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The "RedOmen-Project”: Molecular Mechanisms of Alpha-Linolenic Acid (ALA) in Platelets and Translational Applications in Models of Stroke and Thromboembolism

English title The "RedOmen-Project”: Molecular Mechanisms of Alpha-Linolenic Acid (ALA) in Platelets and Translational Applications in Models of Stroke and Thromboembolism
Applicant Beer Hans-Jürg
Number 163339
Funding scheme Project funding (special)
Research institution Departement Innere Medizin Kantonsspital Baden
Institution of higher education Kantonsspital Baden - KSPB
Main discipline Clinical Cardiovascular Research
Start/End 01.10.2015 - 30.09.2018
Approved amount 555'380.00
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All Disciplines (2)

Discipline
Clinical Cardiovascular Research
Internal Medicine

Keywords (4)

Platelets; Thromboembolism; Alpha-linolenic acid (ALA); Omega 3

Lay Summary (German)

Lead
Alpha-Linolensäure (ALA) ist eine aus Pflanzen stammende Omega-3-Fettsäure (n3-FA), bei welcher wir antithrombotische, antiatherosklerotische und plättchenaggregationshemmende Wirkung zeigen konnten. Dieses Projekt untersucht die kardioprotektiven Eigenschaften von ALA in drei pathologischen Settings, wie Venenthrombose bei älteren Menschen, Herzrhythmusstörungen und Sichelzellenanämie, wobei ein Schwerpunkt insbesondere bei der Thrombozytenfunktion liegt.
Lay summary

Inhalt und Ziele des Forschungsprojekts

Die potentielle therapeutische Verwendung von n3-FA (insbesondere ALA) bei Sichelzellanämie und die langfristigen Auswirkungen von n3-FA aus der Nahrung in Bezug auf Mortalität und kardiovaskulären Erkrankungen wurden noch nicht untersucht oder es ergaben sich widersprüchliche Ergebnisse. Das Ziel dieses Projektes ist daher dessen Untersuchung in einem Mausmodell der Sichelzellenkrankheit, und seine Korrelation zwischen Blut-n3-FA-Konzentrationen und kardiovaskulären Ereignissen, Mortalität und Herzrhythmusstörungen / Vorhofflimmern.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Das Projekt wird unser Verständnis der grundlegenden molekularen Mechanismen von ALA verbessern, wobei der Schwerpunkt auf der Sichelzellenkrankheit und dem vorteilhaften Zusammenhang von höherem Vollblut-Gehalt an n-3 FA und relevanten klinischen Ereignissen liegt. Unsere Daten könnten die Basis für Ernährungsempfehlungen liefern, und, angesichts der dramatischen Reduktion von Fischbeständen, zur Substitution von Fisch mit pflanzlichem ALA führen.

Direct link to Lay Summary Last update: 05.01.2016

Lay Summary (English)

Lead
Alpha-linolenic acid is a plant-derived omega-3 fatty acid, which we have shown to have anti-thrombotic, anti-atherosclerotic and anti-platelet effects. This project investigates the cardio-protective properties of ALA in three pathological settings: venous thrombosis in the elderly, heart arrhythmia / atrial fibrillation and sickle cell disease.
Lay summary

Content and Aim of the Research Project

Long-chain omega-3 fatty acids (n3-FA) of marine origin have been recognized as cardioprotective since the 60s and recent work has emphasized similar properties also for the plant-derived alpha-linolenic acid (ALA). The potential therapeutic use of n3-FA (ALA in particular) in sickle cell disease and the long-term effects of dietary n3-FA in mortality and cardiovascular disease have not been investigated or gave contradictory results. Therefore, our project aims at investigating the potential therapeutic properties of dietary ALA in a mouse model of sickle cell disease, and the correlation between blood n3-FA concentrations and cardiovascular events, mortality and heart arrhythmias/atrial fibrillation.

Scientific and Social Context of the Research Project

The project will increase our understanding of the basic molecular mechanism of ALA, with a focus on sickle cell disease, and the beneficial association of higher whole blood content of n-3 FA with relevant clinical outcome. Our data could set the basis for nutritional recommendations, and, given the dramatic limitation of fishery resources, for the substitution of the fish intake by plant-derived ALA.

