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Philipp Mahlknecht,
Klaus Seppi,
Heike Stockner,
Michael Nocker,
Christoph Scherfler,
Stefan Kiechl, Johann Willeit,
Christoph Schmidauer,
Arno Gasperi,
Gregorio Rungger,
Werner Poewe
[show abstract]
[hide abstract]
ABSTRACT: Background: The clinical diagnosis of Parkinson's disease (PD) is currently anchored in its cardinal motor symptoms. According to hospital-based studies, an enlarged echogenicity in the area of the substantia nigra (SN) assessed with transcranial sonography (TCS) may represent a useful biomarker in the diagnosis of PD. Objective: To evaluate SN hyperechogenicity as a marker for PD in the Bruneck Study cohort, which is representative of the general elderly community. Methods: The diagnostic accuracy of TCS in distinguishing clinically diagnosed PD from nonparkinsonian subjects was assessed in 574 subjects from this cohort. Results: There was a good diagnostic accuracy of TCS in distinguishing PD subjects from nonparkinsonian subjects with an area under the curve value of 0.82. At a receiver-operating characteristic curve analysis-based cutoff value for SN hyperechogenicity of 0.18 cm(2), TCS had a sensitivity of 88.2% (95% confidence interval, CI, 64.4-98.0), a specificity of 77.0% (95% CI 72.8-80.6), a positive predictive value of 12.7% (95% CI 7.8-20.0) and a negative predictive value of 99.4% (95% CI 97.8-100.0) for subjects with clinically definite PD at baseline. When analyzing the same population after 5 years with regard to the presence of known and newly diagnosed PD cases, baseline TCS yielded very similar diagnostic accuracy values. Conclusion: SN hyperechogenicity may represent a useful biomarker for PD not only in a hospital-based setting but also in the general community.
Neurodegenerative Diseases 05/2013; · 3.06 Impact Factor
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[show abstract]
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ABSTRACT: OBJECTIVE: Prominent fibrinogen cleavage by recombinant tissue plasminogen activator and formation of fibrinogen degradation products with anticoagulant properties was proposed to amplify the risk of thrombolysis-related bleeding complications, but supportive evidence mainly derived from studies on myocardial infarction. METHODS: This study included 547 consecutive stroke patients treated with recombinant tissue plasminogen activator, who underwent repeated assessment of fibrinogen levels before and 6 hours after thrombolysis. Symptomatic intracranial hemorrhages were ascertained using National Institute of Neurological Disorders and Stroke criteria. RESULTS: Intracranial hemorrhage or systemic bleeding events manifested in 47 patients (8.6%). A decrease ≥200 mg/dL in the fibrinogen level 6 hours after thrombolysis emerged as a significant and independent predictor for bleeding risk (multivariable odds ratio [95% confidence interval] 4.53 [2.39-8.60], p < 0.001). The population-attributable risk was 39.9% (95% confidence interval, 19.0-60.2) for any major bleeding, causality assumed, and surpassed 50% in patients with less severe strokes (NIH Stroke Scale score ≤16). Quantification of fibrinogen depletion after stroke thrombolysis significantly improved routine risk prediction of bleeding complications as indicated by an increase in the C-statistics from 0.712 to 0.798 (p = 0.015) and a net reclassification index of 0.341 (p < 0.001). A prospective bicenter validation sample (n = 148) corroborates the key findings of this study and suggests positive and negative predictive values of fibrinogen depletion for any major bleeding of 29.2% and 93.5%. CONCLUSION: This study lends strong support to the concept that prominent fibrinogen turnover after IV stroke thrombolysis-a condition termed "early fibrinogen degradation coagulopathy"-is a relevant cause of major bleeding complications. Rigorous testing of more fibrin-specific thrombolytic agents in the setting of acute stroke is warranted.
