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IMPORTANCE Accumulating evidence links inflammation and atrial fibrillation (AF). OBJECTIVE To assess whether markers of systemic and atrial inflammation are associated with incident AF in the general population. DESIGN, SETTING, AND PARTICIPANTS The Bruneck Study is a prospective, population-based cohort study with a 20-year follow-up (n = 909). The population included a random sample of the general community aged 40 to 79 years. Levels of 13 inflammation markers were measured at baseline indoi:10.1001/jamacardio.2017.0064 pmid:28355442 pmcid:PMC5814989 fatcat:rrwozscw2rd3jepnmbpvrfmhum
more »... 90. Findings were replicated in a case-control sample nested within the prospective Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk (SAPHIR) study (n = 1770). Data analysis was performed from February to May 2016. EXPOSURES Levels of 13 inflammation markers. MAIN OUTCOMES AND MEASURES Incident AF over a 20-year follow-up period in the Bruneck Study. RESULTS Of the 909 participants included in the Bruneck Study, mean [SD] age was 58.8 (11.4) years and 448 (49.3%) were women. Among the 880 participants free of prevalent AF (n = 29) at baseline, 117 developed AF during the 20-year follow-up period (incidence rate, 8.2; 95% CI, 6.8-9.6 per 1000 person-years). The levels of soluble vascular cell adhesion molecule 1 (VCAM-1) and osteoprotegerin were significantly associated with incident AF (hazard ratio [HR], 1.49; 95% CI, 1.26-1.78; and 1.46; 95% CI, 1.25-1.69, respectively; P < .001 with Bonferroni correction for both), but osteoprotegerin lost significance after age and sex adjustment (HR, 1.05; 95% CI, 0.87-1.27; P > .99 with Bonferroni correction). Matrix metalloproteinase 9, metalloproteinase inhibitor 1, monocyte chemoattractant protein-1, P-selectin, fibrinogen, receptor activator of nuclear factor-κB ligand, high-sensitivity C-reactive protein, adiponectin, leptin, soluble intercellular adhesion molecule 1, and E-selectin all fell short of significance (after Bonferroni correction in unadjusted and age-and sex-adjusted analyses). The HR for a 1-SD higher soluble VCAM-1 level was 1.34 (95% CI, 1.11-1.62; Bonferroni-corrected P = .03) in a multivariable model. The association was of a dose-response type, at least as strong as that obtained for N-terminal pro-B-type natriuretic peptide (multivariable HR for a 1-SD higher N-terminal pro-B-type natriuretic peptide level, 1.15; 95% CI, 1.04-1.26), internally consistent in various subgroups, and successfully replicated in the SAPHIR Study (age-and sex-adjusted, and multivariable odds ratios for a 1-SD higher soluble VCAM-1 level, 1.91; 95% CI, 1.24-2.96, P = .003; and 2.59; 95% CI, 1.45-4.60; P = .001). CONCLUSIONS AND RELEVANCE Levels of soluble VCAM-1, but not other inflammation markers, are significantly associated with new-onset AF in the general community. Future studies should address whether soluble VCAM-1 is capable of improving AF risk classification beyond the information provided by standard risk scores.
