Publications by authors named "Raimund Pechlaner"

37 Publications

PCSK9 Activity Is Potentiated Through HDL Binding.

Circ Res 2021 Oct 4. Epub 2021 Oct 4.

School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre, UNITED KINGDOM.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) circulates in a free and lipoprotein-bound form, yet the functional consequence of the association between PCSK9 and high-density lipoprotein (HDL) remains unexplored. This study sought to interrogate the novel relationship between PCSK9 and HDL in humans. Comparing lipoprotein and apolipoprotein profiles by nuclear magnetic resonance and targeted mass spectrometry measurements with PCSK9 levels in the community-based Bruneck (n=656) study revealed a positive association of plasma PCSK9 with small HDL, alongside a highly significant positive correlation between plasma levels of PCSK9 and apolipoprotein-C3, an inhibitor of lipoprotein lipase. The latter association was replicated in an independent cohort, the SAPHIR study (n=270). Thus, PCSK9-HDL association was determined during the postprandial response in two dietary studies (n=20 participants each, 8 times points). Peak triglyceride levels coincided with an attenuation of the PCSK9-HDL association, a loss of apolipoprotein-C3 from HDL and lower levels of small HDL as measured by nuclear magnetic resonance. Crosslinking mass spectrometry (XLMS) upon isolated HDL identified PCSK9 as a potential HDL-binding partner. PCSK9 association with HDL was confirmed through size-exclusion chromatography and immuno-isolation. Quantitative proteomics upon HDL isolated from patients with coronary artery disease (n=172) returned PCSK9 as a core member of the HDL proteome. Combined interrogation of the HDL proteome and lipidome revealed a distinct cluster of PCSK9, phospholipid transfer protein, clusterin and apolipoprotein-E within the HDL proteome, that was altered by sex and positively correlated with sphingomyelin content. Mechanistically, HDL facilitated PCSK9-mediated low-density lipoprotein receptor degradation and reduced low-density lipoprotein uptake through the modulation of PCSK9 internalisation and multimerisation. This study reports HDL as a binder of PCSK9 and regulator of its function. The combination of -omic technologies revealed postprandial lipaemia as a driver of PCSK9 and apolipoprotein-C3 release from HDL.
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http://dx.doi.org/10.1161/CIRCRESAHA.121.319272DOI Listing
October 2021

Predictors of Carotid Intima-Media Thickness Progression in Adolescents-The EVA-Tyrol Study.

J Am Heart Assoc 2021 Sep 6;10(18):e020233. Epub 2021 Sep 6.

Department of Neurology Medical University of Innsbruck Innsbruck Austria.

Background Cardiovascular disease depends on the duration and time course of risk factor exposure. Previous reports on risk factors of progression of carotid intima-media thickness (cIMT) in the young were mostly restricted to high-risk populations or susceptible to certain types of bias. We aimed to unravel a risk factor signature for early vessel pathology based on repeated ultrasound assessments of the carotid arteries in the general population. Methods and Results Risk factors were assessed in 956 adolescents sampled from the general population with a mean age of 15.8±0.9 years, 56.2% of whom were female. cIMT was measured at baseline and on average 22.5±3.4 months later by high-resolution ultrasound. Effects of baseline risk factors on cIMT progression were investigated using linear mixed models with multivariable adjustment for potential confounders, which yielded significant associations (given as increase in cIMT for a 1-SD higher baseline level) for alanine transaminase (5.5 μm; 95% CI: 1.5-9.5), systolic blood pressure (4.7 μm; 0.3-9.2), arterial hypertension (9.5 μm, 0.2-18.7), and non-high-density (4.5 μm; 0.7-8.4) and low-density lipoprotein cholesterol (4.3 μm; 0.5-8.1). Conclusions Systolic blood pressure, arterial hypertension, low-density and non-high-density lipoprotein cholesterol, and alanine transaminase predicted cIMT progression in adolescents, even though risk factor levels were predominantly within established reference ranges. These findings reemphasize the necessity to initiate prevention early in life and challenge the current focus of guideline recommendations on high-risk youngsters. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03929692.
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http://dx.doi.org/10.1161/JAHA.120.020233DOI Listing
September 2021

Dietary spermidine improves cognitive function.

Cell Rep 2021 Apr;35(2):108985

Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, 6020 Innsbruck, Austria.

Decreased cognitive performance is a hallmark of brain aging, but the underlying mechanisms and potential therapeutic avenues remain poorly understood. Recent studies have revealed health-protective and lifespan-extending effects of dietary spermidine, a natural autophagy-promoting polyamine. Here, we show that dietary spermidine passes the blood-brain barrier in mice and increases hippocampal eIF5A hypusination and mitochondrial function. Spermidine feeding in aged mice affects behavior in homecage environment tasks, improves spatial learning, and increases hippocampal respiratory competence. In a Drosophila aging model, spermidine boosts mitochondrial respiratory capacity, an effect that requires the autophagy regulator Atg7 and the mitophagy mediators Parkin and Pink1. Neuron-specific Pink1 knockdown abolishes spermidine-induced improvement of olfactory associative learning. This suggests that the maintenance of mitochondrial and autophagic function is essential for enhanced cognition by spermidine feeding. Finally, we show large-scale prospective data linking higher dietary spermidine intake with a reduced risk for cognitive impairment in humans.
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http://dx.doi.org/10.1016/j.celrep.2021.108985DOI Listing
April 2021

Cardiovascular health behaviors and associations of sex, age, and education in adolescents - Results from the EVA Tyrol study.

Nutr Metab Cardiovasc Dis 2021 04 10;31(4):1286-1292. Epub 2020 Nov 10.

Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria. Electronic address:

Background And Aims: Ideal cardiovascular health (CVH) behaviors in adolescents are defined by body mass index (BMI), diet, physical activity and smoking, and are directly associated with better health in later life. To further improve health prevention programs we investigated the prevalence of these behaviors in a cohort of healthy adolescents and focused on the associations with sex, age, and education.

Methods And Results: The Early Vascular Aging Tyrol study is a cross-sectional study assessing 14- to 19-year-old pupils and apprentices in Western Austria and South Tyrol. Between May 2015 and July 2018 2047 adolescents (43.6% males, mean age 16.4 years) with complete data for all 4 health behaviors were included. The prevalence of ideal body mass index (BMI) was 78.3%, of ideal physical activity 42.5%, of non-smoking 70.4% and of ideal diet 8.1%. Females showed a higher smoking prevalence and a lower physical activity, but better dietary habits than males. Older adolescents of both sexes had lower prevalence of ideal smoking and diet. Apprentices and pupils of vocational schools had a higher BMI and a less favorable diet compared to secondary academic school students. Smoking prevalence was highest in apprentices. Non-ideal BMI was independently associated with smoking.