Neurology 03/2013; · 8.31 Impact Factor
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Xiangyuan Pu,
Qingzhong Xiao,
Stefan Kiechl,
Kenneth Chan,
Fu Liang Ng,
Shivani Gor,
Robin N Poston,
Changcun Fang,
Ashish Patel,
Ece C Senver,
Sue Shaw-Hawkins, Johann Willeit,
Chuanju Liu,
Jianhua Zhu,
Arthur T Tucker,
Qingbo Xu,
Mark J Caulfield,
Shu Ye
[show abstract]
[hide abstract]
ABSTRACT: Recent genome-wide association studies have revealed an association between variation at the ADAMTS7 locus and susceptibility to coronary artery disease (CAD). Furthermore, in a population-based study cohort, we observed an inverse association between atherosclerosis prevalence and rs3825807, a nonsynonymous SNP (A to G) leading to a Ser-to-Pro substitution in the prodomain of the protease ADAMTS7. In light of these data, we sought a mechanistic explanation for this association. We found that ADAMTS7 accumulated in smooth muscle cells in coronary and carotid atherosclerotic plaques. Vascular smooth muscle cells (VSMCs) of the G/G genotype for rs3825807 had reduced migratory ability, and conditioned media of VSMCs of the G/G genotype contained less of the cleaved form of thrombospondin-5, an ADAMTS7 substrate that had been shown to be produced by VSMCs and inhibit VSMC migration. Furthermore, we found that there was a reduction in the amount of cleaved ADAMTS7 prodomain in media conditioned by VSMCs of the G/G genotype and that the Ser-to-Pro substitution affected ADAMTS7 prodomain cleavage. The results of our study indicate that rs3825807 has an effect on ADAMTS7 maturation, thrombospondin-5 cleavage, and VSMC migration, with the variant associated with protection from atherosclerosis and CAD rendering a reduction in ADAMTS7 function.
The American Journal of Human Genetics 02/2013; · 10.60 Impact Factor
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Stefan Kiechl,
Jürgen Wittmann,
Andrea Giaccari,
Michael Knoflach,
Peter Willeit,
Aline Bozec,
Alexander R Moschen,
Giovanna Muscogiuri,
Gian Pio Sorice,
Trayana Kireva, [......],
Agnes Mayr,
Friedrich Oberhollenzer,
Florian Kronenberg,
Michael Orthofer,
Josef M Penninger,
James B Meigs,
Enzo Bonora,
Herbert Tilg, Johann Willeit,
Georg Schett
[show abstract]
[hide abstract]
ABSTRACT: Hepatic insulin resistance is a driving force in the pathogenesis of type 2 diabetes mellitus (T2DM) and is tightly coupled with excessive storage of fat and the ensuing inflammation within the liver. There is compelling evidence that activation of the transcription factor nuclear factor-κB (NF-κB) and downstream inflammatory signaling pathways systemically and in the liver are key events in the etiology of hepatic insulin resistance and β-cell dysfunction, although the molecular mechanisms involved are incompletely understood. We here test the hypothesis that receptor activator of NF-κB ligand (RANKL), a prototypic activator of NF-κB, contributes to this process using both an epidemiological and experimental approach. In the prospective population-based Bruneck Study, a high serum concentration of soluble RANKL emerged as a significant (P < 0.001) and independent risk predictor of T2DM manifestation. In close agreement, systemic or hepatic blockage of RANKL signaling in genetic and nutritional mouse models of T2DM resulted in a marked improvement of hepatic insulin sensitivity and amelioration or even normalization of plasma glucose concentrations and glucose tolerance. Overall, this study provides evidence for a role of RANKL signaling in the pathogenesis of T2DM. If so, translation to the clinic may be feasible given current pharmacological strategies to lower RANKL activity to treat osteoporosis.
Nature medicine 02/2013; · 27.14 Impact Factor
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[show abstract]
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ABSTRACT: The postgenomic shift in paradigm from reductionism to systems-wide network inference has increased recognition that cardiovascular diseases are not simply determined by the genome but arise from an interaction and dynamic dysregulation of gene regulatory networks, proteins, and metabolic alterations. The advent of postgenomic technologies promises to interrogate these complex pathophysiological perturbations by applying concepts of systemic relationships to biomarker discovery. A multibiomarker panel consisting of biomarkers capturing different levels of information (eg, microRNAs to assess endothelial and platelet activation, molecular lipid species to profile metabolic status, and proteolytic degradation products to assess vascular integrity) could outperform inflammatory biomarkers without vascular specificity in their ability of predicting cardiovascular risk. As atherosclerosis develops over decades, different biomarkers may be required for different stages of disease. Thus far, there is no simple blood test to directly assess the health of blood vessels or identify vulnerable patients. We discuss strategies for biomarker discovery using post genomics technologies, with a particular focus on circulating microRNAs. The aim is to reveal distinctive cardiovascular phenotypes and identify biomarker signatures that complement the Framingham risk scores in clinical decision-making and in a stratified medicine approach for early preventive treatment of disease.