Willeit is supported by a Translational-Research-Program grant funded by the Land Tirol. R. ...doi:10.1161/atvbaha.113.302272 pmid:24030550 fatcat:jw6qmyxqyvdltbhuyfd6zqplj4
Three researchers -Johann Willeit, Friedrich Oberhollenzer, and Georg Egger (online suppl. ... Johann Willeit, the neurologist in the team, ensured scientific rigor and quality and set new methodological standards in epidemiological research at that time. ...doi:10.1159/000492329 pmid:30179866 fatcat:repsfg7mubca5grhzo5xwyazwa
Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number. 2doi:10.1371/journal.pone.0183910 pmid:28837646 pmcid:PMC5570489 fatcat:fxspx72slfgu3bpi3mbn47zqxa
The natural course of early atherogenesis is not well established. The current prospective survey was designed to monitor 5-year changes in carotid atherosclerosis in a large, stratified random sample of the general population using high-resolution duplex ultrasound (Bruneck Study). Incidence rates of carotid atherosclerosis ranged from near zero to 184 per 1000 person-years. Most atherosclerotic lesions developed at sites with enhanced wall thickness. Incidence of atherosclerosis indoi:10.1161/01.atv.19.6.1484 pmid:10364079 fatcat:cjfh54vkjrfcjjerbsskqrkd3q
more »... al women was less than half of that observed in men of equal age. The sex difference disappeared within 5 years after menopause and may possibly be attributed to sex variations in body iron stores. Preexisting atherosclerotic lesions may experience 1 of 2 different types of disease progression. 1) The first main type of plaque growth causing nonstenotic or diffuse dilative atherosclerosis was characterized by slow and continuous plaque extension, which usually affected several lesions simultaneously and did not primarily focus on the carotid bifurcation. This step-by-step process relied on a cumulative exposure to well-known risk factors such as hyperlipidemia. Compensatory enlargement of the artery at the site of active atherosclerosis effectively preserved a (near) normal lumen. 2) The second main type of plaque growth was characterized by occasional prominent increases in lesion size. This process primarily occurred in the internal carotid artery and was mediated by procoagulant risk factors in a way that peak levels were relevant rather than cumulative exposure. As the main underlying pathomechanism, atherothrombosis may be hypothesized. Marked increases in plaque size and insufficient vascular remodeling acted synergistically in producing a significant compromise of the lumen. The current study provides novel insights into the natural course of early carotid atherosclerosis, thereby focusing on disease incidence and various types of spontaneous disease progression. Nonstenotic or diffuse dilating atherosclerosis and focal stenotic disease were found to constitute epidemiologically and etiologically distinct disease entities that develop and proceed independently of each other.
Arterial remodelling is a potentially important component in atherogenesis aimed at delaying the development of significant lumen compromise. Current knowledge on this phenomenon is mainly restricted to experimental evaluations and a few postmortem studies. We used high-resolution duplex ultrasound to study 5-year changes (1990 to 1995) in vessel geometry in a large random sample of the general population (Bruneck Study). Carotid arteries free of atherosclerosis and wall thickening preserved adoi:10.1161/01.atv.19.6.1491 pmid:10364080 fatcat:6eqfj56ccve3fl2pq3knowra5q
more »... ormal size to high ages. In contrast, common and internal carotid arteries with elevated intima-media thickness (Ն50th percentile) experienced marked age-dependent dilation that started already in the 5th decade and continuously accelerated thereafter (structural ageing). Vessel diameters were subject to complex regulation involving morphometric characteristics, sex, wall thickness, hypertension, LDL cholesterol levels, and alcohol consumption. Vascular remodelling secondary to incident or slowly progressive (mural) atherosclerosis included local compensation and a generalised dilation response of vascular segments not primarily affected. Adaptive enlargement at the site of active atherogenesis effectively preserved a near-normal lumen in most instances. The current study identified a second main type of plaque growth, characterized by episodic marked increase in lesion volume probably on the basis of plaque thrombosis. In this setting, we did not observe maximum but insufficient compensation but instead usually observed no compensation at all. Failure of vascular remodelling and marked expansion in plaque size acted synergistically in producing significant lumen compromise. The current prospective survey describes fundamental principles and various facets of arterial remodelling and vascular biology in the general population (in vivo). Vessel geometry was subject to marked temporal changes and showed a correspondingly complex (multifactorial) and dynamic regulation. Vascular remodelling emerged as an important compensatory process in human atherogenesis, which crucially contributed to the determination of lumen obstruction. Efficacy and failure of compensation primarily depended on the type and pathomechanisms of underlying atherogenesis and only in second instance on plaque size and location.
