Atrial fibrillation (AF) is a serious health issue that increases morbidity and mortality, with a prevalence of 1-2% in the Netherlands. The document outlines a study involving a consortium of specialists aiming to explore the interconnected electrical and vascular mechanisms of AF to develop personalized therapies and reduce related complications. Key research questions focus on the molecular links between AF and vascular dysfunction, the impact of thrombosis, and aims to assess new treatments using thrombin inhibitors and evaluate risk factors in well-characterized patient cohorts.

1. Atrial Fibrillation as ElectroVasculopathy Interaction of electrical and vascular factors for the progression of AF I.C. Van Gelder, MD, PhD Prof. of Cardiology Dept. of Cardiology UMCG, Groningen U. Schotten, MD, PhD Prof. of Cardiac Electrophysiology Dept. of Physiology UM, Maastricht

2. Consortium Principal Investigators Van Gelder Cardiology UMCG Schotten Physiology UM, MUMC+ Crijns Cardiology AZM, MUMC+ Rabelink Vascular Physiology LUMC Spronk Biochemistry UM, MUMC+ De Groot Biochemistry UMCU Further Investigators Schalij Cardiology LUMC Ten Cate Biochemistry UM, MUMC+ Van der Worp Neurology UMCU Hillege Epidemiology UMCG Verheule Physiology UM, MUMC+ Maass Cardiology UMCG

3. Health Care problem - AF is not a benign disease, doubles morbidity and mortality in CVD patients Prevalence 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 disease Most important manifestation of AF is stroke Risk factors of AF and of stroke in patients with AF are virtually identical 70% 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

4. 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?

5. 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 WP5 AF Registry Electrical Versus Vascular Markers for Prediction of AF Progression WP6 Clinical Trial Prevention of AF Progression By Direct Thrombin Inhibitors 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

6. WP5 AF Registry Electrical Versus Vascular Markers for Prediction of AF Progression WP6 Clinical Trial Prevention of AF Progression By Direct Thrombin Inhibitors WP 6: RACE 4 : Prospective, multicenter randomized study of uncomplicated hypertension and AF patients: R andomized study of upstream therapy to prevent A F progression by reducing the hyper C oagulable state by dabigatran and fibrosis forming by E plerenone Hypothesis : 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 maps Aim 2: To study the correlation & predictive value of both electrical and vascular imaging techniques and new coagulation tests for progression of AF

7. Translation Gene Molecule Cell Tissues Organ Animals Patients WP1 WP2 WP3 WP4 WP5 WP6 Thrombin ROS, endothelin, PAI-1, … Microvascular Imaging (SDF) Fibrosis Cognitive Function Hypercoagulation Monocyte recruitment in plaques VSMC proliferation migration Apoptosis Inflammation Microembolism Stroke Body Surface Potential Maps AF Mapping Tissue factor? Factor XII? PAR Dabigatran

8. 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 Prevalence of AF Metabolic Disorders Metabolic syndrome components multivariately associated with new onset AF (Watanabe Circ 2008)

9. Perspective NL ElectroVascular approach links expertises with strong reputation in NL Europa Future research areas identified by the EC (FP7, FP8): Active and Healthy Aging Noninvasive diagnostics Prevention Life style / metabolism Individualized medicine