (P<0.05) and decreased responses to ACh by 48% (P<0.05) but did not decrease FBF responses to NTG. Simvastatin completely preserved responses to NE and to ACh. The LPS-induced increases in neutrophil oxidative burst and plasma tumor necrosis factor-α concentrations were mitigated by simvastatin (P<0.05 versus placebo). Conclusions—This study demonstrates potent vasoprotective properties of high-dose simvastatin during endotoxemia that may be useful for patients with acute systemic inflammation and associated vascular hyporeactivity.

Evidence of a U‐shaped association between factor XII activity and overall survival

Summary.  Introduction: The clinical relevance of decreased coagulation factor XII (FXII) plasma activity as a risk factor for both venous and arterial thrombosis is still discussed controversially. The current study evaluated the predictive value of FXII levels for all‐cause mortality in a large Viennese patient cohort. Patients and methods: Individuals, whose FXII activity levels were determined for suspected coagulation disorders or thrombophilia screening between 1991–2003 were included in this study (n = 8936, 51% male, 49% female, median age 43 years). Death/survival was determined by record linkage with the Austrian Death Registry. The median observation period was 5 years covering a total of 46 400 person years; the death rate was 17.1%. For Cox regression analysis, FXII plasma activity was divided into 11 categories of 10% steps with the category of > 100% FXII serving as a reference category. Results: With decreasing FXII plasma activity, hazard ratios for all‐cause mortality gradually increased linearly from 1.0 in the > 100% category to 1.5 (95% CI: 1.2–1.9) in the 80–90% category to 4.7 (95% CI: 3.4–6.5) in the 10–20% category. Similar results were obtained, when only vascular mortality or death as a result of ischemic heart disease was considered. No significant increase in all‐cause mortality (HR: 1.4, 95%CI 0.7–2.8) was observed in the small group of FXII‐deficient subjects [0–10% category (n = 58)]. Conclusions: This study first demonstrates a strong and almost linear association of FXII plasma activity between 90% and 10% with all‐cause mortality in a large Viennese patient cohort. Interestingly, mortality rates are not increased when FXII activity is below 10%, resulting in a U‐shaped survival curve.

Genetic variation in heme oxygenase 1 (HMOX1) and the risk of recurrent venous thromboembolism.

BACKGROUND/OBJECTIVE Products of heme oxygenase 1 (HO1) possess antithrombotic properties, and impairment of HO1 activity may contribute to thrombus formation. Transcriptional activity of long GT-repeat alleles in HO1 gene (HMOX1) is lower as compared with short alleles. We hypothesize that these long alleles are associated with decreased HO1 anticoagulant activity and, thus, an increased risk of thrombosis.. DESIGN/METHODS In a prospective cohort study, we followed 860 patients with a first VTE, and investigated the impact of a promoter GT-dinucleotid length polymorphism in HOMX1 on the risk of recurrent venous thromboembolism (VTE). RESULTS Allele groups short (S), medium (M) and long (L) of the promoter GT-dinucleotide length polymorphism were distinguished. L-alleles, but not M- or S-alleles, were found to be more frequent among patients with recurrence. Heterozygous carriers of L-alleles had a two-fold higher relative risk of recurrence [(RR 2.2 (95% CI: 1.4-3.4)] as compared to wild type, which was independent of other thrombotic risk factors. At five years, the cumulative probability of recurrence was 18% (95% CI: 15%-22%) in patients without an L-allele compared to 32% (95% CI: 19%-46%) in patients heterozygous for the L-allele (P = .001). CONCLUSION Patients with first VTE and long GT-repeat alleles in HMOX1 have an increased risk of recurrence. Genetically determined alterations in HO1 function may represent a new pathomechanism in VTE.

Differentiation of nonalcoholic from alcoholic steatohepatitis : are routine laboratory markers useful?