Willeit, Karin Willeit, Peter Willeit. ... Raimund Pechlaner, Thomas Porpaczy, Gerhard Rumpold, Christoph Schmidauer, Gudrun Schoenherr, Lisa Seekircher, Martin Sojer, Christine Span, Lydia Thiemann, Thomas Toell, Lena Tschiderer, Marlies Wichtl, Johann ... Willeit et al. / EClinicalMedicine 25 (2020) 100476 ...doi:10.1016/j.eclinm.2020.100476 pmid:32954239 pmcid:PMC7486330 fatcat:5bmwbc64lzfkznwy3f2n5wfqpe
BACKGROUND Recent studies showed that lipoprotein(a) [Lp(a)] is a causal risk factor for cardiovascular disease (CVD). However, whether Lp(a) modifies clinical risk assessment was not established. OBJECTIVES This study was conducted to determine whether Lp(a) improves CVD risk prediction. METHODS In 1995, Lp(a) was measured in 826 men and women (age range, 45 to 84 years) from the general community. Incidence of CVD was recorded over 15 years of follow-up. RESULTS In models adjusted fordoi:10.1016/j.jacc.2014.03.061 pmid:25169167 fatcat:lp6ep7nu65hrllfxq7uu3du2we
more »... am Risk Score (FRS) and Reynolds Risk Score (RRS) variables, the hazard ratio (HR) for incident CVD was 1.37 per 1-SD higher Lp(a) level (SD ¼ 32 mg/dl) and 2.37 when comparing the top fifth quintile with other quintiles. The addition of Lp(a) to the RRS increased the C-index by 0.016. Of the 502 subjects who remained free of CVD, 82 were correctly reclassified to a lower risk category and 49 were reclassified to a higher risk category (predicted 15-year categories: <7.5%, 7.5% to <15%, 15% to <30%, $30%) (p < 0.001). Of the 148 subjects who developed CVD, 18 were correctly reclassified to a higher risk category and 17 were reclassified to a lower risk category. In subjects at intermediate risk (15% to <30%), the net reclassification improvement afforded by Lp(a) was 22.5% for noncases, 17.1% for cases, and 39.6% overall. Allele-specific Lp(a) levels did not add to the predictive ability of the FRS or RRS or to Lp(a). CONCLUSIONS Elevated Lp(a) predicts 15-year CVD outcomes and improves CVD risk prediction. These findings suggest that Lp(a) levels may be used in risk assessment of subjects in the general community, particularly in intermediate-risk groups. (J Am Coll Cardiol 2014;64:851-60)
Introduction Recent findings have challenged the prevailing histology-or imaging-based definition of the vulnerable plaque. Methods To investigate molecular characteristics associated with clinical instability of atherosclerosis, we performed a proteomics comparison of the vascular extracellular matrix and associated molecules in human carotid endarterectomy specimens from symptomatic versus asymptomatic patients. The proteomics data were integrated with gene expression profiling and andoi:10.1136/heartjnl-2017-311726.201 fatcat:pjkgux7xkzeybbr4t3aukbww2q
more »... of protein secretion by lipid-loaded human vascular smooth muscle cells. Results The molecular signature of plaques from symptomatic patients identified by proteomics and at least one of the other two approaches comprised matrix metalloproteinase-9, chitinase-3-like protein 1, S100 calcium binding protein A8, S100 calcium binding protein A9, cathepsin B, fibronectin and galectin-3-binding protein. Biomarker candidates were measured in 685 subjects of the Bruneck Study and found to be significantly associated with the progression to advanced atherosclerosis (as assessed by repeated carotid ultrasound) and the incidence of cardiovascular disease over a 10 year follow-up period. A 4-biomarker signature (matrix metalloproteinase-9, S100A8/S100A9, cathepsin D, and galectin-3-binding protein) improved risk prediction in terms of risk discrimination and classification and was successfully replicated in a second independent population (SAPHIR Study). Conclusion Our study highlights the strength of tissue-based proteomics for biomarker discovery.