Direct link to Lay Summary Last update: 05.01.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Anticoagulation Management Practices and Outcomes in Elderly Patients with Acute Venous Thromboembolism: A Clinical Research Study.
C Insam, M Méan, A Limacher, A Angelillo-Scherrer, M Aschwanden, M Banyai, JH Beer, H Bounameaux, M Egloff, B Frauchiger, M Husmann, N Kucher, D Aujesky (2016), Anticoagulation Management Practices and Outcomes in Elderly Patients with Acute Venous Thromboembolism: A Clinical Research Study., in PLoS ONE, 11(2), e0148348.
Association between thyroid dysfunction and venous thromboembolism in the elderly: a prospective cohort study.
D Segna, M Méan, A Limacher, C Baumgartner, MR Blum, JH Beer, N Kucher, M Righini, CM Matter, B Frauchiger, J Cornuz, M Aschwanden, M Banyai, N Rodondi (2016), Association between thyroid dysfunction and venous thromboembolism in the elderly: a prospective cohort study., in Journal of thrombosis and haemostasis : JTH, 14(4), 685-694.

Collaboration

Group / person Country
Types of collaboration
University Hospital Basel, Dr. A. Buser Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
ETH Zurich, Prof. J. Klohs and Prof. Rudin Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
University Hospital of Zurich, Dr. J. Goede Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Brigham and Women's Hospital Boston, Prof. K. Hoffmeister United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Harvard Medical School, Prof. D. Wagner United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Center for Molecular Cardiology, Prof T. Lüscher and PD G. Camici Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
University of Munich, Prof. C. von Schacky Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
University of Zurich, Prof. O. Medalia Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Fortbildung am Kantonsspital Baselland Talk given at a conference Update Antikoagulation - was, wie lange? 27.09.2018 Liestal, Switzerland Beer Hans-Jürg;
Annual Meeting of the European Society of Cardiology (ESC) Poster Rheumatoid arthritis and stroke - study of the role of chronic inflammation in ischemia/reperfusion brain injury 25.08.2018 München, Germany Pasterk Lisa; Beer Hans-Jürg;
Annual Meeting of the European Society of Cardiology (ESC) Poster Age-dependent change in platelet function and outcome after stroke: Is there a pathogenic link? 25.08.2018 München, Germany Beer Hans-Jürg; Gobbato Sara; Stivala Simona; Pasterk Lisa;
32. Mediweek Davos Talk given at a conference Cholesterin: Wie tief? 05.07.2018 Davos, Switzerland Beer Hans-Jürg;
Jahresversammlung der Schweiz. Gesellschaft für Kardiologie (SGK) Talk given at a conference Age-dependent platelet changes and their putative role for stroke in a mouse model of aging 06.06.2018 Basel, Switzerland Gobbato Sara; Stivala Simona; Beer Hans-Jürg; Pasterk Lisa;
Jahresversammlung der Schweiz. Gesellschaft für Allgemeine Innere Medizin (SGAIM) Poster A dual antiplatelet (AP) and anticoagulant (AC) compound - APAC- inhibits collagen-induced platelet aggregation in miche and protects against arterial thrombosis 30.05.2018 Basel, Switzerland Gobbato Sara; Stivala Simona; Pasterk Lisa; Beer Hans-Jürg;
6. Interdisziplinärer Hämostaseologischer Intensivworkshop für OP und Intensivstation Talk given at a conference "Bridging“ im perioperativen Setting – pro und contra 20.04.2018 St. Gallen, Switzerland Beer Hans-Jürg;
16. Zürcher Review Kurs in Kardiologischer Kardiologie Talk given at a conference Thrombophilia in Cardiology 12.04.2018 Zürich, Switzerland Beer Hans-Jürg;
24. Diagnostik-Symposium Talk given at a conference Blutungs- und Thromboembolie-Risiko 08.03.2018 Schaan, Liechtenstein Beer Hans-Jürg;
LS2 Annual Meeting Talk given at a conference Age-dependent chage in platelet function and outcome arter stroke: Is there a pathogenic link? 12.02.2018 Lausanne, Switzerland Gobbato Sara; Beer Hans-Jürg; Pasterk Lisa; Stivala Simona;
