Presentatie Prof. Dr. van Gelder en Prof. Dr. Schotten
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Transcript of Presentatie Prof. Dr. van Gelder en Prof. Dr. Schotten
Atrial Fibrillation as ElectroVasculopathyInteraction of electrical and vascular factors for the progression of AF
I.C. Van Gelder, MD, PhDProf. of CardiologyDept. of CardiologyUMCG, Groningen
U. Schotten, MD, PhDProf. of Cardiac ElectrophysiologyDept. of PhysiologyUM, Maastricht
Consortium
Principal InvestigatorsVan Gelder Cardiology UMCG
Schotten Physiology UM, MUMC+
Crijns Cardiology AZM, MUMC+
Rabelink Vascular Physiology LUMC
Spronk Biochemistry UM, MUMC+
De Groot Biochemistry UMCU
Further InvestigatorsSchalij Cardiology LUMC
Ten Cate Biochemistry UM, MUMC+
Van der Worp Neurology UMCU
Hillege Epidemiology UMCG
Verheule Physiology UM, MUMC+
Maass Cardiology UMCG
Health Care problem
- AF is not a benign disease, doubles morbidity and mortality in CVD patientsPrevalence large (1-2%), 240000 patients with AF in NL
- Neither prevention nor therapy of AF satisfactory so far.
- AF shows large variability in mechanisms -> need for tailored therapy
- AF is both an electrical and a vascular diseaseMost important manifestation of AF is strokeRisk factors of AF and of stroke in patients with AF are virtually identical70% of all patients with AF have hypertention
- Electrical mechanisms and the role of vascular dysfunction and hypercoagulation have traditionally been explored by different research groups.
- Our innovative consortium of vascular and arrhythmia specialists aims to identify pathomechanisms of AF and vascular function in order to find new patient tailored therapies and reduce AF associated complications and costs
Research Questions
1. What molecular and cellular mechanisms explain the association between AF and vascular dysfunction?
2. How does AF cause vascular dysfunction and hypercoagulable state?
3. How do vascular dysfunction and hypercoagulable state promote progression of AF?
4. Which risk factors are associated with AF progression (incl. electrical, vascular and coagulation parameters) in a meticulously characterized cohort of patients with uncomplicated AF and hypertension?
5. Does protection of vascular function by direct thrombin inhibition prevent AF progression?
WP2: Vascular Dysfunction Causes AF- Hypoxia-induced Signaling Effects on fibroblasts and myocytes- AF substrates in Models of Atrial Ischemia
WP1: AF Causes Vascular Dysfunction- Tachycardia-induced Signaling Effects on fibroblasts and endothelial cells - Vascular Dysfunction in models of AF
WP3: Common Cause for AF and Vascular Dysfunction- Metabolic Stimuli for signaling in myocytes, fibroblasts and endothelial cells- AF substrates in Models of Metabolic Disorders
Atrial Fibrillation Vascular Dysfunction
WP5AF
Registry
Electrical Versus
Vascular Markers forPrediction
of AF Progression
WP6Clinical
Trial
Preventionof AF
Progression By
DirectThrombinInhibitors
WP4: AF Promotion by Thrombin generation- Mechanisms of hypercoagulation in AF (extrinsic, intrinsic, role of endothelial cells)- Pro-artherosclerotic and pro-fibrotic effects of thrombin
WP5AF
Registry
Electrical Versus
Vascular Markers forPrediction
of AF Progression
WP6Clinical
Trial
Preventionof AF
Progression By
DirectThrombinInhibitors
WP 6: RACE 4: Prospective, multicenter randomized study of uncomplicated hypertension and AF patients: Randomized study of upstream therapy to prevent AF progression by reducing the hyperCoagulable state by dabigatran and fibrosis forming by EplerenoneHypothesis: Interventions protecting the vascular integrity of the atrium by direct thrombin inhibition with dabigatran reduces vascular remodeling, atrial fibrosis and dilatation in patients with AF and that this can be further reduced by an ARA.Design: Randomization (2 by 2 fashion) to dabigatran or VKA and to and ARA (eplerenone) and placebo. Primary endpoints are progression of AF and thromboembolic events.
WP 5: Meticulously prospectively characterized patient cohort with AF and uncomplicated hypertension:Aim 1: to assess differences and risk factors for AF progression (permanent AF, increase in atrial volume and vascular complications). Vascular function will be assessed by sidestream dark field imaging, atrial remodeling by body surface potential mapsAim 2: To study the correlation & predictive value of both electrical and vascular imaging techniques and new coagulation tests for progression of AF
TranslationGene Molecule Cell Tissues Organ Animals Patients
WP1
WP2
WP3
WP4
WP5
WP6
Thrombin
ROS,endothelin,PAI-1, …
MicrovascularImaging (SDF)
Fibrosis
CognitiveFunction
Hypercoagulation
Monocyte recruitment in plaquesVSMC proliferation migration
ApoptosisInflammation
MicroembolismStroke
Body SurfacePotential Maps
AF Mapping
Tissue factor?Factor XII?
PAR
Dabigatran
Focus areas Dutch Heart Foundation
Effect of AF on incidence stroke 4x higher in females (Friberg Am J Cardiol 2004)
%
AF is a disease of the elderly(Heeringa Eur Heart J 2006)
yrs
Ageing Gender
Pre
vale
nce
of
AF
Metabolic Disorders
Metabolic syndrome components multivariately associated with new onset AF (Watanabe Circ 2008)
Perspective
NLElectroVascular approach links expertises with strong reputation in NL
EuropaFuture research areas identified by the EC (FP7, FP8):
Active and Healthy Aging• Noninvasive diagnostics• Prevention• Life style / metabolism • Individualized medicine