BACKGROUND. The identification of patients with high-risk atherosclerotic plaques prior to the manifestation of clinical events remains challenging. Recent findings question histologyand imaging-based definitions of the "vulnerable plaque," necessitating an improved approach for predicting onset of symptoms. METHODS. We performed a proteomics comparison of the vascular extracellular matrix and associated molecules in human carotid endarterectomy specimens from 6 symptomatic versus 6doi:10.1172/jci86924 pmid:28319050 pmcid:PMC5373893 fatcat:grp7pg66nbdzjdsyc6jrm7w544
more »... patients to identify a protein signature for high-risk atherosclerotic plaques. Proteomics data were integrated with gene expression profiling of 121 carotid endarterectomies and an analysis of protein secretion by lipid-loaded human vascular smooth muscle cells. Finally, epidemiological validation of candidate biomarkers was performed in two community-based studies. RESULTS. Proteomics and at least one of the other two approaches identified a molecular signature of plaques from symptomatic patients that comprised matrix metalloproteinase 9, chitinase 3-like-1, S100 calcium binding protein A8 (S100A8), S100A9, cathepsin B, fibronectin, and galectin-3-binding protein. Biomarker candidates measured in 685 subjects in the Bruneck study were associated with progression to advanced atherosclerosis and incidence of cardiovascular disease over a 10-year follow-up period. A 4-biomarker signature (matrix metalloproteinase 9, S100A8/S100A9, cathepsin D, and galectin-3binding protein) improved [...] Clinical Medicine Vascular biology Find the latest version: Atherosclerosis is a chronic and progressive disease of the arterial wall and the main underlying cause of stroke, myocardial infarction (MI), and cardiac death (1, 2). The evolution of atherosclerotic plaques involves endothelial dysfunction, accumulation of lipids and inflammatory cells, as well as remodeling of the extracellular matrix (ECM). Previously, atherosclerotic plaques were defined by histological appearance. Plaques with thin fibrous caps and a large lipid pool were classified as "vulnerable lesions." Lipid-poor plaques rich in ECM with thick fibrous caps were considered "stable." Recent findings have challenged this "vulnerable plaque" concept (3, 4): First, intravascular imaging revealed that only a small percentage of thin-capped plaques cause clinical events (4, 5). Second, shifts in risk factor profiles (e.g., smoking cessation) and widespread use of statins are associated with a change in histopathological appearance of atherosclerotic lesions: "vulnerable plaques" with large lipid pools are far less common (3). Instead, superficial plaque erosions may trigger more cardiovascular events (3, 4) . BACKGROUND. The identification of patients with high-risk atherosclerotic plaques prior to the manifestation of clinical events remains challenging. Recent findings question histology-and imaging-based definitions of the "vulnerable plaque," necessitating an improved approach for predicting onset of symptoms. METHODS. We performed a proteomics comparison of the vascular extracellular matrix and associated molecules in human carotid endarterectomy specimens from 6 symptomatic versus 6 asymptomatic patients to identify a protein signature for high-risk atherosclerotic plaques. Proteomics data were integrated with gene expression profiling of 121 carotid endarterectomies and an analysis of protein secretion by lipid-loaded human vascular smooth muscle cells. Finally, epidemiological validation of candidate biomarkers was performed in two community-based studies. RESULTS. Proteomics and at least one of the other two approaches identified a molecular signature of plaques from symptomatic patients that comprised matrix metalloproteinase 9, chitinase 3-like-1, S100 calcium binding protein A8 (S100A8), S100A9, cathepsin B, fibronectin, and galectin-3-binding protein. Biomarker candidates measured in 685 subjects in the Bruneck study were associated with progression to advanced atherosclerosis and incidence of cardiovascular disease over a 10-year follow-up period. A 4-biomarker signature (matrix metalloproteinase 9, S100A8/S100A9, cathepsin D, and galectin-3binding protein) improved risk prediction and was successfully replicated in an independent cohort, the SAPHIR study. CONCLUSION. The identified 4-biomarker signature may improve risk prediction and diagnostics for the management of cardiovascular disease. Further, our study highlights the strength of tissue-based proteomics for biomarker discovery.
Additional file 1. Online appendix.doi:10.6084/m9.figshare.c.3721624_d1 fatcat:xptfmhiwozemvflcpbwdhllfh4
Patients with ischaemic stroke or transient ischaemic attack (TIA) are at high risk of future cardiovascular events. Despite compelling evidence about the efficacy of secondary prevention, a substantial gap exists between risk factor management in real life and that recommended by international guidelines. Moreover, stroke is a leading cause of disability and morbidity which partly emerges from post-stroke complications. We designed a block-randomised (2:1 ratio) open pragmatic trialdoi:10.1186/s12883-018-1185-2 pmid:30400876 pmcid:PMC6219064 fatcat:lnxkn73marf27dt6yop5yv65ci
more »... 8] with blinded outcome assessment comparing STROKE-CARD to usual post-stroke-patient care. STROKE-CARD is a multifaceted post-stroke disease management program with the objective of reducing recurrent cardiovascular events and improving quality of life in ischaemic stroke and TIA-patients. It combines intensified multi-domain secondary prevention, systematic detection and treatment of post-stroke complications, and patient self-empowerment. Enrolment of 2160 patients with acute ischaemic stroke or TIA (ABCD2-Score ≥ 3) is planned at two study centres in Austria. The co-primary efficacy endpoints are (i) the composite of major recurrent cardiovascular events (nonfatal stroke, nonfatal myocardial infarction, and vascular death) occurring within 12 months after the index event and (ii) one-year health-related quality-of-life measured with the European Quality of Life-5 Dimensions (EQ-5D-3 L) questionaire. Secondary endpoints include all-cause mortality, functional outcome, and target-level achievement in risk factor management. This trial will provide evidence on whether the pragmatic post-stroke intervention program STROKE-CARD can help prevent cardiovascular events and improve quality-of-life within the setting of a high-quality acute stroke care system. In case of success, STROKE-CARD may be implemented in daily clinical routine and serve as a model for other disease management initiatives. ClinicalTrials.gov: NCT02156778 . (June 5, 2014, retrospectively registered).