Arteriosclerosis Thrombosis and Vascular Biology 02/2013; 33(2):206-14. · 6.37 Impact Factor
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[show abstract]
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ABSTRACT: Although extracranial internal carotid artery (e-ICA) occlusion is a common pathology in patients undergoing intravenous thrombolysis for treatment of acute ischemic stroke, no data on e-ICA recanalization rate or potential effects on outcome are yet available.
This study included 52 consecutive patients with e-ICA occlusion and ischemic stroke undergoing standard intravenous thrombolysis. The rate of e-ICA recanalization was 30.8% [95%CI, 18.2-43.3], documented at 3.5 [2.0-11.8] (median [IQR]) days after stroke, as compared to 8.6% [95%CI, 3.5-13.7] in a series of 116 consecutive patients with symptomatic e-ICA occlusion not undergoing thrombolysis (P<0.001 for difference). Functional outcome three months after stroke did not significantly differ for those with or without e-ICA recanalization following intravenous thrombolysis (modified Rankin scale ≤2: 31.3% vs. 22.2%, odds ratio 1.6 [95%CI, 0.4-5.9], P = 0.506). In patients with e-ICA occlusion of atherothrombotic origin, recanalization resulted in most instances in residual high-grade stenosis (13 of 14).
Recanalization of e-ICA occlusion after stroke thrombolysis occurred in about one third of patients. Although e-ICA recanalization had no significant effect on patient outcome, control sonography in the early days after thrombolysis is recommended for the detection of potential residual e-ICA stenosis.
PLoS ONE 01/2013; 8(1):e55318. · 4.09 Impact Factor
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Daniela Berg,
Stefanie Behnke,
Klaus Seppi,
Jana Godau,
Stefanie Lerche,
Philipp Mahlknecht,
Inga Liepelt-Scarfone,
Christoph Pausch,
Niko Schneider,
Alexandra Gaenslen, [......],
Karin Srulijes,
Heiko Huber,
Isabel Wurster,
Heike Stockner,
Stefan Kiechl, Johann Willeit,
Arno Gasperi,
Klaus Fassbender,
Thomas Gasser,
Werner Poewe
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: SN hyperechogenicity (SN+), determined by transcranial sonography, has been proposed as a risk factor for Parkinson's disease (PD). Recently, we reported a 17.4-fold increased risk for PD in individuals with SN+ older than 50 years within 3 years. METHODS: This is the second follow-up of a prospective, longitudinal, three-center observational study after 5 years. Of the initial 1,847 at baseline PD-free participants 50 years or older, 1,271 underwent the 5-year reassessment. RESULTS: Within 5 years, 21 individuals developed incident PD. Participants with SN+ at baseline had a more than 20.6 times increased risk to develop PD in this time span than those without this echo feature. CONCLUSION: We thus confirm our finding of the 3-year follow-up examination in a longer observation time and higher number of individuals with incident PD and suggest SN+ as an important risk marker for PD. © 2012 Movement Disorder Society.