ZusammenfassungHINTERGRUND: Spezifische Marker für die Differenzierung der nicht alkoholischen (NASH) von der alkoholischen Steatohepatitis (ASH) fehlen. Wir untersuchten den Stellenwert von routinemäßig eingesetzten Laborparametern in der Differenzierung von NASH von ASH. METHODEN: Leberbiopsien, die über einen Zeitraum von 10 Jahren in unserem Krankenhaus durchgeführt wurden, wurden nochmals durchgesehen, 95 Patienten mit Steatohepatitis identifiziert und Ihre Daten zum Zeitpunkt der Biopsie reevaluiert. Basierend auf Ergebnisse der Leberbiopsie und Anamnese von Alkoholkonsum (< 140 g/Woche) wurde die Diagnose NASH oder ASH zugeteilt (andere Lebererkrankungen ausgeschlossen). Die Analyse erfolgte mittels logistischer Regression. ERGEBNISSE: NASH wurde bei 58 (61%; 30 w) und ASH bei 37 (39%; 9 w) Patienten diagnostiziert. Höhergradige Fibrose (59% vs. 19%, p < 0,0001) und AST/ALT Ratio > 1 (54,1% vs 20,7%, p = 0,0008) waren häufiger bei ASH zu finden. MCV war bei 53% der ASH Patienten erhöht and bei allen NASH Patienten (p < 0,0001) im Normbereich. Die multivariate Analyse identifizierte MCV (p = 0,0013), AST/ALT Ratio (p = 0,011) und Geschlecht (p = 0.0029) als die relevanten Regressoren (aROC = 0,92). AST/ALT Ratio (p < 0,0001) and Alter (p = 0,00049) waren unabhängige Prädiktoren für höhergradige Fibrose. Die Unterschiede bei MCV waren deutlicher bei höhergradiger Fibrose. SCHLUSSFOLGERUNGEN: Höheres MCV und AST/ALT Ratio bei ASH reflektieren den Schweregrad der zugrunde liegenden Lebererkrankung und können nicht zur Unterscheidung von ASH von NASH beitragen. Statt dessen könnten sich diese Marker als nützlich für die Patientenselektion für Leberbiopsie und in der Therapieplanung erweisen.SummaryBACKGROUND/AIMS: Specific markers for differentiation of nonalcoholic (NASH) from alcoholic steatohepatitis (ASH) are lacking. We investigated the role of routine laboratory parameters in distinguishing NASH from ASH. METHODS: Liver biopsies performed at our hospital over a 10-year period were reviewed, 95 patients with steatohepatitis identified and their data prior to biopsy reevaluated. The diagnosis NASH or ASH was assigned (other liver diseases excluded) on the basis of the biopsy and history of alcohol consumption (< 140 g/week). Logistic regression models were used for analysis. RESULTS: NASH was diagnosed in 58 patients (61%; 30 f) and ASH in 37 (39%; 9 f). High-grade fibrosis (59% vs. 19%, P < 0.0001) and an AST/ALT ratio > 1 (54.1% vs 20.7%, P = 0.0008) were more common in ASH. The MCV was elevated in 53% of ASH patients and normal in all NASH patients (P < 0.0001). Multivariate analysis identified the MCV (P = 0.0013), the AST/ALT ratio (P = 0.011) and sex (P = 0.0029) as relevant regressors (aROC = 0.92). The AST/ALT ratio (P < 0.0001) and age (P = 0.00049) were independent predictors of high-grade fibrosis. Differences in MCV were more marked in high-grade fibrosis. CONCLUSIONS: Higher MCVs and AST/ALT ratios in ASH reflect the severity of underlying liver disease and do not differentiate NASH from ASH. Instead, these biomarkers might prove useful in guiding selection of patients for liver biopsy and in targeting therapy.

Classification of chronic kidney disease by estimated glomerular filtration rate

Background  Serum creatinine concentration alone as a marker of kidney function is inadequate. Thus several equations for estimating glomerular filtration rate (eGFR) have been proposed within the last years.

Polymorphism in the tissue factor region is associated with basal but not endotoxin-induced tissue factor-mRNA levels in leukocytes