22. Zürcher Herzkreislauftag Talk given at a conference Risiko-Scores praktisch 30.11.2017 Zürich, Switzerland Beer Hans-Jürg;
KLIFO 2017 Talk given at a conference Choosing Wisely – Moderne Antikoagulation 07.09.2017 Bruderholz, Switzerland Beer Hans-Jürg;
Annual Meeting of the European Socieety of Cardiology (ESC) Poster Rheumatoid arthritis and stroke: study of the role of chronic immflammation in ischemia reperfusion brain injury. 26.08.2017 Barcelona, Spain Beer Hans-Jürg; Stivala Simona;
Annual Meeting of the European Society of Cardiology (ESC) Poster Trimethylamine-N-oxide (TMAO) predicts mortality, but not recurrent venous thromboembolism in elderly patients with acute venous thromboembolism 26.08.2017 Barcelona, Spain Stivala Simona; Beer Hans-Jürg;
Annual Meeting of the International Society of Thrombosis and Hemostasis (ISTH) Poster A dual antiplatelet (AP) and anticoagulant (AC) compound - APAC- inhibits collagen-induced platelet aggregation in mice and protects arterial thrombosis 08.07.2017 Berlin, Germany Gobbato Sara; Stivala Simona; Beer Hans-Jürg;
Annual Meeting of the International Society of Thrombosis and Hemostasis (ISTH) Poster Dietary alpha-linolenic acid reduces platelet activation and ex vivo thrombus formation in sickle cell disease mice 08.07.2017 Berlin, Germany Stivala Simona; Gobbato Sara; Beer Hans-Jürg;
SSO- Kongress 2017: Zahnmedizin als integrativer Teil der Humanmedizin Talk given at a conference Der antikoagulierte Patient in der Zahnarztpraxis 09.06.2017 Fribourg, Switzerland Beer Hans-Jürg;
SGK 2017 Talk given at a conference Anticoagulation - News from Guidelines 09.06.2017 Baden, Switzerland Beer Hans-Jürg;
Jahresversammlung der Schweiz. Gesellschaft für Kardiologie Talk given at a conference Whole blood-omega-3 fatty acid concentrations are associated with lower blood pressure in young, healthy adults 07.06.2017 Baden, Switzerland Gobbato Sara; Stivala Simona; Beer Hans-Jürg;
Jahresversammlung der Schweiz. Gesellschaft für Kardiologie (SGK) Talk given at a conference Trimethylamine-N-oxide (TMAO) predicts mortality, but not recurrent venous thromboembolism 07.06.2017 Baden, Switzerland Stivala Simona; Gobbato Sara; Beer Hans-Jürg;
Jahresversammlung der Schweiz. Gesellschaft für Allgemeine Innere Medizin (SGAIM) Talk given at a conference Mice generated by in vitro fertilization show a reduced platelet count accompanied by a heightend response to thrombin 03.05.2017 Lausanne, Switzerland Gobbato Sara; Stivala Simona; Beer Hans-Jürg;
Jahresversammlung der Schweiz. Gesellschaft für Allgemeine Innere Medizin (SGAIM) Talk given at a conference A model of platelets in the aging organism reveals increased numbers eand enhanced activatability, possibly mediating a larger stroke burden 03.05.2017 Lausanne, Switzerland Gobbato Sara; Beer Hans-Jürg; Stivala Simona;
GTH 2017 - 61. Annual Meeting of the Society of Thrombosis and Hemostasis Research Talk given at a conference Effects of omega-3 alpha-linolenic acid on platelets and endothelial cells 15.02.2017 Basel, Switzerland Beer Hans-Jürg;
Cardiovascular and Metabolic Research Meeting Talk given at a conference A model of platelets in the aging organism reveals increased numbers due to reduced clearance and enhanced activatability of Gp2b/3a and P-selectin, resulting in larger stroke burden 19.01.2017 Fribourg, Switzerland Beer Hans-Jürg; Gobbato Sara; Stivala Simona;
21. St. Galler IPS Symposium Talk given at a conference Intensive Care Platelet Syndrome 10.01.2017 St. Gallen, Switzerland Beer Hans-Jürg;
Annual Meeting of the American Society of Hematology (ASH) Poster High shear induced platelet rolling velocity and adhesion onto van Willebrand factor are mediated by GpIb alpha clustering as demonstrated by FRET/FLIM and can be inhibited by alpha linolenic acid 03.12.2016 San Diego, United States of America Beer Hans-Jürg; Gobbato Sara; Stivala Simona;