Movement Disorders 10/2012; · 4.51 Impact Factor
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[show abstract]
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ABSTRACT: OBJECTIVES: This study sought to assess the long-term predictive value and net reclassification for risk of cardiovascular disease (CVD) of biomarkers reflecting oxidation-specific epitopes (OSEs). BACKGROUND: OSEs are immunogenic, proinflammatory, and proatherogenic. The long-term predictive value and net reclassification of OSEs for risk of CVD events are not known. METHODS: Oxidized phospholipids on apolipoprotein B-100 (OxPL/apoB) and immunoglobulin (Ig)-G (IgG) and IgM autoantibodies to malondialdehyde-modified, low-density lipoprotein (MDA-LDL) and copper-oxidized LDL (Cu-OxLDL) were measured in 765 subjects in 1995 and 656 subjects in 2000 in the Bruneck study, representing 45- to 84-year-old men and women from the general community. RESULTS: Over 15 years of follow-up, 138 subjects reached the primary endpoint of incident CVD (ischemic stroke, myocardial infarction, new-onset unstable angina, acute coronary interventions, and vascular death). In a multivariable Cox model, the highest tertile of OxPL/apoB was associated with higher risk of CVD (hazard ratio [HR]: 2.4; 95% confidence interval [CI]: 1.5 to 3.7) and stroke (HR: 3.6; 95% CI: 1.8 to 7.4) compared with the lowest tertile. IgG Cu-OxLDLs were associated with higher risk of CVD, whereas IgM MDA-LDLs were associated with lower risk. Using OxPL/apoB, IgG Cu-OxLDL, and IgM MDA-LDL variables, the area under the curve (AUC) for CVD risk prediction increased from 0.664 (95% CI: 0.629 to 0.697) to 0.705 (95% CI: 0.672 to 0.737) (p = 0.048). The net reclassification index (NRI) was 0.163 (p = 0.0044) and 0.332 (p < 0.0001) in all subjects (n = 765) and in subjects with intermediate risk (n = 305), respectively. Of 627 subjects who remained free of CVD, 108 were correctly reclassified to a lower risk category, and 83 were reclassified to a higher category (categories: 15-year risk <15%, 15% to 30%, >30%). CONCLUSIONS: OSE biomarkers predict 15-year CVD and stroke outcomes and provide potential clinical utility by reclassifying a significant proportion of individuals into higher or lower risk categories after traditional risk assessment.
Journal of the American College of Cardiology 10/2012; · 14.16 Impact Factor
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JAMA The Journal of the American Medical Association 10/2012; 308(13):1318; author reply 1319-20. · 30.03 Impact Factor
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Anna Zampetaki,
Peter Willeit,
Lindsey Tilling,
Ignat Drozdov,
Marianna Prokopi,
Jean-Marie Renard,
Agnes Mayr,
Siegfried Weger,
Georg Schett,
Ajay Shah,
Chantal M Boulanger, Johann Willeit,
Philip J Chowienczyk,
Stefan Kiechl,
Manuel Mayr
[show abstract]
[hide abstract]
ABSTRACT: This study sought to explore the association between baseline levels of microRNAs (miRNAs) (1995) and incident myocardial infarction (1995 to 2005) in the Bruneck cohort and determine their cellular origin.
Circulating miRNAs are emerging as potential biomarkers. We previously identified an miRNA signature for type 2 diabetes in the general population.
A total of 19 candidate miRNAs were quantified by real-time polymerase chain reactions in 820 participants.
In multivariable Cox regression analysis, 3 miRNAs were consistently and significantly related to incident myocardial infarction: miR-126 showed a positive association (multivariable hazard ratio: 2.69 [95% confidence interval: 1.45 to 5.01], p = 0.002), whereas miR-223 and miR-197 were inversely associated with disease risk (multivariable hazard ratio: 0.47 [95% confidence interval: 0.29 to 0.75], p = 0.002, and 0.56 [95% confidence interval: 0.32 to 0.96], p = 0.036). To determine their cellular origin, healthy volunteers underwent limb ischemia-reperfusion generated by thigh cuff inflation, and plasma miRNA changes were analyzed at baseline, 10 min, 1 h, 5 h, 2 days, and 7 days. Computational analysis using the temporal clustering by affinity propagation algorithm identified 6 distinct miRNA clusters. One cluster included all miRNAs associated with the risk of future myocardial infarction. It was characterized by early (1 h) and sustained activation (7 days) post-ischemia-reperfusion injury and consisted of miRNAs predominantly expressed in platelets.
In subjects with subsequent myocardial infarction, differential co-expression patterns of circulating miRNAs occur around endothelium-enriched miR-126, with platelets being a major contributor to this miRNA signature.
Journal of the American College of Cardiology 07/2012; 60(4):290-9. · 14.16 Impact Factor
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Philipp Mahlknecht,
Heike Stockner,
Michael Nocker,
Stefan Kiechl, Johann Willeit,
Christoph Scherfler,
Martin Sojer,
Arno Gasperi,
Gregorio Rungger,
Werner Poewe,
Klaus Seppi
Movement Disorders 06/2012; 27(9):1196-7. · 4.51 Impact Factor
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Movement Disorders 06/2012; 27(9):1194-6. · 4.51 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: To quantify the risk for bleeding complications after thrombolysis for ischemic stroke in patients on warfarin (international normalized ratio [INR] ≤ 1.7) and to put these data into perspective with previous studies.
