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