Conclusion: In our cohort, only a minority showed ideal CVH behaviors which were best in adolescents younger than 16 years. We observed significant differences between males and females and a clear impact of school education with apprentices being at risk for non-ideal CVH behaviors.

Clinical Trial Registration Number: NCT03929692, clinicaltrials.gov.
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http://dx.doi.org/10.1016/j.numecd.2020.11.002DOI Listing
April 2021

Extracellular matrix protein signature of recurrent spontaneous cervical artery dissection.

Neurology 2020 10 4;95(15):e2047-e2055. Epub 2020 Sep 4.

From the Departments of Neurology (L.M., R.P., C.B., T.T., J.W., S.K., M.K.), Neuroradiology (E.R.G.), Internal Medicine IV (P.P.), and Dermatology (G.R.), Medical University Innsbruck, Austria; King's British Heart Foundation Centre (J.B.-B., M.L., X.Y., M.M.), King's College London, London, UK; and VASCage (S.K.), Research Centre on Vascular Ageing and Stroke, Innsbruck, Austria.

Objective: To assess whether connective tissue disorder is evident in patients with spontaneous cervical artery dissection and therefore identify patients at risk of recurrence using a cutting-edge quantitative proteomics approach.

Methods: In the ReSect study, all patients with spontaneous cervical artery dissection treated at the Innsbruck University Hospital since 1996 were invited to attend a standardized clinical follow-up examination. Protein abundance in skin punch biopsies (n = 50) was evaluated by a cutting-edge quantitative proteomics approach (liquid chromatography-mass spectrometry) that has hitherto not been applied to such patients.

Results: Patients with 1-time single-vessel (n = 19) or multiple-vessel (n = 13) dissections did not differ between each other or compared to healthy controls (n = 12) in protein composition. Patients with recurrent spontaneous cervical artery dissection (n = 6), however, showed significantly different expression of 25 proteins compared to the other groups combined. Literature review and Gene Ontology term annotation check revealed that 13 of the differently expressed proteins play a major role in the structural integrity of connective tissue or are linked to connective tissue disorders. These proteins showed clustering to a collagen/elastin cluster and one consisting of desmosome related proteins.

Conclusion: This study unravels an extracellular matrix protein signature of recurrent spontaneous cervical artery dissection. In the long run and after large-scale validation, our findings may well assist in identifying patients at risk of recurrent spontaneous cervical artery dissection and thus guide therapy.
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http://dx.doi.org/10.1212/WNL.0000000000010710DOI Listing
October 2020

Very preterm birth results in later lower platelet activation markers.

Pediatr Res 2021 04 22;89(5):1278-1282. Epub 2020 Jul 22.

Department of Pediatrics II, Medical University of Innsbruck, Innsbruck, Tyrol, Austria.

Background: Premature birth entails an adverse cardiovascular risk profile, but the underlying mechanisms are insufficiently understood. Here, we employed an unbiased cardiovascular proteomics approach to profile former very preterm-born preschoolers.

Methods: This observational study investigated differences in plasma concentrations of 79 proteins, including putative cardiovascular biomarkers between very preterm- and term-born children on average 5.5 years old (53.1% male) using multiple-reaction monitoring mass spectrometry.

Results: Very preterm-born (n = 38; median gestational age 29.6 weeks) compared to term-born (n = 26; 40.2 weeks) children featured lower plasma concentrations of platelet factor 4 (PLF4; -61.6%, P < 0.0001), platelet basic protein (CXCL7; -57.8%, P < 0.0001), and hemoglobin subunit beta (-48.3%, P < 0.0001). Results remained virtually unchanged when adjusting for complete blood count parameters, including platelet count. Conversely, whole blood hemoglobin was higher (+7.62%, P < 0.0001) in preterm-born children.

Conclusions: Very preterm birth was associated with decreased markers of platelet activation among preschoolers. These findings are consistent with reduced platelet reactivity persisting from very preterm birth to a preschool age.

Impact: Former very preterm-born preschoolers featured reduced levels of platelet activation markers. While lower platelet reactivity in very preterm-born compared to term-born infants in the first days of life was established, it was unknown when, if at all, reactivity normalizes. The current study suggests that platelet hyporeactivity due to very preterm birth persists at least up to a preschool age. "Immaturity of the hemostatic system" may be a persistent sequel of preterm birth, but larger studies are needed to investigate its potential clinical implications.
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http://dx.doi.org/10.1038/s41390-020-1070-8DOI Listing
April 2021

Spermidine intake is associated with cortical thickness and hippocampal volume in older adults.

Neuroimage 2020 11 3;221:117132. Epub 2020 Jul 3.

Department of Neurology, University Medicine Greifswald, Greifswald, Germany; German Center for Neurodegenerative Diseases (DZNE) Standort Greifswald, Greifswald, Germany. Electronic address:

Background: The natural polyamine spermidine, known to be important for cellular function, decreases during aging. Previous research has demonstrated beneficial impact of spermidine intake on memory functions in both animal models and humans, suggesting that spermidine may be a preventive approach to delay age-related cognitive decline and possibly even Alzheimer's disease (AD). However, the association of spermidine intake with brain health in humans is still unknown. In this study, we aimed to determine the association between dietary spermidine intake and structural brain measures in older individuals with subjective cognitive decline (SCD) and healthy controls (HC).

Methods: Dietary spermidine intake and adherence to Mediterranean Diet (MeDi) were assessed by a self-reported food frequency questionnaire in 90 older adults with SCD and 47 HC. Processing of structural MRI data yielded global brain volumes, hippocampal volume, mean and regional cortical thickness, and cortical thickness in a template encompassing AD-vulnerable regions. In exploratory analyses, the association between spermidine intake and structural brain measures was assessed using adjusted and unadjusted linear regression models. Additionally, we tested for differential associations as a function of group. Mediation analyses were performed to examine whether dietary spermidine intake mediates the associations between adherence to MeDi and structural brain measures.