A total of 548 consecutive stroke patients receiving IV recombinant tissue plasminogen activator (rtPA) were prospectively evaluated and details about warfarin pretreatment were carefully recorded. Prothrombin time-based INR values were measured before thrombolysis and 6 and 24 hours thereafter. Intracranial hemorrhage occurring within 72 hours was assessed by CT examinations and defined according to National Institute of Neurological Disorders and Stroke criteria. Main outcome variables were symptomatic intracranial and major systemic bleedings.
Of the 548 patients, 33 (6.0%) and 14 (2.6%) experienced symptomatic intracranial and major systemic bleedings, respectively. Patients taking warfarin until the day of or day before admission (n = 15, mean ± SD INR 1.21 ± 0.32 vs 1.01 ± 1.12, p = 0.030) faced an approximately 4-fold risk for intracranial hemorrhage (20.0% vs 5.6%, unadjusted odds ratio [OR] [95% confidence interval (CI)] 4.2 [1.1-15.7], p = 0.033). Findings were similar after adjustment for age, NIH Stroke Scale score, and diabetes (adjusted OR [95% CI] 4.1 [1.0-16.1], p = 0.044) and when focusing on any major bleeding (intracranial or systemic) (unadjusted OR [95% CI] 4.1 [1.3-13.6], p = 0.019). Half of the patients with bleedings showed an INR rise above 1.7 6 hours after thrombolysis. A meta-analysis yielded confirmatory yet heterogeneous results (unadjusted OR [95% CI] derived from a random effects model, 2.31 [1.15-4.62], p = 0.018, I(2) = 58% [11%-80%]).
Our data suggest a statistically significant and clinically meaningful increase in the risk for symptomatic intracranial and major systemic bleedings among patients with stroke thrombolysis receiving warfarin up to the day of or day before stroke.
Neurology 05/2012; 79(1):31-8. · 8.31 Impact Factor
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Benjamin Matošević,
Alexandra Zangerle,
Martin Furtner,
Michael Knoflach,
Philipp Werner,
Barbara Prantl,
Georg Wille,
Arne Illmer,
Artur Mair,
Michael Spiegel,
Christoph Schmidauer,
Martin Sojer,
Armin Muigg, Johann Willeit,
Stefan Kiechl
[show abstract]
[hide abstract]
ABSTRACT: HINTERGRUND: Die Wirksamkeit der systemischen Thrombolyse mit rekombinantem Gewebs- Plasminogen-Aktivator (rt-PA) beim akuten
ischämischen Schlaganfall wurde in klinischen Studien dokumentiert . Die Umsetzung der Studienergebnisse in den klinischen
Alltag ist bei Einhaltung der Richtlinien gegeben. STUDIENDESIGN: Im Zeitraum von 1998–2007 wurden an der Universitätsklinik
für Neurologie in Innsbruck 302 PatientInnen mit akutem ischämischem Schlaganfall mit rt-PA in einer Dosis von 0,9 mg/kg Körpergewicht
systemisch lysiert. Der initiale Schweregrad, prä- und intrahospitale Organisationsabläufe, die Sicherheit und das funktionelle
Outcome nach drei Monaten wurden anhand validierter Parameter prospektiv in einer Datenbank erfasst. ERGEBNISSE: Die Lysefrequenz
stieg kontinuierlich von initial 2 (1998) auf zuletzt 67 (2007) bzw. 87 (2008) pro Jahr. 43% der PatientInnen waren Frauen.
Das durchschnittliche Alter lag bei 67 Jahren, der NIHSS-Score bei Aufnahme betrug im Mittel 16. Die mittlere Onset-to-needle-time
verkürzte sich von 171 min auf 110 min – v.a. bedingt durch eine Verbesserung der Door-to-needle-time von 105 min auf 45 min.