Summary.  Objective: Tissue factor (TF) plays a central role during disseminated intravascular coagulation (DIC) in sepsis. We hypothesized that a frequent D/I polymorphism, at nucleotide position −1208 in the promoter region, could influence TF‐mRNA and downstream coagulation. Methods: Basal‐ and lipopolysaccharide (LPS)‐induced TF‐mRNA expression, microparticle‐associated TF‐procoagulant activity and coagulation were determined in healthy men (n = 74) before and after endotoxin (LPS) infusion (2 ng kg−1). Basal values of TF‐mRNA ranged between 34 and >37.5 cycles. Results: Baseline TF‐mRNA levels significantly differed between genotypes: I/I carriers had almost 2‐fold higher TF‐mRNA levels compared to D/D carriers at baseline (P < 0.01). In accordance, higher levels of microparticle‐associated TF‐procoagulant activity could be seen in I/I carriers. However, the genotype did not affect basal or LPS‐induced levels of prothrombin fragment F1+2, D‐dimer or cytokines including tumor necrosis factor and interleukin‐6. Conclusion: The TF–1208 polymorphism is functional in that it regulates basal TF‐mRNA in circulating monocytes and circulating microparticle‐associated TF‐procoagulant activity in vivo, but does not influence the relative increase in TF‐mRNA or coagulation activation during low‐grade endotoxemia.

Sex differences in the association between albumin and all-cause and vascular mortality

Background  Low serum albumin levels are associated with cardiovascular disease and mortality risk. This study evaluated the predictive value of low serum albumin for all‐cause‐mortality in a large Viennese patient cohort and investigated sex differences in the association between serum albumin and mortality.

Coagulation factor VIII levels are associated with long-term survival – interactions with gender in a large hospital-based cohort

ZusammenfassungHINTERGRUND: In der Literatur ist eine gesteigerte Faktor VIII Aktivität mit einem erhöhten Risiko für arterielle und venöse Thrombosen assoziiert. Die vorliegende Studie untersucht den Einfluss von Faktor VIII Spiegeln auf die Gesamtmortalität unter Berücksichtigung geschlechtsspezifischer Unterschiede in einer groß angelegten Studie in Österreich. PATIENTEN UND METHODE: In dieser Studie wurden zwischen 1991 und 2003, 11203 Patienten eingeschlossen. Der durchschnittliche Beobachtungszeitraum betrug 5 Jahre mit insgesamt 46000 Personenjahren. Insgesamt sind während des Beobachtungszeitraumes 17,1 % der Studienpopulation verstorben. ERGEBNISSE: Im Vergleich zu Patienten in der Referenzkategorie (FVIII: C <94 %) stiegen die Hazard Ratios von 1,4 (95 % CI: 1,1 – 1,8) in der 152 – 170 % Kategorie (5th Dezile) auf letztlich 4,4 (95 % CI: 3,5 – 5,5) in der >313 % Kategorie (höchste Dezile, alle p < 0,05). Die Assoziation zwischen FVIII: C Spiegeln und Mortalität bleibt unverändert hinsichtlich nicht Krebs-assoziierte Mortalität, vaskuläre Mortalität und ischämischer Herzerkrankungen. Im Vergleich zu Männern, haben Frauen mit erhöhten FVIII: C Spiegeln ein schlechteres Outcome, resultierend in höheren Hazard Ratios 6,8 (95 % CI: 4,6 – 9,9) im Vergleich zu Männern (HR: 3,4 (95 % CI: 2,6 – 4,5)). SCHLUSSFOLGERUNGEN: In unserer groß angelegten Studie konnten wir erstmals zeigen, dass FVIII: C Plasma Aktivität mit einer erhöhten Gesamtmortalität assoziiert ist. Außerdem scheint es auch eine geschlechtsspezifische Interaktion von FVIII: C zu geben. Vor allem bei Frauen mit erhöhten FVIII: C Spiegeln dürfte es daher hilfreich sein Hochrisikogruppen zu identifizieren, die von individuellen Präventionsstrategien profitieren würden.SummaryINTRODUCTION: Elevated coagulation factor VIII activity has been associated with increased risk for both venous and arterial thrombosis. The current study evaluated the influence of Factor VIII levels and interactions with gender on all cause mortality in a large Austrian cohort. PATIENTS AND METHODS: During 1991 and 2003, 11203 individuals, first ever request for laboratory analyses of FVIII: C, age ≥18 years, were included in this study. The median observation period was 5 years covering a total of 46000 person-years. The death rate was 17.1%. RESULTS: Compared to individuals within the reference category (FVIII: C <94%) hazard ratios gradually increased from 1.4 (95% CI: 1.1–1.8) in the 152–170% category (5th decile) to finally 4.4 (95% CI: 3.5–5.5) in the >313% category (highest decile, all p < 0.05). The association between FVIII: C levels and mortality remained essentially unchanged when considering non-cancer mortality, all cause vascular mortality or mortality due to ischemic heart disease. Compared to males females with elevated FVIII: C had a worse outcome resulting in higher hazard ratios reaching 6.8 (95% CI: 4.6–9.9) within the highest decile compared to males (HR: 3.4 (95% CI: 2.6–4.5)). CONCLUSIONS: In our large patient cohort we might be able to demonstrate for the first time that FVIII: C plasma activity is strongly associated with all cause mortality. Additionally, FVIII: C appears to interact with gender. Especially in women FVIII: C might help identifying high-risk cohorts, which might benefit from individualized prevention strategies.