Identifying individuals at risk of developing Parkinson's disease (PD) is critical to define target populations for future neuroprotective trials. The objective of this study was to apply the PREDICT-PD algorithm of risk indicators for PD in a prospective community-based study (the Bruneck study), representative of the general elderly population. PREDICT-PD risk scores were calculated based on risk factor assessments obtained at baseline (2005, n = 574 participants). Cases of incident PD weredoi:10.1002/mds.28127 pmid:32491231 fatcat:ya3i3imnprexhmiwiqfqzvps74
more »... entified at 5-year and 10-year follow-ups. Participants with PD or secondary parkinsonism at baseline were excluded (n = 35). We analyzed the association of log-transformed risk scores with the presence of well-established markers as surrogates for PD risk at baseline and with incident PD at follow-up. A total of 20 participants with incident PD were identified during follow-up (11 after 5 years and 9 after 10 years). Baseline PREDICT-PD risk scores were associated with incident PD with odds ratios of 2.09 (95% confidence interval, 1.35-3.25; P = 0.001) after 5 years and of 1.95 (1.36-2.79; P < 0.001) after 10 years of follow-up per doubling of risk scores. In addition, higher PREDICT-PD scores were significantly correlated with established PD risk markers (olfactory dysfunction, signs of rapid eye movement sleep behavior disorder and motor deficits) and significantly associated with higher probability for prodromal PD according to the Movement Disorder Society research criteria at baseline. The PREDICT-PD score was associated with an increased risk for incident PD in our sample and may represent a useful first screening step in future algorithms aiming to identify cases of prodromal PD. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
Aims: We aimed to (1) assess the association between lipoprotein(a) [Lp(a)] concentration and incident type-2 diabetes in the Bruneck study, a prospective population-based study, and (2) combine findings with evidence from published studies in a literature-based meta-analysis. Methods: We used Cox proportional hazards models to calculate hazard ratios (HR) for incident type-2 diabetes over 20 years of follow-up in 815 participants of the Bruneck study according to their long-term average Lp(a)doi:10.1186/s12933-017-0520-z pmid:28320383 pmcid:PMC5359972 fatcat:hwwdd4gsnjbablcrgojtesre6e
more »... oncentration. For the meta-analysis, we searched Medline, Embase and Web of Science for relevant prospective cohort studies published up to October 2016. Results: In the Bruneck study, there was a 12% higher risk of type-2 diabetes for a one standard deviation lower concentration of log Lp(a) (HR = 1.12 [95% CI 0.95-1.32]; P = 0.171), after adjustment for age, sex, alcohol consumption, body mass index, smoking status, socioeconomic status, physical activity, systolic blood pressure, HDL cholesterol, log high-sensitivity C-reactive protein and waist-hip ratio. In a meta-analysis involving four prospective cohorts with a total of 74,575 participants and 4514 incident events, the risk of type-2 diabetes was higher in the lowest two quintiles of Lp(a) concentrations (weighted mean Lp(a) = 3.3 and 7.0 mg/dL, respectively) compared to the highest quintile (62.9 mg/dL), with the highest risk of type-2 diabetes seen in quintile 1 (HR = 1.28 [1.14-1.43]; P < 0.001). Conclusions: The current available evidence from prospective studies suggests that there is an inverse association between Lp(a) concentration and risk of type-2 diabetes, with a higher risk of type-2 diabetes at low Lp(a) concentrations (approximately <7 mg/dL).
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).doi:10.1016/j.jacc.2012.08.979 pmid:23122790 fatcat:bbctpun74fbmtkczhidme7mkhe
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