In der Regeldienstzeit wurden 41%, im Nacht- und Wochenenddienst 59% der PatientInnen lysiert. 38% der PatientInnen waren
nach drei Monaten funktionell unabhängig (mRS 0–2). Bei Anpassung und Korrektur des Schweregrades entsprechend der internationalen
Studien erreichen 56% ein gutes Outcome. Die Rate an symptomatischen intracerebralen Blutungen betrug 6,3%. KONKLUSION: Die
Daten belegen die Sicherheit der i.v. Thrombolyse beim ischämischen Schlaganfall in der klinischen Routine und zeigen, dass
Verbesserungen der Infrastruktur, der prä- und intrahospitalen Organisationsabläufe an der Stroke Unit Innsbruck zu einer
gesteigerten Lyserate führten, verbunden mit einer Verkürzung der mittleren Door-to-needle-time. Durch Aufklärungskampagnen
der Bevölkerung, Verbesserung der Triagealgorithmen im Notarztwesen und der Ausweitung des Lysezeitfensters von 3 auf 4,5
Stunden nach Symptombeginn kann die Therapiefrequenz in Zukunft noch gesteigert werden.
BACKGROUND: Randomized controlled trials have yielded evidence for the efficacy and safety of intravenous alteplase in the
therapy of acute ischemic stroke. A large patient registry has recently confirmed the safe implementation of this therapy
in the clinical routine setting. METHODS: Between January 1998 and December 2007 302 stroke patients were treated with 0.9
mg/kg rt-PA at the stroke unit of the Innsbruck University Hospital. Severity and circumstances of the stroke event, indicators
of pre- and intrahospital management as well as safety and outcome at three months were prospectively assessed in the local
thrombolysis database. RESULTS: The number of patients receiving intravenous thrombolysis increased continuously from 2 patients
in 1998 to 67 in 2007 and 87 patients in 2008. 43% of our patients were females. The median age and NIHSS-score on admission
was 67 and 16, respectively. The mean onset-to-needle time decreased from 171 min to 110 min – mainly due to a substantial
shortening of the door-to-needle time from 105 min to 45 min. A proportion of 41% of our patients were treated in the main
working time while 59% received rt-PA during night and weekend service. A total of 38% of our patients were functionally independent
at three months (mRS 0–2). Once considering the high initial stroke severity in our patient series and correcting the NIHSS
scores to levels usually seen in randomized control trials and patient registries, 56% of our patients would reach a good
outcome (mRS 0–2). The rate of symptomatic intracranial bleedings was low at 6.3%. CONCLUSION: Our data reinforce that intravenous
thrombolysis is safe in the treatment of acute ischemic stroke in clinical routine setting. Establishment of modern stroke
services and the implementation of structural operating procedures have contributed to an increase in the number of treated
patients and a parallel decrease in door-to-needle time at our hospital. Widespread educational programs in the general community,
introduction of optimized pre-hospital triage algorithms as well as the potential extension of the 3-hour window to 4.5 hours
all are suitable measures to further extend the benefit of i.v. thrombolysis to large proportion of stroke patients.
SchlüsselwörterThrombolyse-Schlaganfallepidemiologie-Patientenmanagement-Outcome-Schlaganfall
KeywordsThrombolytic therapy-Stroke-epidemiology-Patient care management-Stroke-Outcome assessment
Wiener klinische Wochenschrift 04/2012; 121(23):750-756. · 0.81 Impact Factor
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Nadeem Sarwar,
Adam S Butterworth,
Daniel F Freitag,
John Gregson,
Peter Willeit,
Donal N Gorman,
Pei Gao,
Danish Saleheen,
Augusto Rendon,
Christopher P Nelson, [......],
Alison H Goodall,
Paul M Ridker,
Hilma Hólm,
Hugh Watkins,
Willem H Ouwehand,
Nilesh J Samani,
Stephen Kaptoge,
Emanuele Di Angelantonio,
Olivier Harari,
John Danesh
[show abstract]
[hide abstract]
ABSTRACT: Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling.
In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125,222 participants. We also compared the frequency of Asp358Ala in 51,441 patients with coronary heart disease and in 136,226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6.
The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele ≥0·04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34·3% (95% CI 30·4-38·2) and of interleukin 6 by 14·6% (10·7-18·4), and mean concentration of C-reactive protein was reduced by 7·5% (5·9-9·1) and of fibrinogen by 1·0% (0·7-1·3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3·4% (1·8-5·0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes.
Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease.
British Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation.