Results: Higher spermidine intake was associated with larger hippocampal volume (standardized β ​= ​0.262, p ​= ​0.002), greater mean cortical thickness (standardized β ​= ​0.187, p ​= ​0.031), and greater cortical thickness in AD-vulnerable brain regions (standardized β ​= ​0.176, p ​= ​0.042), the parietal (standardized β ​= ​0.202, p ​= ​0.020), and temporal lobes (standardized β ​= ​0.217, p ​= ​0.012). No significant differential effect emerged between older adults with SCD and HC. Moreover, a substantial mediating effect of dietary spermidine intake on the associations between adherence to MeDi and structural brain measures was observed.

Conclusion: Higher dietary spermidine intake was positively associated with several structural brain measures, irrespective of the presence of SCD, and substantially mediated the relationship of adherence to MeDi and structural brain measures. Our data suggest that higher spermidine intake might be a promising dietary approach to preserve brain health in older adults, a hypothesis currently tested in an interventional trial.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117132DOI Listing
November 2020

Impact of lifestyle and cardiovascular risk factors on early atherosclerosis in a large cohort of healthy adolescents: The Early Vascular Ageing (EVA)-Tyrol Study.

Atherosclerosis 2020 07 13;305:26-33. Epub 2020 Jun 13.

Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria. Electronic address:

Background And Aims: Atherosclerosis starts early in life. We aimed to assess the dimension and progression of the intima-media thickness, a surrogate marker for early vascular aging, and its association with a broad palette of cardiovascular risk and lifestyle factors in a large cohort of healthy adolescents.

Methods: The EVA-Tyrol cohort study enrolled 1573 adolescents with a mean age of 16.0 years (SD 0.9). 1000 participants had a prospective follow-up after 22.1 months on average (SD 3.4). Cardiovascular risk and lifestyle factors were evaluated by standardized interviews, physical examination, and fasting blood analyses. Carotid intima-media thickness (cIMT) was measured at baseline and follow-up by high-resolution ultrasound. Aortic intima-media thickness (aIMT) was assessed during follow-up only.

Results: Several vascular risk factors like elevated blood pressure (4.7% > 95th percentile), overweight (9.2% > 95th percentile) and smoking (29.7%) were already prevalent at this age. Maximum cIMT progressed by 2.78 μm (95% CI, 0.39-5.17) per year. In multivariable linear regression analysis, sex, body weight, systolic blood pressure, LDL-cholesterol and physical activity were independent predictors of cIMT both at baseline and follow-up. In addition, alanine-aminotransferase, a laboratory surrogate of non-alcoholic fatty liver disease, was independently associated with cIMT at follow-up and pack-years of smoking with aIMT.

Conclusions: Unfavourable lifestyle and vascular risk factors were prevalent in adolescents and several of them were associated with vessel wall thickness, even though effect sizes were modest and cIMT variability was limited. These data suggest adolescence as a prime age range for early vascular prevention.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.05.011DOI Listing
July 2020

Circulating MicroRNA Levels Indicate Platelet and Leukocyte Activation in Endotoxemia Despite Platelet P2Y Inhibition.

Int J Mol Sci 2020 Apr 21;21(8). Epub 2020 Apr 21.

King's British Heart Foundation Centre, King's College London, London SE5 9NU, UK.

There is evidence for the effects of platelet inhibition on innate immune activation. Circulating microRNAs (miRNAs) have been implicated as markers of platelet and leukocyte activation. In the present study, we assessed the effects of P2Y inhibitors on platelet and leukocyte miRNAs during endotoxemia. Healthy volunteers were randomly assigned to receive oral ticagrelor ( = 10), clopidogrel ( = 8) or no drug ( = 8) for one week, followed by an intravenous bolus of 2 ng/kg endotoxin. Serum was collected at baseline, after one week of antiplatelet treatment and 6 and 24 h after endotoxin administration. MiRNAs were screened using LNA-based qPCR, followed by TaqMan-qPCR validation of candidates. Clinical validation was performed in 41 sepsis patients. Platelet-enriched miR-197, miR-223 and miR-223* were decreased in volunteers following antiplatelet therapy. Endotoxin increased platelet miRNAs, whilst the opposite effect was seen for leukocyte-enriched miR-150. Neither of these endotoxin-mediated effects were altered by P2Y inhibitors. Sepsis patients with fatal outcomes ( = 12) had reduced miR-150 levels compared with survivors ( = 29). In conclusion, we show that miR-150 is downregulated in experimental endotoxemia and can predict survival in sepsis but is unaffected by P2Y inhibition. While P2Y inhibition reduces platelet-associated miRNAs in healthy volunteers, it fails to attenuate the response of platelet miRNAs to endotoxemia.
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http://dx.doi.org/10.3390/ijms21082897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215420PMC
April 2020

The haemochromatosis gene Hfe and Kupffer cells control LDL cholesterol homeostasis and impact on atherosclerosis development.

Eur Heart J 2020 10;41(40):3949-3959

Department of Cardiac Surgery, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria.

Aims: Imbalances of iron metabolism have been linked to the development of atherosclerosis. However, subjects with hereditary haemochromatosis have a lower prevalence of cardiovascular disease. The aim of our study was to understand the underlying mechanisms by combining data from genome-wide association study analyses in humans, CRISPR/Cas9 genome editing, and loss-of-function studies in mice.

Methods And Results: Our analysis of the Global Lipids Genetics Consortium (GLGC) dataset revealed that single nucleotide polymorphisms (SNPs) in the haemochromatosis gene HFE associate with reduced low-density lipoprotein cholesterol (LDL-C) in human plasma. The LDL-C lowering effect could be phenocopied in dyslipidaemic ApoE-/- mice lacking Hfe, which translated into reduced atherosclerosis burden. Mechanistically, we identified HFE as a negative regulator of LDL receptor expression in hepatocytes. Moreover, we uncovered liver-resident Kupffer cells (KCs) as central players in cholesterol homeostasis as they were found to acquire and transfer LDL-derived cholesterol to hepatocytes in an Abca1-dependent fashion, which is controlled by iron availability.

Conclusion: Our results disentangle novel regulatory interactions between iron metabolism, KC biology and cholesterol homeostasis which are promising targets for treating dyslipidaemia but also provide a mechanistic explanation for reduced cardiovascular morbidity in subjects with haemochromatosis.
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http://dx.doi.org/10.1093/eurheartj/ehaa140DOI Listing
October 2020

Trajectories of Age-Related Arterial Stiffness in Chinese Men and Women.