The inflammatory response is influenced by FXIII VAL 34 LEU polymorphism in a human LPS model

ZusammenfassungHINTERGRUND: Bei septischen Patienten führen die Aktivierung des Gerinnungssystems und die Blockierung der Fibrinolyse zur mikrovaskulären Thrombose. Der Val34Leu Polymorphismus beeinflusst die Funktion des Faktor XIII durch die Erhöhung des FXIII Spiegels durch die Aktivierung von Thrombin, welches zu einer erhöhten und beschleunigten Fibrinstabilisierung führt. Sepis und Multi Organ Failure (MOF) stören das fundamentale Gleichgewicht zwischen Gerinnung und Entzündung, welches einer der häufigsten Todesursachen bei Intensivpatienten darstellt. Neueste Ergebnisse von der Polymorphismen Erforschung lassen vermuten, dass es zu einer Beeinflussung des Entzündugs- und Gerinnungssystem kommt. METHODEN: In unserer Studie haben wir den Einfluss des FXIII Val34Leu Polymorphismus auf Entzündungs- und Gerinnungsparameter in einem menschlichen Sepsismodell untersucht. Gesunden Probanden wurde 2ng/kg Endotoxin (LPS, n = 62) als Bolus über 2 Minuten intravenös verabreicht. Für die Bestimmung des FXIII Promotor – Polymorphismus haben wir einen neuen PCR assay etabliert. ERGEBNISSE: FXIII Werte waren höher für homozygote Träger des Polymorphismus, im Vergleich zum wild-Type 34 Val/Val und heterozygoten Träger. Homozygote Träger hatten niedrigere Monozyten und Neutrophile Zellzahlen während des Beobachtungszeitraumes. F1+2 or D-Dimer Werte veränderten sich nicht nach LPS Gabe. KONKLUSION: Mit unseren Ergebnissen konnten wir zeigen, dass der FXIII Val34Leu Polymorphismus mit Veränderungen in bestimmten Entzündungsparametern und Veränderungen in Monozyten und Neutrophile Zellzahlen im LPS Modell in Zusammenhang steht. Dieses Ergebnis lässt den Schluss zu, dass der FXIII Val34Leu Polymorphismus bei Sepsis Patienten möglicherweise eine immunogene modulatorische Rolle spielen kann.SummaryBACKGROUND: In sepsis, activation of coagulation and inhibition of fibrinolysis lead to microvascular thrombosis. The Val34Leu polymorphism affects the function of FXIII by increasing the rate of FXIII activation by thrombin, which results in an increased and faster rate of fibrin stabilization. Sepsis and multi-organ failure cause disturbance of the normal balance of inflammation and coagulation, one of the most frequent causes of death in ICU patients. Research in polymorphism has shown the possible influence of FXIII in coagulation and inflammation. METHODS: We analyzed the influence of the common FXIII Val34Leu polymorphism on inflammatory and coagulation parameters in human experimental endotoxinemia. Healthy volunteers (n = 62) received 2 ng endotoxin (LPS) per kg body weight as a bolus infusion over 2 min. We developed a new mutagenic separated PCR assay for determination of the FXIII promoter polymorphism. RESULTS: FXIII levels were higher for homozygous carriers of the FXIII polymorphism in comparison with wild-type 34 Val/Val and heterozygous 34 Val/Leu. Interestingly, persons homozygous for the FXIII Val34Leu polymorphism had lower monocyte and neutrophil counts throughout the observation period, yet prothrombin fragment 1+2 and D-dimer levels did not differ after LPS challenge. CONCLUSION: Our findings indicate that the common FXIII Val34Leu polymorphism is associated with differences in monocyte and neutrophil cell counts in response to systemic LPS infusion in humans.