The Lancet 03/2012; 379(9822):1205-13. · 38.28 Impact Factor
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Michael Knoflach,
Stefan Kiechl,
Alberto Mantovani,
Ivan Cuccovillo,
Barbara Bottazzi,
Qingbo Xu,
Qingzhong Xiao,
Arno Gasperi,
Agnes Mayr,
Marlene Kehrer, Johann Willeit,
Georg Wick
[show abstract]
[hide abstract]
ABSTRACT: Pentraxins like C-reactive protein are key components of the innate immune system. Recently, pentraxin-3 (PTX3) has been proposed to be a specific marker of vascular inflammation, yet its association with atherosclerosis is still unclear.
PTX3 serum levels were measured in three independent studies of 132 young men (ARMY Study), 205 young women (ARFY Study) and 562 individuals 55 to 94 years old (Bruneck Study). In contrast to C-reactive protein, PTX3 showed little relationships with classic vascular risk factors and pro-inflammatory conditions. In the population based Bruneck Study, PTX3 level was independently associated with prevalent cardiovascular diseases (multivariable odds ratio [95%CI] 3.09 [1.65-5.79]; P<0.001). Moreover, PTX3 level correlated with the severity of carotid and femoral atherosclerosis and was highest in individuals with multiple vascular territories affected. In contrast, there was no association with elevated intima-media thickness, a precursor lesion of atherosclerosis, in any of the three populations investigated.
Level of PTX3 is independently associated with atherosclerosis and manifest cardiovascular disease but not early vessel pathology. Unlike C-reactive protein, PTX3 is not a component of the classic acute phase response (systemic inflammation) but appears to be more specific for vascular inflammation.
PLoS ONE 01/2012; 7(2):e31474. · 4.09 Impact Factor
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Joanne M Murabito,
Charles C White,
Maryam Kavousi,
Yan V Sun,
Mary F Feitosa,
Vijay Nambi,
Claudia Lamina,
Arne Schillert,
Stefan Coassin,
Joshua C Bis, [......],
H-Erich Wichmann,
James F Wilson,
Jacqueline C M Witteman,
Yongmei Liu,
Caroline Hayward,
Ingrid B Borecki,
Andreas Ziegler,
Kari E North,
L Adrienne Cupples,
Florian Kronenberg
[show abstract]
[hide abstract]
ABSTRACT: Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts.
Continuous ABI and PAD (ABI ≤0.9) phenotypes adjusted for age and sex were examined. Each study conducted genotyping and imputed data to the ≈2.5 million single nucleotide polymorphisms (SNPs) in HapMap. Linear and logistic regression models were used to test each SNP for association with ABI and PAD using additive genetic models. Study-specific data were combined using fixed effects inverse variance weighted meta-analyses. There were a total of 41 692 participants of European ancestry (≈60% women, mean ABI 1.02 to 1.19), including 3409 participants with PAD and with genome-wide association study data available. In the discovery meta-analysis, rs10757269 on chromosome 9 near CDKN2B had the strongest association with ABI (β=-0.006, P=2.46×10(-8)). We sought replication of the 6 strongest SNP associations in 5 population-based studies and 3 clinical samples (n=16 717). The association for rs10757269 strengthened in the combined discovery and replication analysis (P=2.65×10(-9)). No other SNP associations for ABI or PAD achieved genome-wide significance. However, 2 previously reported candidate genes for PAD and 1 SNP associated with coronary artery disease were associated with ABI: DAB21P (rs13290547, P=3.6×10(-5)), CYBA (rs3794624, P=6.3×10(-5)), and rs1122608 (LDLR, P=0.0026).
Genome-wide association studies in more than 40 000 individuals identified 1 genome wide significant association on chromosome 9p21 with ABI. Two candidate genes for PAD and 1 SNP for coronary artery disease are associated with ABI.
Circulation Cardiovascular Genetics 12/2011; 5(1):100-12. · 6.11 Impact Factor
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Stefan Kiechl,
Guillaume Paré,
Maja Barbalic,
Lu Qi,
Josée Dupuis,
Abbas Dehghan,
Joshua C Bis,
Ross C Laxton,
Qingzhong Xiao,
Enzo Bonora, Johann Willeit,
Qingbo Xu,
Jacqueline C M Witteman,
Daniel Chasman,
Russell P Tracy,
Christie M Ballantyne,
Paul M Ridker,
Emelia J Benjamin,
Shu Ye
[show abstract]
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ABSTRACT: Circulating levels of soluble intercellular adhesion molecule-1, soluble P-selectin, and soluble E-selectin have been associated with variation at the ABO locus. To evaluate these associations and the effect sizes, we performed a meta-analysis with new and previous reported data for polymorphism rs579459.