J Am Coll Cardiol 2020 03;75(8):870-880

School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre, London, United Kingdom; Department of Cardiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China. Electronic address:

Background: Arterial stiffening is central in the vascular aging process. Traditionally, vascular research has focused on atherosclerotic vascular disease, whereas arterial stiffness has not attracted similar attention.

Objectives: The purpose of this study was to assess lifetime trajectories of arterial stiffening in Chinese populations facing a high burden of cardiovascular disease, with a particular focus on age-sex interactions and potential determinants.

Methods: This large-scale observational study comprised 2 independent cross-sectional population samples and 1 prospective cohort totaling 80,415 healthy subjects with brachial-ankle pulse wave velocity (baPWV) measurements available. Associations with potential risk conditions were analyzed using linear regression, linear random intercepts mixed models, and L1-regularized linear models.

Results: The dynamics of age-dependent arterial stiffening differed in sexes, with stiffer vessel observed in men from adolescence to age 58 years and in women thereafter. The steeper increase in baPWV in women after menopause is partly explained by the fact that vascular risk factors are more strongly associated with arterial stiffness in women than in men. Age and systolic blood pressures were the strongest determinants of baPWV, whereas other vascular and metabolic risk factors, except low-density lipoprotein cholesterol, showed consistent associations of moderate strength.

Conclusions: The significant age-sex interaction in arterial stiffening provides an important clue of explanation for the heightened cardiovascular disease risk in postmenopausal women. Detailed knowledge on lifetime trajectories of arterial stiffening, and its potential risk factors is a prerequisite for the development of new prevention strategies counteracting vascular aging.
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http://dx.doi.org/10.1016/j.jacc.2019.12.039DOI Listing
March 2020

The Tyrolean early vascular ageing-study (EVA-Tyrol): study protocol for a non-randomized controlled trial : Effect of a cardiovascular health promotion program in youth, a prospective cohort study.

BMC Cardiovasc Disord 2020 02 5;20(1):59. Epub 2020 Feb 5.

Department of Pediatrics II, Medical University of Innsbruck, Anichstrasse 35, A-6020, Innsbruck, Austria.

Background: According to the World Health Organization, cardiovascular diseases (CVDs) are the leading non-communicable cause of death. Awareness of the individual risk profile is crucial to implement a healthy lifestyle and prevent CVDs. Multiple studies demonstrated that atherosclerosis, the main cause of CVDs, begins early in life. Therefore, it may be necessary to start prevention programs already in childhood.

Methods: The EVA-Tyrol study is a population-based non-randomized controlled trial that will prospectively enroll 2000 participants from high schools and training companies in North- and East-Tyrol (Austria) and South-Tyrol (Italy). Participants will be assigned to either an intervention (n = 1500) or a control (n = 500) group. Intervention group participants will be enrolled at the 10th school grade (mean age 15-16 years), undergo two examinations within a two-year interval, with follow-up at the 12th grade (mean ages 17-18 years). Control group participants will be enrolled at the 12th grade (mean age 17-18 years). Medical examination will include anthropometric measurements, comprehensive lifestyle and dietary questionnaires, a fasting blood sample, high-resolution ultrasound of the carotid arteries, and measurement of carotid-femoral pulse wave velocity. Active intervention will consist of (1) enhancing knowledge about CVDs, (2) individual medical counseling based on the results of the baseline examination, (3) an online health promotion tool and (4) involvement of participants in planning and implementation of health promotion projects. Effectiveness of the intervention will be assessed by comparing the proportion subjects with ideal health metrics as defined by the American Heart Association between study groups.

Discussion: This study aims to improve cardiovascular health in Tyrolean adolescents by demonstrating the efficacy of a multi-layer health promotion program and may yield novel insights into the prevalence of vascular risk conditions and mechanisms of early vascular pathologies in adolescents.

Trial Registration: EVA-Tyrol has been retrospectively registered at clinicaltrials.gov under NCT03929692 since April 29, 2019.
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http://dx.doi.org/10.1186/s12872-020-01357-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001281PMC
February 2020

The dimension of preventable stroke in a large representative patient cohort.

Neurology 2019 12 31;93(23):e2121-e2132. Epub 2019 Oct 31.

From the Department of Neurology (C.B., T.T., L.M., L.D., R.P., K.W., L.T., L.S., P.W., M.K., J.W., S.K.), Medical University of Innsbruck, Austria; Department of Neurology (K.W.), Inselspital, University Hospital of Bern, Switzerland; Department of Public Health and Primary Care (P.W.), University of Cambridge, UK; and Central Institute for Medical and Chemical Laboratory Diagnosis (A.G.), Medical University of Innsbruck, Austria.

Objective: To analyze the frequency of inadequately treated risk factors in a large representative cohort of patients with acute ischemic stroke or TIA and to estimate the proportion of events potentially avertable by guideline-compliant preventive therapy compared to the status quo.

Methods: A total of 1,730 patients from the Poststroke Disease Management STROKE-CARD trial (NCT02156778) were recruited between 2014 and 2017. We focused on 8 risk conditions amenable to drug therapy and 3 lifestyle risk behaviors and assessed pre-event risk factor control in retrospect.

Results: The proportion of patients with at least 1 inadequately treated risk condition was 79.5% (95% confidence interval [CI] 77.6%-81.4%) and increased to 95.1% (95% CI 94.1%-96.1%) upon consideration of the lifestyle risk behaviors. Risk factor control was worse in patients with recurrent vs first-ever events ( < 0.001), men vs women ( = 0.003), and patients ≤75 vs >75 years of age ( < 0.001). The estimated degree of stroke preventability ranged from 0.4% (95% CI 0.2%-0.6%) to 13.7% (95% CI 12.2%-15.2%) for the individual risk factors. Adequate control of the 5 most relevant risk factors combined (hypertension, hypercholesterolemia, atrial fibrillation, smoking, and overweight) would have averted ≈1 of 2 events or 1 in 4 with a highly conservative computation approach.

Conclusions: Our study confirms the existence of a considerable gap between risk factor control recommended by guidelines and real-world stroke prevention. Our study intends to increase awareness among physicians about stroke preventability and provides a quantitative basis for the emerging discussion on how to best tackle this challenge.
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http://dx.doi.org/10.1212/WNL.0000000000008573DOI Listing
December 2019

Apolipoprotein Profiles in Very Preterm and Term-Born Preschool Children.