Annual Meeting of the American Society of Hematology (ASH) Poster A model of platelets in the aging organism reveals increased numbers due to reduced clearance and enhanced activitability of GPIIb/IIIa and P-selectin, resulting in a larger stroke burden. 03.12.2016 San Diego, United States of America Beer Hans-Jürg; Stivala Simona; Gobbato Sara;
Annual Meeting of the American Society of Hematology (ASH) Poster The omega-3 index is inversely associated with blood pressure in large cohort of young healthy adults 12.11.2016 Louisiana, United States of America Beer Hans-Jürg; Gobbato Sara; Stivala Simona;
17. Unionstagung der Schweiz. Gesellschaften für Gefässkrankheiten Talk given at a conference Optimum vs Maximum –or How Long to Anticoagulate? 05.10.2016 Basel, Switzerland Beer Hans-Jürg;
What are the risks of discontinuing medications? Talk given at a conference SGG Kongress – Session: GI Bleeding and risks 22.09.2016 Interlaken, Switzerland Beer Hans-Jürg;
2. Schweizer Herztag Talk given at a conference New and Old Platelet Inhibitors in Secondary Prevention: Update and Guidelines 10.09.2016 Zürich, Switzerland Beer Hans-Jürg;
Kongress der International Society for the Study of Fatty Acids and Lipids (ISSFAL) Talk given at a conference Whole blood omega-3 fatty acid content predicts recurrent venous thromboembolism and death in elderly patients with acute venous thromboembolism 05.09.2016 Stellenbosch, South Africa Beer Hans-Jürg; Stivala Simona;
Jahresversammlung der Schweiz. Gesellschaft für Kardiologie (SGK) Poster A model of platelets in the aging: Increased platelet counts and - activation are associated with reduced clearance. 15.06.2016 Ecublens, Switzerland Stivala Simona; Beer Hans-Jürg;
Jahresversammlung der Schweiz. Gesellschaft für Allgemeine Innere Medizin (SGAIM) Talk given at a conference N3 fatty acid as a treatment approach in a mouse model of sickle cell disease is partly mediated by the inhibition of P-selectin expression on platelets. 25.05.2016 Basel, Switzerland Beer Hans-Jürg; Gobbato Sara; Stivala Simona;
Jahresversammlung der Schweiz. Gesellschaft für Allgemeine Innere Medizin (SGAIM) Talk given at a conference Ticagrelor, but not Clopidogrel, reduces arterial thrombosis via endothelial tissue factor suppression 25.05.2016 Basel, Switzerland Stivala Simona; Beer Hans-Jürg;
Zurich Heart House Expert Course in Preventive Cardiology Talk given at a conference From Dietary Measures to Statins 21.04.2016 Zürich, Switzerland Beer Hans-Jürg;
Aarauer Gefässtage, Thema “Reisethrombose” Talk given at a conference Reisen und Thromboembolie-Prophylaxe 08.04.2016 Aarau, Switzerland Beer Hans-Jürg;
Cardiovascular and Metabolic Research Meeting Talk given at a conference Dietary alpha-linolenic acid reduces platelet activation and ex vivo thrombus formation in sickle cell disease 14.01.2016 Fribourg, Switzerland Beer Hans-Jürg; Gobbato Sara; Stivala Simona;
55. Ärztefortbildungskurs Davos Talk given at a conference Praktische Top Ten der NOACs 08.01.2016 Davos, Switzerland Beer Hans-Jürg;
20. Zürcher Herzkreislauftag-Jahresrückblick rund ums Herz: Neues für Praxis und Klinik Talk given at a conference Lungenembolie: Erkennen und ambulant behandeln 03.12.2015 Zürich, Switzerland Beer Hans-Jürg;
1. Schweizer Herztag Talk given at a conference Neue Antikoagulantien 07.11.2015 Zürich, Switzerland Beer Hans-Jürg;
Hausärzte-FB Münsigen Individual talk Perioperatives ambulantes resp. stationäres Gerinnungsmanagement bei Antikoagulation 03.11.2015 Spital Münsingen, Switzerland Beer Hans-Jürg;
Diagnostisch Therapeutisches Seminar, Inselspital Bern Talk given at a conference News and Red Flags bei NOAC’s 15.10.2015 Bern, Switzerland Beer Hans-Jürg;


