1 I schem ia Causes Upregulation of TF in Cardiom yocytes AF Causes - - PDF document

SLIDE 1

1

The Vicious Circle of Hypercoagulability and AF

Ulrich Schotten

Disclosures:

Consultant & Honoraria: Roche Diagnostics, Bayer AG, Johnson and Johnson, AOP Orphan Pharmaceuticals. Research Grants: Medtronic, Roche, European Union, Center of Translational and Molecular Medicine (Ministry for Economic Affairs of NL), Netherlands Genomics Initiative, Leducq Foundation, Dutch Heart Foundation.

Brambatti M, et al. Circulation 2014 ASSERT Study

stroke

VKA therapy AF monitoring

Tem poral disconnect betw een subclinical AF and em bolic events

Parekh et al. Circ 2006

Virchow’s trias 1. Slow blood flow 2. Increased blood coagulation 3. Vascular wall abnormalities Coagulation Activation (Thrombin)

Hypercoagulability

Atrial Fibrillation Atrial Fibrillation

Stroke Atrial Fibrosis Microvascular Rarefaction Angiopoietin-2 Atherosclerosis Heart Failure Hypertension Heart Failure Hypertension Fibroblast PAR PAR PAR

WP1 Pro‐coagulant Mechanisms

EC SMC Thrombocytes

Atrial Fibrillation causes Hypercoagulability … … and Hypercoagulability causes AF

SLIDE 2

2

AF Causes Atrial Supply-Dem and I schem ia

Van Bragt, Verheule, Cardiovasc Res 2014;101:9–19

Sinus Rhythm

200ms Supply Demand

3-6 fold increase in frequency

AF LA LV

I schem ia Causes Upregulation of TF in Cardiom yocytes

Erlich et al Am J Pathol 2000; 1 5 7 :1 8 4 9 – 1 8 6 2

Control I schemic Zone

Thrombin Cardiac fibroblast Pro-fibrotic and inflammatory cytokines Collagen synthesis Differentiation (Myofibroblasts) Xa

Hyper- coagulability

MCP-1 IL-6 TGF-β

WP2 Pro‐fibrotic Effects

Profibrotic Effects of PAR Activation in Cardiac Fibroblasts

MCP-1 IL 6 TGF-β α-SMA

3H-proline

incorporation

WP2 Pro‐fibrotic Effects

Thrombin induces Expression of IL-6 and MCP-1

Anne Margreet de Jong, Thesis at UMCG 2014

SLIDE 3

3

Thrombin Promotes Inducibility / Stability of AF in Mice

Wt

burst

normal sinus rhythm

P QRS

TMpro/pro atrial fibrillation

QRS P

burst 0.5 s

A

Cell-Cell Distances

C

• n

t r

• l

N a d r

• p

a r i n 2 4 6 8 µm

Activation Timemax

C

• n

t r

• l

N a d r

• p

a r i n 10 20 30 40 ms

TF-ind. Thrombin

B a s e l i n e C

• n

t r

• l

N a d r

• p

a r i n 100 200 300 400 nM/min Thrombin Generation 10 20 30 40 10 20 30 40 Time [min] Thrombin [nM ] Baseline AF

15 AF Goats

Nadroparin (anti-Xa/IIa, n=6) Control (saline, n=9) AF Mapping Histology Immunohistochemistry

*

High Density Mapping Ctr Nadroparin

Nadroparin Inhibits the Development of a Substrate for AF

4 Weeks of AF

Ctr Nadroparin

* * * *

Histology α-SMA Thrombin Generation

Time (min) Thrombin (nM)

nM/min ms µm AU Ctr Nadro- parin Ctr Nadro- parin Ctr Nadro- parin Ctr Nadro- parin Base- line

Gla Domain Deficient Xa still Stimulates 3H-proline Incorporation

Vit K Antagonists Vit K Antagonists Physiological Physiological PAR1-Inhibition

PAR1 Gla Gla IIa Xa Gla Gla II

PAR2

PAR2-Inhibition Anti-coagulation

• +

+ + + + +

Thrombin Inhibitor Thrombin Inhibitor Xa Inhibitor Xa Inhibitor

PAR1 IIa Xa II

PAR2

PAR1 IIa Xa II

PAR2

PAR1 IIa Xa II

PAR2

Direct Thrombin / Xa Inhibitors, but not VitK Antagonists, Inhibit PAR Signaling NOAC: Anticoagulation plus Upstream Therapy?

SLIDE 4

4

Stroke Atrial Fibrillation

Ectopy Reentry Ion channel Remodeling Ca2+‐handling instability Ischemia

Heart Failure Hypertension Diabetes

Conduction Heterogeneities

Aging Obesity Coronary Artery Disease

Vascular remodeling PAI‐1 Fribrinolysis

Hypercoagulability

TF TF TF FXII FIIa IL‐6 VCAM‐1 Thrombocyte Activation Inflammation Fatty Infiltration Atrial Cavity Atrial Myocardium Atrial Stretch Atrial Tachycardia Shear AngII Fibrosis Hypocontractility TF PAR

AF as ElectroVasculoCoagulopathy

FIIa

Coagulation Factors Induce Expression of Profibrotic and Proinflammatory Responses in Fibroblasts. In Transgenic Mice with Enhanced Thrombin Activity Inducibility and Stability of AF is Enhanced. Nadroparin can Inhibit the Development of a Substrate for AF. Hypercoagulability Causes Atrial Fibrosis and Promotes Atrial Fibrillation. NOACs but not Vit K Antagonists Inhibit PAR-mediated Collagen Synthesis.