J Am Heart Assoc 2019 04;8(8):e011199

1 Pediatrics II (Neonatology) Department of Pediatrics Medical University of Innsbruck Austria.

Background Little is known about plasma apolipoprotein profiles in very preterm-born and term-born preschool children compared with the adult population. This is of particular interest because apolipoprotein composition might contribute to cardiometabolic outcome in later life. Methods and Results Children aged 5 to 7 years born at term or with <32 weeks of gestation were included. Apolipoprotein concentrations were measured in plasma collected after an overnight fast using multiple-reaction monitoring-based mass spectrometry. Twelve apolipoproteins were measured in 26 former term and 38 former very preterm infants. Key findings were confirmed by assessing apolipoprotein levels using antibody-based assays. Comparing children born term and preterm, apolipoprotein A-I, A- IV , C- II , and C- III were significantly higher in the latter group. Term-born children showed plasma levels of apolipoprotein C- II and C- III quantitatively similar to the adult range (Bruneck study). Hierarchical clustering analyses suggested that a higher proportion of apolipoprotein C- III and C- II reside on high-density lipoprotein particles in children than in adults given the marked correlations of apolipoprotein C- III and C- II with high-density lipoprotein cholesterol and apolipoprotein A-I in children but not adults. High-density lipoprotein cholesterol concentrations were similar in children and adults but the pattern of high-density lipoprotein cholesterol-associated apolipoproteins was different (lower apolipoprotein A-I and C-I but higher A- II , A- IV , and M). Conclusions Our study defines apolipoprotein profiles in preschoolers and reports potential effects of prematurity. Further large-scale studies are required to provide evidence whether this apolipoprotein signature of prematurity, including high apolipoprotein C- II and C- III levels, might translate into adverse cardiometabolic outcome in later life.
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http://dx.doi.org/10.1161/JAHA.118.011199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6507182PMC
April 2019

Reply to Gostner and Fuchs.

Am J Clin Nutr 2019 01;109(1):218-219

Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.

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http://dx.doi.org/10.1093/ajcn/nqy222DOI Listing
January 2019

Inhibition of profibrotic microRNA-21 affects platelets and their releasate.

JCI Insight 2018 11 2;3(21). Epub 2018 Nov 2.

King's British Heart Foundation Centre, King's College London, London, United Kingdom.

Fibrosis is a major contributor to organ disease for which no specific therapy is available. MicroRNA-21 (miR-21) has been implicated in the fibrogenetic response, and inhibitors of miR-21 are currently undergoing clinical trials. Here, we explore how miR-21 inhibition may attenuate fibrosis using a proteomics approach. Transfection of miR-21 mimic or inhibitor in murine cardiac fibroblasts revealed limited effects on extracellular matrix (ECM) protein secretion. Similarly, miR-21-null mouse hearts showed an unaltered ECM composition. Thus, we searched for additional explanations as to how miR-21 might regulate fibrosis. In plasma samples from the community-based Bruneck Study, we found a marked correlation of miR-21 levels with several platelet-derived profibrotic factors, including TGF-β1. Pharmacological miR-21 inhibition with an antagomiR reduced the platelet release of TGF-β1 in mice. Mechanistically, Wiskott-Aldrich syndrome protein, a negative regulator of platelet TGF-β1 secretion, was identified as a direct target of miR-21. miR-21-null mice had lower platelet and leukocyte counts compared with littermate controls but higher megakaryocyte numbers in the bone marrow. Thus, to our knowledge this study reports a previously unrecognized effect of miR-21 inhibition on platelets. The effect of antagomiR-21 treatment on platelet TGF-β1 release, in particular, may contribute to the antifibrotic effects of miR-21 inhibitors.
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http://dx.doi.org/10.1172/jci.insight.123335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6238735PMC
November 2018

Higher spermidine intake is linked to lower mortality: a prospective population-based study.

Am J Clin Nutr 2018 08;108(2):371-380

Departments of Neurology, Medical University of Innsbruck, Innsbruck, Austria.

Background: Spermidine administration is linked to increased survival in several animal models.

Objective: The aim of this study was to test the potential association between spermidine content in diet and mortality in humans.

Design: This prospective community-based cohort study included 829 participants aged 45-84 y, 49.9% of whom were male. Diet was assessed by repeated dietitian-administered validated food-frequency questionnaires (2540 assessments) in 1995, 2000, 2005, and 2010. During follow-up between 1995 and 2015, 341 deaths occurred.

Results: All-cause mortality (deaths per 1000 person-years) decreased across thirds of increasing spermidine intake from 40.5 (95% CI: 36.1, 44.7) to 23.7 (95% CI: 20.0, 27.0) and 15.1 (95% CI: 12.6, 17.8), corresponding to an age-, sex- and caloric intake-adjusted 20-y cumulative mortality incidence of 0.48 (95% CI: 0.45, 0.51), 0.41 (95% CI: 0.38, 0.45), and 0.38 (95% CI: 0.34, 0.41), respectively. The age-, sex- and caloric ratio-adjusted HR for all-cause death per 1-SD higher spermidine intake was 0.74 (95% CI: 0.66, 0.83; P < 0.001). Further adjustment for lifestyle factors, established predictors of mortality, and other dietary features yielded an HR of 0.76 (95% CI: 0.67, 0.86; P < 0.001). The association was consistent in subgroups, robust against unmeasured confounding, and independently validated in the Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk (SAPHIR) Study (age-, sex-, and caloric ratio-adjusted HR per 1-SD higher spermidine intake: 0.71; 95% CI: 0.53, 0.95; P = 0.019). The difference in mortality risk between the top and bottom third of spermidine intakes was similar to that associated with a 5.7-y (95% CI: 3.6, 8.1 y) younger age.

Conclusion: Our findings lend epidemiologic support to the concept that nutrition rich in spermidine is linked to increased survival in humans. This trial was registered at www.clinicaltrials.gov as NCT03378843.
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http://dx.doi.org/10.1093/ajcn/nqy102DOI Listing
August 2018

Plasma Proteomics for Epidemiology: Increasing Throughput With Standard-Flow Rates.