Associated projects

Number Title Start Funding scheme
182328 “RedOmen II”: New Strategies to Reverse Plt Activation in the Aging (The NESTOR Project) 01.10.2018 Project funding (special)
139470 The Swiss Venous Thromboembolism Cohort 65+ (SWITCO-65+) 01.04.2012 Cohort Studies Large
144152 The Alpine Paradox Research Project. Mechanisms of Alpha-Linolenic Acid (ALA) in Platelet Kinetics and Thrombosis 01.11.2012 Project funding (Div. I-III)
144152 The Alpine Paradox Research Project. Mechanisms of Alpha-Linolenic Acid (ALA) in Platelet Kinetics and Thrombosis 01.11.2012 Project funding (Div. I-III)

Abstract

a) Short AbstractWe have shown previously that the plant-derived n-3 fatty acid alpha-linolenic acid (ALA) has antiatherosclerotic, anti-inflammatory, and antiplatelet effects, that it inhibits arterial (but not venous) thrombosis in the mouse model and that it increases platelet counts by reducing their clearance.In the present grant we propose to study the underlying basic platelet membrane mechanisms, including the receptor GPIbalpha clustering and its interference with ALA. Second, we plan the in vivo prophylactic application of ALA in the sickle cell disease mouse model of vaso-occlusion and silent and manifest stroke, because all the above mentioned mechanisms are operative in SCD. Third, 2 translational, human registries will open up the possibility to correlate inversely whole blood ALA/n-3 content with thromboembolism, cardiovascular disease and death.Relevance: To understand the basic mechanisms of ALA in the platelet membrane, to demonstrate their relevance in the in vivo models and to show their prognostic value and their potential clinical applicability in human registries.b) Extended AbstractBackground: In our previous grant, we have focused on the role of omega-3 fatty acids, in particular on alpha-linolenic acid (ALA) in alpine dairy products (i.e. “The Alpine Paradox"). We have demonstrated relevant antiplatelet, antithrombotic, antiinflammatory effects of ALA, and, in its combined form, antiatherosclerotic properties in vitro and in vivo in typical mouse models. We have published on its relevance in platelet survival and thrombosis.The molecular mechanisms of ALA and n-3 FA are still incompletely understood and the value of clinical n-3 supplementation in man is more than ever subject of ongoing controversies.The general aims of the current grant are threefold: a) to characterize the beneficial molecular mechanisms of ALA in platelets, b) to test the effects of ALA- treatment interventions in typical, established mouse models of vascular disease (stroke, sickle cell disease), and c) to evaluate the preventive, therapeutic and prognostic potential in human translational studies and existing registries, respectively.Our specific aims are: 1) On the platelet membrane level: To show that ALA positively interferes with the receptor clustering of platelet GPIbalpha within the lipid rafts by cryoelectron microscopy and tomography, by high resolution fluorescence and by functional platelet adhesion studies under high shear conditions. To show that this mechanism of ALA is particularly effective in hypercholesterolemic patients and reduced in families with genetically determined extremely low LDL-cholesterol levels and pts treated with the new PCSK-9 inhibitors.2) On the level of two typical mouse models: To demonstrate by functional testing and brain MRI that the combined antiplatelet, anticoagulant and anti-inflammatory effect of ALA is an ideal therapeutic intervention tool to protect against inflammation, vaso-occlusion as well as silent and manifest ischemic stroke in the model of sickle cell disease and in a typical, well characterized mouse stroke model (in collaboration with PD G Camici).3) In a well characterized human SNF cohort: To show that long term exposure to n-3 FA and/or ALA as measured in whole blood is predictive not only for arterial but also for venous thromboembolism and death in man in 2 well characterized Swiss cohorts (SWITCO 65+ and Track or Treat Study), as proof of principle (endpoint: venous TE and death).Methods planned to achieve these aims:1) Structurally, the GPIb receptor clustering and its inhibition/absence after exposure to ALA will be shown by cryo-ET (collaboration Prof O. Medalia, Zürich) after vitrification, by super-resolution-immune fluorescence (collaboration Prof. U. Ziegler) and by ultracentrifugation and immunoblotting (collaboration Prof K. Clemetson, Bern). Functional changes will be demonstrated by differential platelet adhesion under typical high shear micro-flow conditions and by hepatosplenic platelet clearance in vitro models; clustering will be analyzed in high and genetically extremely low cholesterol levels as well as after treatment with PCSK9 inhibitors.2) A reduction in silent and manifest strokes by ALA will be shown by MRI and functional neurological assessment in the mouse model of sickle cell disease (collaboration with Prof J. Klohs, Prof M. Rudin, ETH Zürich). The effects on microcirculation, platelet and leucocyte adhesion and rolling, liver infarction and platelet clearance will be established in the same model.3) Nutritional long-term effects of n-3 FA in men will be analyzed by whole blood gas chromatography in a well-defined cohort of 1,000 elderly patients with VTE (Switco65+) and in a cohort of 750 patients with non-valvular atrial fibrillation (Track or Treat Study) in order to test for the protective effects of n-3 FA and ALA on recurrent VTE and death. Major bleeding will be analysed as potential adverse effect.Relevance of the results obtained: a) A better understanding of the basic molecular mechanism of the platelet receptor GPIb clustering and its (beneficial) disruption by ALA. b) The animal models will show in vivo the proofs of concept of these mechanisms in sickle cell disease and stroke. c) The beneficial association of higher whole blood content of ALA and n-3 FA with relevant clinical outcome in large human registries will translate our findings into clinical applications in prognosis and interventions and may provide the basis for a randomized controlled trial.General relevance: Our data could provide the basis for nutritional recommendations, and, given the dramatic limitation of fishery resources, for the substitution of the fish intake by plant derived ALA.
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