Compared with major allele homozygotes, heterozygotes and minor allele homozygotes had 4.6% (95% CI, 3.4%-5.8%, P=7.3 × 10(-14)) and 7.2% (95% CI, 4.7%-9.7%, P=1.5 × 10(-8)), respectively, lower soluble intercellular adhesion molecule-1 levels (n=33 671). An allele dose-dependent association also was observed for soluble P-selectin (n=4921) with heterozygotes and minor allele homozygotes having 11.5% (95% CI, 7.2%-15.8%, P=1.7 × 10(-7)) and 18.6% (95% CI, 9.1%-28.1%, P=1.2 × 10(-4)), respectively, lower levels than in major allele homozygotes. A larger effect size, again consistent with an additive genetic model, was seen for soluble E-selectin (n=2860) whose level was 25.6% (95% CI, 19.0%-32.2%, P=2.1 × 10(-14)) lower in heterozygotes and 43.3% (95% CI, 36.9%-49.3%, P=4.3 × 10(-42)) lower in minor allele homozygotes than in major allele homozygotes.
The data support the association of variation at the ABO locus with soluble intercellular adhesion molecule-1, soluble P-selectin, and soluble E-selectin levels.
Circulation Cardiovascular Genetics 12/2011; 4(6):681-6. · 6.11 Impact Factor
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ABSTRACT: In vitro studies have shown that matrix metalloproteinase-12 (MMP12) can degrade fibrinogen, a clotting factor whose level predicts risk of advanced atherosclerosis and myocardial infarction. In this study, we found that mean plasma fibrinogen level was approximately 10-fold higher in MMP12 knockout mice than wildtype mice (p=0.0006). Differential allelic expression analysis of human MMP12 gene polymorphism rs17368582 in human vascular tissues showed an allele-specific effect on MMP12 expression, with one allele (T) having 1.6 fold higher expression level than the other allele (C) (p=0.0006). In a population cohort, we found that individuals homozygous for the MMP12 low expression allele had higher plasma fibrinogen levels (2.95 mg/mL compared with 2.61 mg/mL in other individuals, p=0.029) and increased risk of advanced atherosclerosis [odds ratio 6.3 (95% CI 1.9-20.8), p=0.003] and myocardial infarction [hazard ratio 5.6 (95% CI 1.7-18.3), p=0.005]. In summary, our study in mouse and humans provides in vivo evidence of an effect of MMP12 on fibrinogen level.
Atherosclerosis 11/2011; 220(2):351-4. · 3.79 Impact Factor
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Michael Knoflach,
Barbera Messner,
Ying H Shen,
Sandra Frotschnig,
Guanghui Liu,
Kristian Pfaller,
Xingli Wang,
Benjamin Matosevic, Johann Willeit,
Stefan Kiechl,
Günther Laufer,
David Bernhard
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ABSTRACT: Cadmium is a potential new risk factor for early atherosclerosis and cardiovascular diseases in humans, yet pathogenetic mechanisms are still a matter of debate.
In-depth histological analysis of 18 sections taken from 6 cadmium-fed ApoE-/- mice and 12 sections from 5 litter-mates not exposed to cadmium by light and scanning electron microscopy was performed. Cadmium-fed mice showed a marked increase in lesion load (plaque area) and severity as classified according to the American Heart Association vascular lesion grading. All inflammatory markers studied (CD68, CD3, CD25, vascular cell adhesion molecule 1 (VCAM-1), and heat shock protein 60 (Hsp60)) yielded a higher expression in cadmium-fed mice. Statistical difference was achieved for VCAM-1 and Hsp60 (P=0.03 and P=0.02). The shoulder region of atherosclerotic plaques in cadmium-fed mice showed a prominent retraction of endothelial cells on electron microscopy.
Our data indicate that cadmium exposure amplifies the development of vessel pathology in atherosclerosis susceptible ApoE-/- mice and suggests upregulation of VCAM-1 and Hsp60 and endothelial leakage as potential pathomechanisms.
Circulation Journal 07/2011; 75(10):2491-5. · 3.77 Impact Factor