Circ Cardiovasc Genet 2017 Dec;10(6)

From the King's British Heart Foundation Centre, King's College London, United Kingdom (X.Y., F.B., E.H., H.H., M.M.); Agilent Technologies Ltd, Cheadle, United Kingdom (R.T.B., A.S.); Biognosys AG, Schlieren, Switzerland (T.G., S.M., L.R.); Department of Neurology, Medical University of Innsbruck, Austria (R.P., J.W., S.K.); School of Medicine, University of California San Diego (S.T., J.L.W.); and Department of Laboratory Medicine, Bruneck Hospital, Italy (P.S.).

Background: Mass spectrometry is selective and sensitive, permitting routine quantification of multiple plasma proteins. However, commonly used nanoflow liquid chromatography (LC) approaches hamper sample throughput, reproducibility, and robustness. For this reason, most publications using plasma proteomics to date are small in study size.

Methods And Results: Here, we tested a standard-flow LC mass spectrometry (MS) method using multiple reaction monitoring for the application to large epidemiological cohorts. We have reduced the LC-MS run time to almost a third of the nanoflow LC-MS approach. On the basis of a comparison of the quantification of 100 plasma proteins in >1500 LC-MS runs, the SD range of the retention time during continuous operation was substantially lower with the standard-flow LC-MS (<0.05 minutes) compared with the nanoflow LC-MS method (0.26-0.44 minutes). In addition, the standard-flow LC method also offered less variation in protein measurements. However, 5× more sample volume was required to achieve similar sensitivity. Two different commercial multiple reaction monitoring kits and an antibody-based multiplexing kit were used to compare the apolipoprotein measurements in a subset of samples. In general, good agreement was observed between the 2 multiple reaction monitoring kits, but some of the multiple reaction monitoring-based measurements differed from antibody-based assays.

Conclusions: The multiplexing capability of LC-MS combined with a standard-flow method increases throughput and reduces the costs of large-scale protein measurements in epidemiological cohorts, but protein rather than peptide standards will be required for defined absolute proteoform quantification.
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http://dx.doi.org/10.1161/CIRCGENETICS.117.001808DOI Listing
December 2017

What Characterizes Depression in Old Age? Results from the Bruneck Study.

Pharmacopsychiatry 2018 Jul 26;51(4):153-160. Epub 2017 Sep 26.

Department of Psychiatry and Psychotherapy A, Landeskrankenhaus Hall, Austria.

Introduction: Depression in old age is associated with functional disabilities, cognitive impairment, lower self-rated quality of life, and increased mortality. The aim of the study was to reveal the prevalence of depression and to investigate the characteristics of patients treated with antidepressants.

Methods: We analyzed data from the Bruneck Study 2010. All participants completed a clinical examination, cognitive screening, the 30-item Geriatric Depression Scale (GDS) (cutoff score of>8 to define relevant depressive symptoms), and the World Health Organization quality of life questionnaire (WHO-QoL). Group differences were calculated using binary logistic regression analysis.

Results: Out of 456 participants (mean age of 73.1±8.2 years), 22.1% showed depressive symptoms, and out of these, 30% were taking antidepressants. The depressed group compared to the GDS ≤8 group showed significantly lower WHO-QoL (p<0.001) and Mini Mental State Examination (p=0.015) score. Further, 13% of the latter compared to the GDS>8 group received antidepressants, and these had a lower WHO-QoL score (p<0.033).

Discussion: Depressive symptoms are frequent in the elderly population. Our results confirm the negative influence of depressive symptoms on cognition and quality of life. Patients with somatic comorbidities are likely to receive more antidepressant medication.
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http://dx.doi.org/10.1055/s-0043-119417DOI Listing
July 2018

Association Between Vascular Cell Adhesion Molecule 1 and Atrial Fibrillation.

JAMA Cardiol 2017 05;2(5):516-523

Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.

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 in 1990. 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.
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http://dx.doi.org/10.1001/jamacardio.2017.0064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814989PMC
May 2017

Very-Low-Density Lipoprotein-Associated Apolipoproteins Predict Cardiovascular Events and Are Lowered by Inhibition of APOC-III.

J Am Coll Cardiol 2017 Feb;69(7):789-800

King's British Heart Foundation Centre, King's College London, London, United Kingdom. Electronic address:

Background: Routine apolipoprotein (apo) measurements for cardiovascular disease (CVD) are restricted to apoA-I and apoB. Here, the authors measured an unprecedented range of apolipoproteins in a prospective, population-based study and relate their plasma levels to risk of CVD.

Objectives: This study sought to measure apolipoproteins directly by mass spectrometry and compare their associations with incident CVD and to obtain a system-level understanding of the correlations of apolipoproteins with the plasma lipidome and proteome.

Methods: Associations of 13 apolipoproteins, 135 lipid species, and 211 other plasma proteins with incident CVD (91 events), defined as stroke, myocardial infarction, or sudden cardiac death, were assessed prospectively over a 10-year period in the Bruneck Study (N = 688) using multiple-reaction monitoring mass spectrometry. Changes in apolipoprotein and lipid levels following treatment with volanesorsen, a second-generation antisense drug targeting apoC-III, were determined in 2 human intervention trials, one of which was randomized.

Results: The apolipoproteins most significantly associated with incident CVD were apoC-II (hazard ratio per 1 SD [HR/SD]: 1.40; 95% confidence interval [CI]: 1.17 to 1.67), apoC-III (HR/SD: 1.38; 95% CI: 1.17 to 1.63), and apoE (HR/SD: 1.31; 95% CI: 1.13 to 1.52). Associations were independent of high-density lipoprotein (HDL) and non-HDL cholesterol, and extended to stroke and myocardial infarction. Lipidomic and proteomic profiles implicated these 3 very-low-density lipoprotein (VLDL)-associated apolipoproteins in de novo lipogenesis, glucose metabolism, complement activation, blood coagulation, and inflammation. Notably, apoC-II/apoC-III/apoE correlated with a pattern of lipid species previously linked to CVD risk. ApoC-III inhibition by volanesorsen reduced plasma levels of apoC-II, apoC-III, triacylglycerols, and diacylglycerols, and increased apoA-I, apoA-II, and apoM (all p < 0.05 vs. placebo) without affecting apoB-100 (p = 0.73).

Conclusions: The strong associations of VLDL-associated apolipoproteins with incident CVD in the general community support the concept of targeting triacylglycerol-rich lipoproteins to reduce risk of CVD.
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http://dx.doi.org/10.1016/j.jacc.2016.11.065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5314136PMC
February 2017

Cardioprotection and lifespan extension by the natural polyamine spermidine.

Nat Med 2016 12 14;22(12):1428-1438. Epub 2016 Nov 14.

Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany.

Aging is associated with an increased risk of cardiovascular disease and death. Here we show that oral supplementation of the natural polyamine spermidine extends the lifespan of mice and exerts cardioprotective effects, reducing cardiac hypertrophy and preserving diastolic function in old mice. Spermidine feeding enhanced cardiac autophagy, mitophagy and mitochondrial respiration, and it also improved the mechano-elastical properties of cardiomyocytes in vivo, coinciding with increased titin phosphorylation and suppressed subclinical inflammation. Spermidine feeding failed to provide cardioprotection in mice that lack the autophagy-related protein Atg5 in cardiomyocytes. In Dahl salt-sensitive rats that were fed a high-salt diet, a model for hypertension-induced congestive heart failure, spermidine feeding reduced systemic blood pressure, increased titin phosphorylation and prevented cardiac hypertrophy and a decline in diastolic function, thus delaying the progression to heart failure. In humans, high levels of dietary spermidine, as assessed from food questionnaires, correlated with reduced blood pressure and a lower incidence of cardiovascular disease. Our results suggest a new and feasible strategy for protection against cardiovascular disease.
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http://dx.doi.org/10.1038/nm.4222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5806691PMC
December 2016

Potential and Caveats of Lipidomics for Cardiovascular Disease.

Circulation 2016 11 18;134(21):1651-1654. Epub 2016 Oct 18.

From Department of Neurology, Medical University of Innsbruck, Austria (R.P., S.K.); and King's British Heart Foundation Centre, King's College London, United Kingdom (M.M.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.116.025092DOI Listing
November 2016

Caveats of Untargeted Metabolomics for Biomarker Discovery.

J Am Coll Cardiol 2016 09;68(12):1294-6

King's British Heart Foundation Centre, King's College London, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.jacc.2016.05.098DOI Listing
September 2016

Optimizing odor identification testing as quick and accurate diagnostic tool for Parkinson's disease.

Mov Disord 2016 09 9;31(9):1408-13. Epub 2016 May 9.

Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.

Introduction: The aim of this study was to evaluate odor identification testing as a quick, cheap, and reliable tool to identify PD.

Methods: Odor identification with the 16-item Sniffin' Sticks test (SS-16) was assessed in a total of 646 PD patients and 606 controls from three European centers (A, B, and C), as well as 75 patients with atypical parkinsonism or essential tremor and in a prospective cohort of 24 patients with idiopathic rapid eye movement sleep behavior disorder (center A). Reduced odor sets most discriminative for PD were determined in a discovery cohort derived from a random split of PD patients and controls from center A using L1-regularized logistic regression. Diagnostic accuracy was assessed in the rest of the patients/controls as validation cohorts.

Results: Olfactory performance was lower in PD patients compared with controls and non-PD patients in all cohorts (each P < 0.001). Both the full SS-16 and a subscore of the top eight discriminating odors (SS-8) were associated with an excellent discrimination of PD from controls (areas under the curve ≥0.90; sensitivities ≥83.3%; specificities ≥82.0%) and from non-PD patients (areas under the curve ≥0.91; sensitivities ≥84.1%; specificities ≥84.0%) in all cohorts. This remained unchanged when patients with >3 years of disease duration were excluded from analysis. All 8 incident PD cases among patients with idiopathic rapid eye movement sleep behavior disorder were predicted with the SS-16 and the SS-8 (sensitivity, 100%; positive predictive value, 61.5%).

Conclusions: Odor identification testing provides excellent diagnostic accuracy in the distinction of PD patients from controls and diagnostic mimics. A reduced set of eight odors could be used as a quick tool in the workup of patients presenting with parkinsonism and for PD risk indication. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5026160PMC
http://dx.doi.org/10.1002/mds.26637DOI Listing
September 2016

Association of MicroRNAs and YRNAs With Platelet Function.

Circ Res 2016 Feb 8;118(3):420-432. Epub 2015 Dec 8.

King's British Heart Foundation Centre, King's College London, UK.

Rationale: Platelets shed microRNAs (miRNAs). Plasma miRNAs change on platelet inhibition. It is unclear whether plasma miRNA levels correlate with platelet function.

Objective: To link small RNAs to platelet reactivity.

Methods And Results: Next-generation sequencing of small RNAs in plasma revealed 2 peaks at 22 to 23 and 32 to 33 nucleotides corresponding to miRNAs and YRNAs, respectively. Among YRNAs, predominantly, fragments of RNY4 and RNY5 were detected. Plasma miRNAs and YRNAs were measured in 125 patients with a history of acute coronary syndrome who had undergone detailed assessment of platelet function 30 days after the acute event. Using quantitative real-time polymerase chain reactions, 92 miRNAs were assessed in patients with acute coronary syndrome on different antiplatelet therapies. Key platelet-related miRNAs and YRNAs were correlated with platelet function tests. MiR-223 (rp=0.28; n=121; P=0.002), miR-126 (rp=0.22; n=121; P=0.016), and other abundant platelet miRNAs and YRNAs showed significant positive correlations with the vasodilator-stimulated phosphoprotein phosphorylation assay. YRNAs, miR-126, and miR-223 were also among the small RNAs showing the greatest dependency on platelets and strongly correlated with plasma levels of P-selectin, platelet factor 4, and platelet basic protein in the population-based Bruneck study (n=669). A single-nucleotide polymorphism that facilitates processing of pri-miR-126 to mature miR-126 accounted for a rise in circulating platelet activation markers. Inhibition of miR-126 in mice reduced platelet aggregation. MiR-126 directly and indirectly affects ADAM9 and P2Y12 receptor expression.

Conclusions: Levels of platelet-related plasma miRNAs and YRNAs correlate with platelet function tests in patients with acute coronary syndrome and platelet activation markers in the general population. Alterations in miR-126 affect platelet reactivity.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5065093PMC
http://dx.doi.org/10.1161/CIRCRESAHA.114.305663DOI Listing
February 2016

Inadequate hepcidin serum concentrations predict incident type 2 diabetes mellitus.

Diabetes Metab Res Rev 2016 Feb 29;32(2):187-92. Epub 2015 Oct 29.

Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.

Background: Type 2 diabetes mellitus (T2DM) is closely associated with elevated body iron stores. The hormone hepcidin is the key regulator of iron homeostasis. Inadequately low hepcidin levels were recently reported in subjects with manifest T2DM. We investigated whether alterations of hepcidin levels precede the manifestation of T2DM and predict T2DM development independently of established risk conditions.

Methods: This prospective population-based study included 675 subjects aged 50-89 years, 51.9% of whom were female. Hepcidin levels were measured by gold standard tandem mass spectrometry. Diabetes was diagnosed according to American Diabetes Association criteria, and incident diabetes was recorded between baseline in 2000 and 2010.

Results: The baseline hepcidin-to-ferritin ratio in subjects that subsequently developed diabetes during follow-up was reduced on average by 29.8% as compared with subjects with normal glucose tolerance (95% confidence interval, -50.7% to -0.2%; p = 0.049). After adjustment for age, sex, and serum ferritin, higher hepcidin levels were associated with reduced risk of incident diabetes (hazard ratio per 1-unit higher log2 hepcidin, 0.80; 95% confidence interval, 0.64-0.98; p = 0.035; 33 events). Additional adjustment for established diabetes risk factors and determinants of hepcidin concentration did not appreciably change these results (HR, 0.81; 95% CI, 0.66-0.99). Likewise, inadequately low hepcidin levels were also detected in subjects with prevalent T2DM (n = 76).

Conclusions: Hepcidin levels that are inadequately low in relation to body iron stores are an independent predictor for incident T2DM and may contribute to diabetes-related tissue iron overload. Copyright © 2015 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/dmrr.2711DOI Listing
February 2016

Correlates of serum hepcidin levels and its association with cardiovascular disease in an elderly general population.

Clin Chem Lab Med 2016 Jan;54(1):151-61

Background: The expression of the key iron regulatory hormone hepcidin is regulated by iron availability, inflammation, hormones, hypoxia, and anaemia. Increased serum concentrations of hepcidin have recently been linked to atherosclerosis. We studied demographic, haematologic, biochemical, and dietary correlates of serum hepcidin levels and its associations with incident cardiovascular disease and with carotid atherosclerosis.

Methods: Serum hepcidin concentrations were measured by tandem mass spectrometry in samples taken in 2000 from 675 infection-free participants of the prospective population-based Bruneck study (age, mean±standard deviation, 66.0±10.2; 48.1% male). Blood parameters were measured by standard methods. Dietary intakes of iron and alcohol were surveyed with a food frequency questionnaire. Carotid atherosclerosis (365 cases) was assessed by ultrasound and subjects were observed for incident stroke, myocardial infarction, or sudden cardiac death (91 events) until 2010.

Results: Median (interquartile range) hepcidin levels were 2.27 nM (0.86, 4.15). Most hepcidin correlates were in line with hepcidin as an indicator of iron stores. Independently of ferritin, hepcidin was related directly to physical activity (p=0.024) and fibrinogen (p<0.0001), and inversely to alcohol intake (p=0.006), haemoglobin (p=0.027), and γ-glutamyltransferase (p<0.0001). Hepcidin and hepcidin-to-ferritin ratio were not associated with prevalent carotid atherosclerosis (p=0.43 and p=0.79) or with incident cardiovascular disease (p=0.62 and p=0.33).

Conclusions: In this random sample of the general community, fibrinogen and γ-glutamyltransferase were the most significant hepcidin correlates independent of iron stores, and hepcidin was related to neither atherosclerosis nor cardiovascular disease.
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http://dx.doi.org/10.1515/cclm-2015-0068DOI Listing
January 2016

Thrombolysis and clinical outcome in patients with stroke after implementation of the Tyrol Stroke Pathway: a retrospective observational study.

Lancet Neurol 2015 Jan 28;14(1):48-56. Epub 2014 Nov 28.

Department of Internal Medicine, Schwaz County Hospital, Schwaz, Austria.

Background: Intravenous thrombolysis for ischaemic stroke remains underused worldwide. We aimed to assess whether our statewide comprehensive stroke management programme would improve thrombolysis use and clinical outcome in patients.

Methods: In 2008-09, we designed the Tyrol Stroke Pathway, which provided information campaigns for the public and standardised the entire treatment pathway from stroke onset to outpatient rehabilitation. It was commenced in Tyrol, Austria, as a long-term routine-care programme and aimed to include all patients with stroke in the survey area. We focused on thrombolysis use and outcome in the first full 4 years of implementation (2010-13).

Findings: We enrolled 4947 (99%) of 4992 patients with ischaemic stroke who were admitted to hospitals in Tyrol; 675 (14%) of the enrollees were treated with alteplase. Thrombolysis administration in Tyrol increased after programme implementation, from 160 of 1238 patients (12·9%, 95% CI 11·1-14·9) in 2010 to 213 of 1266 patients (16·8%, 14·8-19·0) in 2013 (ptrend 2010-13<0·0001). Differences in use of thrombolysis in the nine counties of Tyrol in 2010 (range, 2·2-22·6%) were reduced by 2013 (12·1-22·5%). Median statewide door-to-needle time decreased from 49 min (IQR 35-60) in 2010 to 44 min (29-60) in 2013; symptomatic post-thrombolysis intracerebral haemorrhages occurred in 28 of 675 patients (4·1%, 95% CI 2·8-5·9) during 2010-13. In four Austrian states without similar stroke programmes, thrombolysis administration remained stable or declined between 2010 and 2013 (mean reduction 14·4%, 95% CI 10·9-17·9). Although the 3-month mortality was not affected by our programme (137 [13%] of 1060 patients in 2010 vs 143 [13%] of 1069 patients in 2013), 3-month functional outcome significantly improved (modified Rankin Scale score 0-1 in 375 [40%] of 944 patients in 2010 vs 493 [53%] of 939 in 2013; score 0-2 in 531 [56%] patients in 2010 and 615 [65%] in 2013; ptrend 2010-13<0·0001).

Interpretation: During the period of implementation of our comprehensive stroke management programme, thrombolysis administration increased and clinical outcome significantly improved, although mortality did not change. We hope that these results will guide health authorities and stroke physicians elsewhere when implementing similar programmes for patients with stroke.

Funding: Reformpool of the Tyrolean Health Care Fund.
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http://dx.doi.org/10.1016/S1474-4422(14)70286-8DOI Listing
January 2015
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